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1
Russo, Alexandra, Francesca Alt, Marie Astrid Neu, Stefan Eder, Arthur Wingerter, Khalifa El Malki, Bernhard Lammle, and Joerg Faber. "Hemophagocytic Lymphohistiocytosis in Early Infancy- Pitfall of Differentiation between Hereditary and Infectious Reasons." Blood 132, Supplement 1 (November 29, 2018): 4961. http://dx.doi.org/10.1182/blood-2018-99-117519.
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Abstract Hemophagocytic Lymphohistiocytosis (HLH) is characterized by pathologic immune activation which occurs either as a familial disorder or as an acquired condition. The diagnosis of HLH requires the presence of five out of nine criteria: fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis in bone marrow, hyperferritinemia, low or absent natural killer cell activity and high level of soluble interleukin-2 receptor. Here we present a 6-month-old girl with parents from Southern Italy. She suffered from hepatosplenomegaly and a recurrent high fever for 3 months' duration. On admission, she showed neurological symptoms including irritability and neck stiffness. Blood analysis revealed bicytopenia, namely anemia and thrombocytopenia. The first bone marrow aspirate was indicative for neither malignancies nor HLH. At this time, additional investigations indicated macrophage activation syndrome with elevated ferritin value (11.741ng/ml), soluble interleukin-2 receptor (CD25) levels (16.018U/ml), hypertriglyceridemia (582mg/dl) supportive of the diagnosis of HLH. Because of the worsening of her clinical condition, a second bone marrow aspirate and biopsy was performed 5 days later when the child became pancytopenic. The second bone marrow aspirate still did not show morphological signs of HLH, but microorganisms were detected in at least one macrophage, which were consecutively diagnosed as Leishmania amastigotes within macrophages by positive Leishmanial polymerase chain reaction from bone marrow specimen. Consistent with the diagnosis of visceral Leishmaniasis Amphotericin B (liposomal) therapy was initiated which resulted in dramatic resolution of fever, splenomegaly, ferritin levels, and recovery of blood counts within 96 hours. Familial hemophagocytic lymphohistiocytosis (FHL) manifests as acute illness with prolonged fever, cytopenias and hepatosplenomegaly. Onset typically occurs within the first months of life. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months. Acquired HLH is typically associated with T-/NK-cell lymphomas and autoimmune diseases but also with infections including EBV, malaria and Leishmaniasis. Even in non-endemic areas, our case of vertically transmitted Leishmaniasis highlights the importance of recognizing infectious etiologies of HLH compared with hereditary forms of HLH in early infancy to initiate appropriate therapy to prevent life-threatening complications. Disclosures Russo: Novo Nordisk: Other: conference fee, travel and accomodation support ; Octapharma: Other: conference fee, travel and accomodation support. Lammle:Baxter: Other: congress travel and accomodation support ; Ablynx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: congress travel and accomodation support ; Siemens: Honoraria, Other: congress travel and accomodation support ; Bayer: Honoraria, Other: congress travel and accomodation support; Alexion: Other: congress travel and accomodation support .
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Barco, Stefano, Stefanie Sollfrank, Alice Trinchero, Luigi Tomao, Barbara Zieger, Johanna A. Kremer Hovinga, Laura Conti, et al. "Detection and Differential Diagnosis of Prekallikrein Deficiency: Genetic Study of New Families and Systematic Review of the Literature." Blood 132, Supplement 1 (November 29, 2018): 2496. http://dx.doi.org/10.1182/blood-2018-99-116030.
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Abstract Introduction. Prekallikrein (PK) and high-molecular-weight kininogen (HK) deficiencies are ultra-rare, autosomal-recessive defects of the contact system caused by biallelic mutations in the KLKB1 and KNG1 genes, respectively. Since affected subjects do not manifest a bleeding phenotype, a correct diagnosis is essential to prevent the administration of prohemostatic agents or plasma and to avoid delay of surgery. We describe a new case of PK deficiency identified at UMC Mainz. In addition, we performed a systematic review of the literature in order to i) collect blood material for genetic studies of reported PK deficient cases lacking this information, and ii) perform a comprehensive individual patient analysis for studying the clinical course and diagnostic criteria (analysis ongoing). Methods. MEDLINE and EMBASE were searched without time and language restrictions. Reference lists of retrieved articles, abstract books of hematology congresses, theses, and grey literature were manually reviewed. All the authors of recent articles on PK deficient cases not assessed for genetic defects, were contacted in order to retrieve blood samples. Clotting activities of PK and HK (PK:C and HK:C) were measured using PK and HK deficient plasmas, respectively. PK and HK antigens (PK:Ag and HK:Ag) were determined by ELISA. Routine aPTT and coagulation factor measurements were performed using an ACL TOP (IL). Genetic testing was performed by Sanger-, Pyrosequencing and/or NGS. Results. Our patient was a 69-year-old woman of African descent referred for preoperative evaluation of an isolated aPTT prolongation. Diagnosis of PK deficiency was based on absent PK:C and PK:Ag (≤1% of normal, each). The homozygous KLKB1 mutation p.Ser151Phefs*34 was found, which was not yet described as a cause of PK deficiency, but had been detected in the African sub-collective (MAF 1.3%) of the 1000 Genomes cohort. A total of 1,913 studies were identified by systematic literature review. Eleven studies with genetic data were found. Blood from 4 unrelated European families without previous genetic testing was analysed, including 3 index cases and 5 relatives. The KLKB1 mutation p.Cys548Tyr was found in 2 families with one index patient being homozygous. This data and the literature suggest that p.Cys548Tyr may be the most frequent KLKB1 mutation in Caucasians, associated with lacking PK:C but low amount of PK:Ag. One patient erroneously diagnosed with PK deficiency based on (incomplete) normalization of aPTT with increased preincubation time and low PK:C (7%) was found to carry compound heterozygous mutations in KNG1 (c.1038+1G>A and c.1165C>T, p.Arg389*) but no mutations in KLKB1. His low PK:C was explained by severe HK deficiency. Conclusions. PK deficiency may not be as rare as previously thought, especially in subjects of African origin. Incomplete normalization of severely prolonged aPTT upon prolonged preincubation and low PK levels are not sufficient for the diagnosis of PK deficiency. Our latter case and data from literature suggest that patients with HK deficiency usually present with moderately low PK levels: therefore, PK:C, PK:Ag, HK:C, and HK:Ag should be determined for proper diagnosis. Disclosures Kremer Hovinga: Shire: Other: Member of Advisory Board, Research Funding; Ablynx: Other: Member of Advisory Board. Lammle:Siemens: Honoraria, Other: congress travel and accomodation support ; Bayer: Honoraria, Other: congress travel and accomodation support; Alexion: Other: congress travel and accomodation support ; Baxter: Other: congress travel and accomodation support ; Ablynx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: congress travel and accomodation support .
3
Gorodianska, L., and L. Tsiukalo. "THE SOURCES FOR FINANCING THE ACCOMODATION SUPPORT IN THE ARMED FORCES OF UKRAINE." Visnyk Taras Shevchenko National University of Kyiv. Military-Special Sciences, no. 3 (47) (2021): 31–37. http://dx.doi.org/10.17721/1728-2217.2021.47.31-37.
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The article presents the qualification of types of accommodation support in the Armed Forces of Ukraine (AFU) in accordance to which the military personnel and their family members are to be supported by newly built accommodation, liberated accommodation, acquired accommodation, service accommodation or a monetary compensation for a premise fit for living. The essence of the financial mechanism of accommodation support in the Armed Forces of Ukraine has been analyzed, which is basically comprised of the funds of the state budget according to the types of generic and special funds. It has been demonstrated that the existing financial mechanism is not perfect, limited in resources accompanied by a large number of bureaucratic obstacles, does not satisfy the modern request for accommodation support within the AFU. According to date provided at the 1-st of January 2021 the overall amount of military personnel accountable for accommodation is at 47,2 thousand, whilst at the same time in the years 2020 and 2021 at the costs of the budget it is only possible to build 4000 apartments a year, which is obviously not sufficient to meet the requirements of the Armed Forces of Ukraine as such. The main reason for the insufficient support of military personnel in terms of accommodation are the limited financial resources that are available to build or to buy (accommodation). Following the detailed analyses of the budget expenditures for the finance support in terms of the program of construction (acquiring) accommodation for military personnel in the years 2011-2020 it has been stipulated, that even the assets of the special fund have not been used completely in the course of the years 2011-2017 and the level of using the budget assets for the accommodation support within the AFU in an overall perspective was within the framework of 27-81 %. It has also been pointed out that the reason for the incomplete using of the budget assets is the systematic delay of approval of the passports of the budget approval of construction (acquiring) accommodation for servicemen. The article suggests the introduction of innovative approaches to support the military personnel with accommodation, namely mortgage lending, financial leasing and investment for housing construction on land plots of the Ministry of Defense of Ukraine. It is also suggested to implement the experience of NATO member state countries that happen to present service premises to military personnel situated on the territory of the unit (garrison) for temporary use, presenting monetary support to hire accommodation, interest-free loans or loans on preferential terms for the purchase or construction of accommodation.
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Komorowska, Olga. "Funkcjonowanie dorosłych osób z niepełnosprawnością w Niemczech." Ekonomia 23, no. 1 (March 15, 2017): 11–21. http://dx.doi.org/10.19195/2084-4093.23.1.2.
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Functioning adults with disabilities in GermanyIn Germany, the issue of prevention of social exclusion of people with disabilities is treated as the primary task of public policy. This article presents German solutions for adults with disabilities thanks to they are integrated into professional and social life. Among these solutions are own budget, job’s assistant, work in the professional workshop, support in accomodation, tax breaks, subsidies for rehabilitation equipment.
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Riyanto, Sugeng. "KERANGKA PENGEMBANGAN SITUS CANDI LOSARI: Kajian Awal untuk Pengembangan Penelitian, Pendidikan, dan Kepariwisataan." Berkala Arkeologi 28, no. 1 (May 28, 2008): 46–56. http://dx.doi.org/10.30883/jba.v28i1.354.
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Archaeological research in Losari Temple site also implicates how the site should be developed. There are three frameworks: research framework, educational framework, and tourism framework. Research framework is related to Losari Temple and how its information or its data may support archaeological research or other disciplines. A framework for education is related to how the information may support educational program. In the framework for tourism there are four most important aspects: how to preserve the site, how to present the information, how to manage the access and accomodation, and how to promote the object.
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Szenes, Eva, Andrea Härzschel, Erika Tissino, Pischeli Justine, Julia Gutjahr, Sandra Pennisi, Jan Höpner, et al. "BCR-Induced VLA-4 Activation in the TCL1 Transgenic Mouse Model for Chronic Lymphocytic Leukemia." Blood 134, Supplement_1 (November 13, 2019): 1730. http://dx.doi.org/10.1182/blood-2019-125634.
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Introduction. Ibrutinib, a small molecule inhibitor of Bruton's tyrosine kinase (BTK), has proven to be an efficient treatment for chronic lymphocytic leukemia (CLL). A distinct characteristic of ibrutinib therapy is transient lymphocytosis. Recently, we have demonstrated that CLL patients with high levels of CD49d show reduced lymphocytosis and inferior nodal response under ibrutinib due to residual activity of BCR-induced inside-out activation of the CD49d/CD29 integrin VLA-4 (Tissino E et al. J Exp Med. 2018;215(2):681-697). Here, we used Tcl1 transgenic (tg) mice as a model to further validate the observation of VLA-4 activation under ibrutinib and to study involved signaling pathways and the effect of VLA-4 inhibition in vivo. Methods. Surface receptor expression analysis of various receptors was performed by flow cytometry. The phosphorylation of signaling molecules was measured by phosflow and western blotting. VLA-4 affinity state was determined by a real-time kinetic assay described in Chigaev A et al. J Biol Chem. 2001;276(52):48670-8. To analyze the distribution of individual VLA-4 molecules on the cell surface, immunofluorescence approaches and superresolution microscopy (STORM, Abbelight) were employed. Mouse treatment studies were performed upon transplantation of TCL1-tg splenocytes to wild-type C57BL/6J mice using the small molecule VLA-4 inhibitor firategrast in drinking water. Tumor infiltration of different organs was measured by flow cytometry. Results. Analyzing the surface expression of CD49d and other homing receptors, we found that TCL1-tg mice correspond with the CD49d-high CLL cohort. We found that both CLL cells from TCL1-tg mice and human CD49d-high CLL show similar CD49d expression levels as the corresponding healthy B cells (human: N = 116 CD49d-high CLL and 32 healthy donor, P = 0.8717; mouse: N = 12 per group, P = 0.6845). Next, we analyzed the impact of BCR pathway inhibitors on the phosphorylation of signaling molecules involved in the BCR pathway after activation by anti-IgM (aIgM) in TCL1-tg leukemic cells. Ibrutinib and idelalisib showed specific patterns of inhibition of BTK and PI3K, respectively. The combination of ibrutinib and idelalisib proved to be the most efficient in reducing the phosphorylation of BTK, SYK, ERK1/2 and Akt upon IgM activation, compared to the phosphorylation of stimulated cells without inhibition (N = 6, P = 0.0003, 0.0305, 0.0039, 0.0019, respectively). IgM stimulation induced VLA-4 high affinity as well as a reorganization of VLA-4 molecules on the cell surface, forming areas of high VLA-4 density. BCR-induced inside-out activation of VLA-4 remained functional upon treatment with ibrutinib (N = 5, cnt vs aIgM P = 0.0017, cnt vs ibrutinib+aIgM P = 0.0499), while idelalisib reduced VLA-4 activation more effectively (N = 5, cnt vs aIgM P = 0.0014, cnt vs idelalisib+aIgM P = 0.0803), suggesting a pivotal role of PI3K in the transmission of the exogenous antigen signal to the integrin. Finally, to analyze the potential of VLA-4 blockage in a tumor setting similar to VLA-4-high CLL patients, we treated wild-type C57BL/6J mice (N = 6 mice per group), which were transplanted with TCL1-tg splenocytes, with the CD49d inhibitor firategrast. This treatment reduced the tumor load in spleen and bone marrow. Conclusion. We found that the TCL1-tg mouse model is adequate to study the activity of the BCR-VLA-4 axis in CLL. Using this model, we show that a) BCR stimulation induces both, an increase in VLA-4 affinity as well as avidity (clustering), b) that PI3K is an essential transmitter between BCR and VLA-4, and c) that VLA-4 inhibition alters tumor infiltration patterns in vivo. Synergies of VLA-4 blockage with established therapy options as a possible way of reducing microenvironment-induced resistance development are currently been investigated. Disclosures Egle: Celgene: Honoraria, Other: Advisory board and Travel support. Greil:Eisai: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Sandoz: Honoraria; Genentech: Honoraria, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Janssen-Cilag: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Boehringer Ingelheim: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding.
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Pleyer, Lisa, Michael Pfeilstocker, Reinhard Stauder, Sonja Heibl, Heinz Sill, Michael Girschikofsky, Margarete Stampfl-Mattersberger, et al. "Expanding on Current Definitions of Hematologic Improvement in MDS, CMML and AML: Landmark Analyses of 1301 Patients Treated with Azacitidine in the Austrian Registry of Hypomethylating Agents By the AGMT-Study Group." Blood 134, Supplement_1 (November 13, 2019): 3821. http://dx.doi.org/10.1182/blood-2019-128153.
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Background In myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML), achievement of morphologic complete response (CR) is a prerequisite for potential cure. In AML, CR is deemed the major outcome associated with improved overall survival (OS); patients (pts) without CR are considered non-responders, and hematologic improvement (HI) without bone marrow blast (BMB) clearance is considered treatment (trt) failure (Cheson 2003). Evidence suggests that these definitions may not be applicable to older pts treated with hypomethylating agents (HMA), and that achievement of CR may not be necessary for prolonged OS (Pleyer 2013, 2014, 2015; Schuh 2015; Bloomfield 2018). IWG response criteria for HI do not differentiate between pts who qualify for response (QFR) vs those that do not. Pts with 'normal' blood counts at trt start are per definition HI non-responders. This may obscure potential survival benefits of responding pts. Aims 1) Assess the impact of HI irrespective of BMB clearance and excluding immortal time bias via landmark analyses. 2) Differentiate between pts who QFR, and those with 'normal' baseline values (not-QFR) defined according to IWG prerequisites for CR. 3) Introduce 3 new categories of HI: peripheral blood blasts (PBB), elevated white blood cells (WBC), and PB-CR (defined as Hb ≥11 g/dl, ANC ≥1.0 G/l, WBC <15 G/l, PB blasts: 0%) in analogy to the concept of complete hematologic response in chronic myelogenous leukemia. Methods 1301 consecutive pts with azacitidine (AZA) trt were analyzed (NCT01595295). Data cut-off 26.07.19. HI was assessed according to IWG criteria (Cheson 2006) and the definitions specified in 3) above. More recent proposals of revision for low-risk MDS pts included in trials (Platzbecker 2018) remain largely idem. Human errors in HI assessment for each AZA cycle and lineage were excluded by automated computational calculation from electronic case report form (eCRF) data. Landmark analyses were performed at 3 months (mo) (HI requires ≥8 weeks response duration) and 6 mo (91, 92 and 88% of MDS, CMML and AML pts respond by cycle 6 [Silverman 2011; Pleyer 2013, 2014]). Statistics were performed by Unidata Geodesign GmbH using DeployR Open 8.0.0. Results In total, 462, 113, and 720 pts had MDS, CMML and AML (n=6 unknown). At AZA start, median age was 73 (range 23-93) years. One, 2 or 3 cytopenias were present in 25, 41 and 29% of pts and 46% were transfusion dependent. 55% received AZA 1st line (26% of whom received prior growth factors or iron chelators). Median AZA dose was 889 mg/cycle and 73 mg/m2/day. Median time to 1st response was 3.0 mo and 95% of pts responded by cycle 6. During AZA trt 1091 BM evaluations (BME) were performed in 599 (46%) pts. At the 3 (6) mo landmark, 44% (47%) of pts with BME achieved CR or CR with incomplete blood count recovery (CRi). Early mortality was 5.6 and 10.3% at 30 and 60 days. Of 932 (598) pts that met the 3 (6) mo landmark, a total of 39% (25%) had no BME. The impact of HI on OS became smaller the later the landmark (Tables 1 and 2). The impact of response on OS was 0.4-4.4 mo longer and significance at the 6 mo landmark was retained using IWG criteria with (Table 1) vs without (Table 2) differentiating between pts who did or did not QFR. Pts who did not QFR had similar or better OS compared with responders. At the 3 mo landmark, proposed additional response parameters HI-PBB, HI-elevated WBC and PB-CR were assoc. with a survival benefit of +7.4, +5.0 and +12.9 mo (Table 1, Fig 1A-C). Conclusions 1) The impact of HI on OS is overestimated without landmark analyses. Median time to 1st response was 3.0 mo and ≥8 weeks response duration required. We therefore suggest using a 3 mo landmark when assessing HI. 2) Using IWG criteria for HI assessment underestimates the impact of response, as non-responders are diluted by pts who do not QFR. Distinguishing QFR/not-QFR seems necessary. 3) Proposed additional HI categories (HI-PBB, HI-elevated WBC, PB-CR) add value to current response criteria. It is often the case that BME are not performed in elderly pts in real-world settings (Dinmohamed 2015; current study). Achievement of HI in any lineage and especially PB-CR might be used as a surrogate for response in pts unable or unwilling to undergo BME for response assessment. This large and growing database is suitable to allow future validation of potential novel response criteria. Disclosures Pleyer: Celgene: Other: Advisory board; Novartis: Other: Advisory board; Inflection Point Biomedical Advisors: Other: Advisory board; Agios: Other: Advisory board; Abbvie: Other: Advisory board. Pfeilstocker:Novartis: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Celgene: Consultancy, Honoraria. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva (Ratiopharm): Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding. Heibl:Daiichi Sankyo: Honoraria; Pfizer: Honoraria; Mundipharma: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sill:Astex: Other: Advisory board; Novartis: Other: Advisory board; AbbVie: Other: Advisory board; Astellas: Other: Advisory board. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria. Petzer:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Personal fees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vallet:MSD: Honoraria; Pfizer: Honoraria; Roche Pharmaceuticals: Consultancy. Geissler:Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; AOP: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Roche: Honoraria; Ratiopharm: Honoraria. Sperr:Novartis: Honoraria; Celgene: Consultancy, Honoraria. Leisch:Novartis: Honoraria, Other: Travel support; Celgene: Other: Travel support; Bristol-Myers-Squibb: Honoraria. Egle:Celgene: Honoraria, Other: Advisory board and Travel support. Melchardt:MSD: Honoraria; Merck: Honoraria, Research Funding; Takeda: Honoraria; Janssen-Cilag: Honoraria; Roche: Honoraria; Novartis: Honoraria; Cephalon: Research Funding. Piringer:Amgen: Research Funding; Roche: Other: Travel support; Merck: Other: Travel support; Bayer: Research Funding. Zebisch:Roche: Honoraria; Novartis: Honoraria, Other: Advisory board; Celgene: Honoraria; AbbVie: Other: Advisory board. Machherndl-Spandl:Celgene: Other: Advisory board. Wolf:Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Keil:Bionorica: Honoraria, Research Funding; Roche: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Novartis: Honoraria; Merck: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Greil:Ratiopharm: Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Sandoz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria. OffLabel Disclosure: Azacitidine is not approved for the treatment of MP-CMML, CMML with <10% BM blasts and IPSS low-risk MDS in the EU
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Simon, Florian, Adam Giza, Sandra Robrecht, Anna-Maria Fink, Paula Cramer, Julia Von Tresckow, Moritz Fürstenau, et al. "Pooled Analysis of First-Line Treatment with Targeted Agents in Patients with Chronic Lymphocytic Leukemia (CLL) Aged 80 Years and Older." Blood 138, Supplement 1 (November 5, 2021): 1552. http://dx.doi.org/10.1182/blood-2021-150698.
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Abstract Background: Patients (pts) aged 80 years or older, albeit making up ≥ 20% of CLL pts, are still underrepresented in clinical trials and treatment outcomes in this cohort remain understudied. We conducted an analysis of pts aged 80 years or older in 6 phase II and III studies of the German CLL Study Group (GCLLSG) in the frontline-setting to elucidate outcomes of targeted treatments with regard to relevant clinical endpoints including overall survival and causes of death. Methods: We pooled data of pts aged 80 years or older at the time of first-line treatment, with at least one administration of a targeted agent as first-line treatment (ibrutinib, idelalisib, or venetoclax) within the following GCLLSG trials: CLL14 (treatment with venetoclax + obinutzumab [GVe]), CLL2-GIVe (venetoclax + obinutuzumab + ibrutinib) and the so-called BXX-studies (CLL2-BIG, CLL2-BAG, CLL2-BIO, CLL2-BCG; treatment with optional bendamustine debulking and either ibrutinib + obinutuzumab, venetoclax + obinutuzumab, ibrutinib + ofatumumab or idelalisib + obinutuzumab). Demographic, laboratory, and genetic data were pooled. Data on treatment exposure and safety (standardized mortality ratios and secondary malignancies) were analyzed accordingly. Kaplan-Meier curves for progression free survival (PFS), overall survival (OS) and time to next treatment (TTNT) were plotted. Results: A total of 716 pts (66 pts each from CLL2-BIG, CLL2-BAG, CLL2-BIO, 45 from CLL2-BCG, 41 from CLL2-GIVe and 432 from CLL14) were analyzed. Of these, 33 (5%) matched the selection criteria for our analysis. The median observation time was 51.8 months. Median age of pts at the time of treatment initiation was 82 years (range 80-89), 18 (55%) pts were male (Table 1). 22 (71%) pts had relevant comorbidities with a cumulative illness rating scale (CIRS) of >6 and 30 (91%) pts having impaired renal function with a GFR <70 mL/min (19 [58%] <50 ml/min). The majority of pts presented with advanced disease with 20 (61%) having a documented Binet stage C and 20 (69%) of 29 pts with an evaluable CLL-IPI risk score being categorized into the high or very high risk group. The type of first-line treatment received was GVe in 27 (82%), bendamustine + ibrutinib + obinutuzumab in 3 (9%), bendamustine + ibrutinib + ofatumumab in 1 (3%) and GIVe in 2 (6%) of pts. 16 pts (48%) discontinued treatment prematurely, in 4 cases because of pts wish, 3 because of progressive disease, 7 pts died (5 due to adverse event, 1 due to cardiac failure and for 1 pt the cause of death is unknown) and 2 discontinued because of reasons classified as "other". The overall response rate was 73%, with 36% CR and 36% PR. Within our sub-cohort, undetectable minimal residual disease (uMRD) rate was 73% in peripheral blood and 39% in bone marrow. Time-to-event analyses showed a median PFS of 49 months (pts <80y: not reached) and a median OS of not reached and 4-year OS of 68% (pts <80y: 4y OS of 92%) (Figure 1). Median TTNT was not reached, with only 2 events in this analysis. There were 11 documented deaths (33%) in our analysis, with adverse events being the most frequent cause of death in 5 cases. Of these, 2 were due to sepsis and 1 each due to heart failure, pulmonary embolism and renal failure. Other reasons not attributed to AEs were progressive disease, infection, respiratory insufficiency and cardiac arrest as well as cardiac failure in 1 case each. For one pt the cause of death is unknown. There were 9 secondary malignancies in 7 pts reported with basal cell carcinoma being the most frequent in 44% of cases. The standardized mortality ratio was 0.78 (95% CI 0.39-1.4) with 11 observed deaths vs. 14 expected deaths compared to the average mortality in this age group. Conclusions: Our analysis demonstrates that this patient population is indeed underrepresented in clinical trials, but anti-leukemic treatment with targeted agents appears feasible and effective in ≥80-year-old pts with CLL, even in presence of coexisting conditions or organ function impairment. Very old pts treated with targeted agents have a comparable survival to an age- and sex-matched population, suggesting that initiating treatment in elderly and potentially frail pts is beneficial. Dedicated studies are warranted for this clinical setting. Hence, our ongoing phase II CLL-Frail trial is evaluating BTK-inhibition for very old (≥80y) or frail pts with CLL (NCT04883749). Figure 1 Figure 1. Disclosures Simon: Gilead: Other: Travel support. Fink: Celgene: Research Funding; AbbVie: Other: travel grant; AstraZeneca: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Cramer: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: Travel support, Research Funding; AbbVie: Honoraria, Other: Travel support; Gilead: Other: Travel support, Research Funding. Von Tresckow: AbbVie: Honoraria, Other: advisory board, travel grant; Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Janssen: Honoraria, Other: Reasearch support, travel grant; Roche: Honoraria, Other: Reasearch support, travel grant. Goede: Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support. Wendtner: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Eichhorst: University Hospital of Cologne: Current Employment; Consultant Department I for Internal Medicine: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Fischer: Roche: Honoraria, Other: Travel Grants; Abbvie: Honoraria. Hallek: Abbvie: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Al-Sawaf: Janssen: Honoraria, Research Funding; Gilead: Honoraria; Beigene: Honoraria, Research Funding; AstraZeneca: Honoraria; Adaptive: Honoraria; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding.
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Bröckelmann, Paul J., Annette Plütschow, Richard Greil, Josée M. Zijlstra, Timothy Illidge, Alexander Fosså, Julia Meissner, et al. "Abscopal Effect of Radiotherapy and Nivolumab in Relapsed or Refractory Hodgkin Lymphoma (AERN): An International Multicenter Single-Arm Two-Stage Phase II GHSG Trial." Blood 134, Supplement_1 (November 13, 2019): 1547. http://dx.doi.org/10.1182/blood-2019-124351.
Full textAbstract:
Background The anti-PD1 antibodies nivolumab and pembrolizumab are approved for relapsed or refractory classical Hodgkin lymphoma (r/r cHL) due to high overall response rates (ORR) with a favorable safety profile. However, complete responses (CR) are rare, and patients eventually develop progressive disease. Treatment options in this situation are very limited and usually regarded palliative. Innovative therapies for patients with progressive r/r cHL or insufficient response to anti-PD1 antibodies are hence an unmet clinical need. Radiotherapy (RT) is highly effective and potentially curative in cHL. Local RT results in immunogeneic cell-death at times leading to immune-mediated systemic effects termed abscopal response (AR). Case reports in different cancers including cHL highlight this effect of local therapies potentially enhanced by systemic immunotherapies. Combining the approved systemic anti-PD1 treatment with local RT to a single cHL lesion might hence work synergistically and result in improved tumor control with limited additional toxicity. It thereby would constitute a viable therapeutic option for patients with r/r cHL and could in the future also be incorporated in earlier lines of therapy. However, prospective data regarding this treatment strategy is lacking and will be generated with the recently activated herein presented GHSG AERN trial. Study Design & Methods AERN is an investigator-sponsored, prospective, international, multicenter, single-arm, two-stage phase II trial (NCT03480334) conducted at 10 European trial sites in Austria, Germany, United Kingdom, Netherlands and Norway. Patients with r/r cHL on active anti-PD1 therapy >18 years of age without serious concomitant diseases or organ dysfunction are eligible for enrollment. Patients either have to present with progressive disease (PD) or stable disease (SD) >6 months as best response to the ongoing anti-PD1 antibody. After registration for the screening phase, eligibility will be verified by a centralized GHSG review facility who will also define a single target lesion for RT to ensure at least one cHL lesion outside the 10% RT isodose for evaluation of the primary endpoint (abscopal response rate after 6x nivolumab, ARR-6). All patients will receive 240mg nivolumab at 2-weekly intervals and 20 Gy RT to the target lesion at 2 Gy fractions on ten consecutive working days starting day 6 of nivolumab treatment. Nivolumab will be discontinued in case of inacceptable toxicity or further disease progression and continued for a maximum of 18 months within the AERN trial. During the first stage of the trial, 9 qualified patients will be treated and their response to treatment will be centrally evaluated after the first 6 nivolumab doses. If no AR is observed in stage I, the trial will be terminated for futility. Otherwise 20 additional patients will be enrolled into the second stage for a total trial population of 29 r/r cHL patients. The null hypothesis H0: ARR-6 < 5% will be tested against a one-sided alternative at a confidence level of α = 5%, and at least 4 AR need to be observed for the rejection of H0. Secondary endpoints include e.g. ORR, overall ARR, CR rate, PFS and OS but also feasibility aspects, (S)AEs and quality of life (QoL) measures. To understand the underlying mechanisms of efficacy but also resistance or toxicity a comprehensive set of correlative studies will be conducted. Baseline and sequential blood samples as well as tumor biopsies and rectal swabs for microbiome analyses will be taken during AERN in patients with separate informed consent. This allows detailed evaluation of serological, cellular, functional, histological and genetic parameters to elucidate synergies between anti-PD1 and RT. Ultimately the correlative studies should help to further refine anti-PD1 based combination therapies, ideally beyond the setting of r/r cHL. In summary AERN, to our knowledge, is the first prospective trial formally evaluating the postulated abscopal effect in r/r cHL. The trial addresses an unmet clinical need in r/r cHL patients with insufficient or lost response to anti-PD1 antibodies. AERN additionally will provide proof-of-concept for a synergy of local RT with checkpoint inhibition substantiated by comprehensive correlative studies in blood, tumor tissue and microbiome. Recruitment has started but preliminary data regarding safety or efficacy are not yet available. Figure Disclosures Bröckelmann: MSD Sharpe & Dohme: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding. Greil:Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Sanofi Aventis: Honoraria; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Sandoz: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; GSK: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria. Zijlstra:Janssen: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Illidge:Div of Cancer Sciences, Faculty of Biology, Medicine and Health, Univ of Manchester, National Institutes of Health and Research Biomedical Research Center, Manchester Academic Health Sciences, Christie Hospital National Health Service Foundation Trust: Employment; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses.
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Riyanti, Anti, and Andhika Chandra Lesmana. "Pengembangan Daya Tarik Wisata di Kaliurang, Yogyakarta." Journal of Indonesian Tourism, Hospitality and Recreation 5, no. 1 (April 1, 2022): 115–26. http://dx.doi.org/10.17509/jithor.v5i1.45008.
Full textAbstract:
A b s t r a c tThis research was conducted to find out more about the potential of tourist attractions and their development in the Kaliurang Yogyakarta tourist area which is located in Sleman Regency, Yogyakarta Special Region with its stunning natural potential. Qualitative methods are used in this study. Data were collected through interviews, questionnaires, and also observation. With the 5A approach in the tourism component (Atraction, Accomodation, Accessibility, Awareness, and Ancillary Services), Kaliurang actually already has these elements, but it is necessary to develop other additional public facilities such as public transportation facilities to locations that are not yet available, providing at least one ATM machines, as well as the nearest health service post around the tourist area, which are currently far enough away to support tourism activities at this location, therefore synergy is needed between the Sleman Tourism Office and the management and local residents.A b s t r a kPenelitian ini dilakukan untuk mengetahui lebih lanjut tentang potensi daya tarik wisata dan pengembangannya di daerah wisata Kaliurang Yogyakarta yang terletak di Kabupaten Sleman, Daerah Istimewa Yogyakarta dengan potensi alamnya yang mempesona. Metode kualitatif digunakan dalam penelitian ini. Data dikumpulkan melalui wawancara, kuisioner, dan juga observasi. Dengan pendekatan 5A dalam komponen pariwisata (Atraction, Accomodation, Accesibility, Awareness, dan Ancillary Services), Kaliurang sebenarnya sudah memiliki unsur-unsur tersebut, namun perlu adanya pengembangan fasilitas umum tambahan lainnya seperti sarana angkutan umum menuju lokasi yang belum tersedia, disediakannya minimal satu mesin ATM, serta pos layanan kesehatan terdekat di sekitar kawasan wisata yang saat inikeberadaannya cukup jauh guna menunjang kegiatan wisata di lokasi ini, oleh karena itu diperlukan sinergitas antara Dinas Pariwisata Sleman dengan pihak pengelola maupun penduduk setempat.
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Fürstenau, Moritz, Anke Schilhabel, Sandra Robrecht, Can Zhang, Julia Von Tresckow, Carsten Utoft Niemann, Arnon P. Kater, et al. "High Resolution Assessment of Minimal Residual Disease (MRD) By Next-Generation Sequencing (NGS) and High-Sensitivity Flow Cytometry (hsFCM) in the Phase 3 GAIA (CLL13) Trial." Blood 138, Supplement 1 (November 5, 2021): 72. http://dx.doi.org/10.1182/blood-2021-147729.
Full textAbstract:
Abstract Background: Venetoclax (ven)-based time-limited combination treatments have yielded high rates of undetectable MRD (uMRD) in patients (pts) with CLL. In correlative analyses, attainment of uMRD status was associated with longer progression-free survival (PFS), making uMRD a robust surrogate parameter for remission duration particularly after time-limited therapy. While MRD is usually assessed by conventional 4-color flow cytometry (FCM) defining uMRD as less than 1 CLL cell in 10 000 leukocytes (<10 -4, uMRD4), a better prognostic discrimination by more sensitive methods appears feasible. In addition to conventional 4-color FCM, we assessed uMRD5 (<10 -5) and uMRD6 (<10 -6) with high-sensitivity FCM (hsFCM) and next-generation sequencing (NGS) of immunoglobulin genes in the GAIA (CLL13) trial. Methods: The phase 3 GAIA (CLL13) trial compared 3 different time-limited ven-based combinations against chemoimmunotherapy (CIT) in fit, treatment-naïve pts with CLL. Pts were randomized to receive CIT for 6 cycles of 28 days each (FCR for pts ≤65 years; BR for pts >65 years), ven and rituximab (RVe), ven and obinutuzumab (GVe), or ven, obinutuzumab and ibrutinib (GIVe), all for 12 cycles with the option for ibrutinib continuation until cycle 36 for pts not obtaining uMRD4. The co-primary endpoints were the rate of uMRD4 at month (MO) 15 (GVe vs CIT) and PFS (GIVe vs CIT). MRD was centrally assessed by FCM at MO2, MO9, MO12 and MO15 in peripheral blood (PB) and at final restaging (RE, two months after the end of treatment) in bone marrow (BM). The following categories were used: high (≥10 -2), intermediate (≥10 -4 to <10 -2), uMRD4 (<10 -4). Exploratory post hoc MRD analyses were performed by hsFCM and/or an amplicon-based one-step NGS protocol by the EuroClonalityNGS group. HsFCM data was generated by reevaluation of FCM data files and reducing the cut off for CLL events to at least 10 events in 2 of 3 MRD tubes. MRD data were evaluated with regard to categories of uMRD5 and uMRD6. Results: In total, 926 pts were randomized (CIT: 229, RVe: 237, GVe: 229, GIVe: 231). Based on the intention-to-treat (ITT) population, rates of uMRD4 in PB by FCM were 62.0% (CIT), 73.0% (RVe), 88.6% (GVe) and 88.3% (GIVe) at MO9 and 52.0% (CIT), 57.0 (RVe), 86.5% (GVe) and 92.2% (GIVe) at MO15. BM uMRD4 results at RE were 37.1% (CIT), 43.0 (RVe), 72.5% (GVe) and 77.9% (GIVe). HsFCM samples were available for 844 (MO9 PB), 863 (MO15 PB) and 744 (RE BM) pts with median limits of detection (LOD) of 1.6x10 -5 (MO9 PB), 1.4x10 -5 (MO15 PB) and 9.9x10 -6 (RE BM) that were similar between the treatment arms. With hsFCM a lower limit of detection (LOD) of ≤10 -5 was achieved in 364 (MO9) and 477 (MO15) PB samples and in 580 BM samples at RE. 480 (MO9 PB), 386 (MO15 PB) and 164 (RE BM) samples did not reach a LOD of ≤10 -5 and were thus not included in the MRD5-evaluable populations (Figure 1). Among pts with samples evaluable for MRD5 in PB at MO15, 26 of 82 (31.7%, CIT), 45 of 132 (34.1%, RVe), 81 of 131 (61.8%, GVe) and 93 of 132 (70.5%, GIVe) achieved uMRD5. BM uMRD5 rates at RE were 24.2% (23 of 95 pts), 16.1% (27 of 168 pts), 41.7% (65 of 156 pts) and 53.4% (86 of 161 pts), respectively (Figure 2A). The median MRD level at MO9 was lower in CIT, GVe, GIVe (all 1x 10 -5) compared with RVe (2x 10 -5) by hsFCM (Figure 2B). While the obinutuzumab-containing arms stayed at this low level between MO9 and MO15, median MRD levels in CIT and RVe increased to 8.9x 10 -5 (CIT) and 3.1x 10 -5 (RVe) in the same period. The different treatment arms showed distinct patterns of differential clearance of CLL in BM and PB. While the fraction of concordant MRD results between PB and BM at RE was lower in the CIT arm with 14/34 (41.2%), the ven-containing arms showed a similar compartment effect with a proportion of concordant results of 67/108 (62.0%, RVe), 70/101 (69.3%, GVe) and 71/104 (68.3%, GIVe). In 9/16 (56.3%, CIT), 23/36 (63.9%, RVe), 22/63 (34.9%, GVe) and 23/73 (31.5%,GIVe) pts who achieved uMRD5 in PB (RE) MRD was still measurable in BM. More sensitive NGS analyses and detailed correlative analyses are pending and will be presented at the conference. Conclusions: HsFCM improves MRD detection in CLL below 10 -4 in PB and BM by capturing low levels of MRD (≥10 -5 to <10 -4) in samples that were assessed as uMRD4 by FCM. HsFCM was able to show differences in uMRD rates between the treatment arms more clearly than FCM. Obinutuzumab-containing arms and in particular the GIVe arm showed the highest uMRD5 rates in PB and BM. Figure 1 Figure 1. Disclosures Von Tresckow: Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant; AbbVie: Honoraria, Other: advisory board, travel grant. Niemann: CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Wendtner: Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Hallek: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. Ritgen: MSD: Consultancy, Other: Travel support; Chugai: Consultancy; Abbvie: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Eichhorst: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. OffLabel Disclosure: The combination of obinutuzumab, venetoclax and ibrutinib is not approved for treatment of CLL
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Abdullah, Taufik, and Kiki Pebriyanti. "PENGARUH PROGRAM GREEN HOTEL TERHADAP KEPUTUSAN MENGINAP TAMU DI THE ROYALE KRAKATAU HOTEL CILEGON BANTEN." Journal : Tourism and Hospitality Essentials Journal 6, no. 1 (April 7, 2016): 1023. http://dx.doi.org/10.17509/thej.v6i1.2013.
Full textAbstract:
Tourism is an industry that is considered promising is helping the economy and prosperity of a country. There are many things that support tourism, a sector that is important in the means of accomodation. There are several accomodation facilities such as travel agent, hotels and restaurants. Hotel is one property which is important for travelers to stay. Nowdays, competition among hotel industries is very high. There are a lot of hotel that have proven strategies in marketing their hotels. The Royale Krakatau is one of hotels which located in Cilegon, Banten area. The royale krakatau hotel is a hotel that has been existing for a long time, was originally only in the form of a guest house, and now it has become a 4 star hotel. Although the royale krakatau hotel has been existing for a long time, the available facilities are not less complete than other hotels. The royale krakatau hotel does various methods to compete than other hotels in order to enhance guest staying decision. One of them is by using green hotel program. Green hotel is a strategy in which the implementation of thie program considers several things such as clean, green, and well-organized environment concept. Green hotel is x variable in this study which consist of recyled materials, recyclable, Low-polluting and energy saving. The depend variable in this study is a decision to stay which consist of product selection, brand selection, visit time, total purchases and payment method. This reserch is descriptive verification, and sampling method is obtained from 100 respondent of FIT guest who stay at The Royale Krakatau Hotel Cilegon. The used technique of data analysis and hypothesis testing is multiple regression analysis. The result showed that the positive influances between hotel program an decison to stay at The Royale Krakatau Hotel Cilegon.
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Fürstenau, Moritz, Sandra Robrecht, Can Zhang, Julia Von Tresckow, Carsten Utoft Niemann, Arnon P. Kater, Michael Gregor, et al. "Comparison of Tumor Lysis Syndrome (TLS) Risk Reduction and Incidence in Different Venetoclax-Based Combinations within the Randomized Phase 3 GAIA (CLL13) Trial." Blood 138, Supplement 1 (November 5, 2021): 2639. http://dx.doi.org/10.1182/blood-2021-147790.
Full textAbstract:
Abstract Background: In early studies of venetoclax (ven) in CLL, severe tumor lysis syndromes (TLS) were observed leading to the implementation of multiple safety measures including a 5-week ramp up schedule. Since then, studies have consistently reported low rates of TLS in ven-treated patients (pts), most likely as a result of strict prophylactic and laboratory monitoring measures. Various lead-in regimens prior to the administration of ven were shown to be feasible and effective in reducing the risk of TLS in pts with CLL. However, no comparison of different pretreatment regimens has been performed so far in a prospective randomized trial. Using the set-up of the GAIA trial, we compared TLS incidence and formal TLS risk reduction between 3 different ven-based combinations. Methods: The phase 3 GAIA (CLL13) trial compared 3 different time-limited ven-based combinations against standard chemoimmunotherapy (CIT) in fit, treatment-naïve pts with CLL. Pts were randomized to receive CIT (FCR in pts ≤65 years; BR in pts >65 years), ven and rituximab (RVe), ven and obinutuzumab (GVe), or ven, obinutuzumab and ibrutinib (GIVe). In RVe, GVe and GIVe, ven was added at cycle 1 day 22 (ramp up day 1) after a 21-day pretreatment with rituximab (1 dose), obinutuzumab (3 doses) or obinutuzumab (3 doses) plus ibrutinib (continuous) (Figure 1A). The safety population (i.e. all pts who received study treatment) of the ven-containing arms was used for this analysis. TLS was reported according to Cairo-Bishop criteria (Cairo M, Bishop M. Br J Haematol. 2004). For TLS risk evaluation, the most recent available CT/MRI and absolute lymphocyte count (ALC) were used. TLS risk was evaluated at baseline and at ramp up day 1, before the first dose of ven. The patients were categorized retrospectively according to the following TLS risk categories: high (any lymph node [LN] with largest diameter ≥10 cm or any LN with largest diameter ≥5 cm and ALC ≥25 G/L), intermediate (any LN ≥5 cm to <10 cm or ALC ≥25 G/L), low (all LN <5 cm and ALC <25 G/L). Results: The safety population of all ven-containing arms comprised of 696 pts (RVe: 237, GVe: 228, GIVe: 231). Baseline TLS risk was high in 22%, 23% and 19% of pts in the RVe, GVe and GIVe arm, intermediate in 62%, 65%, 67% and low in 10.5%, 14.7% and 12.4% of pts, respectively. After the first 21 days of treatment (i.e. at ramp up day 1), the fraction of pts with a reduction in TLS risk varied between the treatment arms with 31.7% (RVe), 71.4% (GVe) and 47.3% (GIVe) of pts decreasing by at least one TLS risk category (Figure 1B). With regard to TLS risk reduction, GVe was superior to RVe (p<0.001) and GIVe (p<0.001) while GIVe was superior to RVe (p=0.001)). At ramp up day 1, 2 patients (1.0%) in the GVe arm versus 60 patients (29.6%) in the GIVe arm had an ALC ≥25 G/L, likely as a correlate of ibrutinib-associated redistribution of lymphocytes to the peripheral blood, readily explaining part of the difference in TLS risk reduction between GVe and GIVe. In total, 36, 30 and 19 cases of TLS occurred in 29 (12.2%), 26 (11.4%) and 19 (8.2%) pts in the RVe, GVe and GIVe arm. The majority of TLS cases were categorized as CTC grade 3 (28 [RVe], 19 [GVe], 12 [GIVe]), only few CTC grade 4 TLS were reported (1 [RVe], 2 [GVe], 3 [GIVe]). There were no cases of fatal TLS and no pts requiring dialysis due to TLS. In the obinutuzumab arms the majority of TLS cases occurred before ramp up day 1 (GVe: 76.7%, GIVe: 68.4%), i.e. before any venetoclax intake, in contrast 80.6% of TLS cases in the RVe arm were reported during ven ramp up (Figure 2). While there was no significant difference in the cumulative TLS incidence between the treatment arms (p=0.334), there was an increase in TLS occurring after ramp up day 1 in the RVe arm compared to GVe (p<0.001) and GIVe (p=0.002). Conclusions: This analysis represents the first comparison of the formal TLS risk reduction and actual TLS incidence of different ven-based combinations in a randomized trial. GVe led to the highest TLS risk reduction, while the lowest number of TLS cases occurred in the GIVe arm. Most TLS cases in the GVe and GIVe arms occurred before the start of ven. RVe was least effective in reducing TLS risk and in contrast to the obinutuzumab-containing arms, the vast majority of TLS cases was reported during the ven ramp up. The relatively high incidence of TLS in comparison to other trials might partly be a consequence of using different reporting criteria (Cairo-Bishop vs Howard criteria). No fatal TLS occurred in any of the treatment arms. Figure 1 Figure 1. Disclosures Von Tresckow: AbbVie: Honoraria, Other: advisory board, travel grant; Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant. Niemann: Novo Nordisk Foundation: Research Funding; CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding. Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: AbbVie: Honoraria; Celgene: Honoraria; Roche: Honoraria; Jansen: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Wendtner: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Ritgen: MSD: Consultancy, Other: Travel support; Chugai: Consultancy; Abbvie: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy. Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Eichhorst: Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. OffLabel Disclosure: The combination of obinutuzumab, venetoclax and ibrutinib is not approved for the treatment of CLL
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Rummel, Mathias J., Christian Lerchenmüller, Manfred Hensel, Martin Goerner, Christian Buske, Holger Schulz, Burkhard Schmidt, et al. "Two Years Rituximab Maintenance Vs. Observation after First Line Treatment with Bendamustine Plus Rituximab (B-R) in Patients with Waldenström's Macroglobulinemia (MW): Results of a Prospective, Randomized, Multicenter Phase 3 Study (the StiL NHL7-2008 MAINTAIN trial)." Blood 134, Supplement_1 (November 13, 2019): 343. http://dx.doi.org/10.1182/blood-2019-121909.
Full textAbstract:
Background: The StiL NHL1-2003 trial demonstrated that Bendamustine-Rituximab (B-R) is a highly effective treatment for patients with WM achieving a median PFS of 69.5 months. Rituximab (R) maintenance is part of a standard treatment for follicular lymphoma. In WM, however, the role of R maintenance is unclear. In this study we compared the effect of 2 years R maintenance vs. observation after first-line treatment with B-R in patients with previously untreated WM. Methods: Patients needed to have advanced stage of disease with indication for treatment (e.g. B-symptoms, anemia, hyperviscosity syndrome, etc.). Primary endpoint was progression free survival (PFS). Secondary endpoints included response rates, overall survival (OS), and toxicity. All patients were treated with up to 6 cycles of B-R plus 2 additional R cycles. Only patients responding to B-R were randomized to either R maintenance (q 2 months for 2 years) or observation. Results: Of 293 registered patients, 5 were excluded due to lack of data and other reasons. Median time of follow-up was 70.2 months at the time of this analysis (July 2019). 257 of 288 patients with a median age of 67 years were evaluable for response evaluation. The median baseline value of IgM was 31.3 g/l, and of Hb 10.1 g/dl. Median PFS for all patients (intention to treat) was 78.0 months. The median OS was not yet reached, with an estimated 5-year-survival of 78%. A total of 38 secondary malignancies were recorded, with 1 AML during observation and 1 MDS in R maintenance. 235 patients (91.4%) responded to B-R induction, with the majority of patients (231, 89.9%) achieving a partial remission. Of 218 randomized patients, 109 (50%) were randomized to R maintenance and 109 (50%) to observation. Median age of randomized patients was 67 years, patient characteristics were comparable for both groups. The 2-year R maintenance provided a better disease control with a median PFS of 101 months in the R maintenance group compared to the median PFS of 83 months in the observation group, however, this difference was not statistically significant with a hazard ratio of 0.80 (95% CI 0.51 - 1.25, p = 0.32). The median PFS of the group of all patients receiving treatment with B-R induction only was 65.3 months and is consistent with the results of the previous StiL NHL1-2003 trial (69.5 months). This group of 179 patients includes both non-randomized patients (B-R non-responder, not randomized for any reason) and patients randomized to observation. There was no difference in OS with the median not yet reached for both R maintenance and observation. Conclusions: We confirmed that induction with B-R is a highly effective treatment for WM. After a median observation time of 5.9 years the results could not demonstrate an improvement in PFS or OS after a 2-year R-maintenance when compared with observation after B-R induction in patients with WM. Disclosures Rummel: Sandoz: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche Pharma AG: Honoraria, Research Funding. Hensel:Roche: Honoraria, Other: travel expenses. Buske:Hexal: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Celltrion: Honoraria, Speakers Bureau; Amgen: Research Funding. Schmidt:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Hexal: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees. Willenbacher:IQVIA: Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; European Commission: Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fujimoto: Consultancy, Honoraria; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria. Dürig:Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Barth:Takeda: Honoraria; Lilly Pharma: Honoraria; Roche: Honoraria; Medac: Honoraria; Hexal: Honoraria. Hinke:Roche: Honoraria. Greil:Genentech: Honoraria, Research Funding; Eisai: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Boehringer Ingelheim: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Sandoz: Honoraria; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Sanofi Aventis: Honoraria; GSK: Research Funding; Daiichi Sankyo: Consultancy, Honoraria.
15
Ludwig, Heinz, Siegfried Sormann, Niklas Zojer, Johannes Andel, Bernd L. Hartmann, Christoph Tinchon, Eberhard Gunsilius, et al. "Carfilzomib-Revlimid-Dexamethasone Vs. Carfilzomib-Thalidomide-Dexamethasone Weekly (After 2 Twice Weekly Cycles) Followed By Carfilzomib Maintenance Vs. Control in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) - Interim Efficacy Analysis of Combined Data (AGMT MM-02)." Blood 134, Supplement_1 (November 13, 2019): 696. http://dx.doi.org/10.1182/blood-2019-127954.
Full textAbstract:
Introduction: Recent data from the ARROW and CHAMPION-1 study show significant activity of once weekly carfilzomib administration. Furthermore, the recent MUK5 and CARF studies show significantly increased PFS with carfilzomib maintenance therapy. Here, we compare 9 cycles of weekly KRd with weekly KTd (after 2 cycles of biweekly therapy) followed by a second randomization to 12 cycles of carfilzomib maintenance or observation only in elderly NDMM. Methods: 75 of 146 planned pts (median age: 75 years, range 55-84) with NDMM have been enrolled so far in this randomized phase 2 study. Treatment regimen: Carfilzomib 20mg/m2 on day 1+2, 27mg/m2 on day 8, 9, 15 and 16; cycle 2: 27mg/m2 on day 1,2,8,9,15 and 16; Carfilzomib was switched to once weekly dosing (56mg/m2, d1, 8, 15) from cycle 3 on until cycle 9. Patients received dexamethasone weekly (20mg in pts ≥75 years) and either lenalidomide 25mg d 1-21, or thalidomide 100mg/day, day 1-28 (50mg in pts ≥75 years). Patients with ≥SD after 9 cycles were randomized to carfilzomib 56mg/m2 (or last tolerated dose) on day 1 and 15 q 4 weeks, or to control for one year. FISH testing was done according recommended standards. NGF MRD testing was done in pts reaching CR or VGPR. Survival estimates were calculated according to Kaplan-Meier. Differences in response rate were assessed using Fisher's exact test, while the Log-Rank test was used for evaluating differences in survival. This trial is registered on clinicaltrials.gov (NCT02891811). Results: Median follow up was 11.7 months. 58 of the 75 pts completed ≥2 cycles (per protocol population (PP)), 12 pts discontinued therapy within the first 2 cycles due to AE/unacceptable toxicity [4 (5.3%)], death [3 (4%)], investigator decision [2 (2.7%)], patient's decision [2 (2.7%)], or other reason [1 (1.3%)]. As the trial is still ongoing, response rates and survival data are given for both groups (KRd and KTd) combined. Overall response was noted in 56 of the 58 pts (96.6%) with response data available, CR in 21 (36.2%), VGPR in 22 (37.9%), PR in 13 (22.4%), and MR in 2 (3.4%) pts. Of the 17 pts with MRD testing available, 47.1% achieved MRD negativity. PFS was 22.3 months in both the PP and ITT pts. Overall survival at 24 months was 78% in the ITT and 79% in the PP group, respectively. Between very elderly pts 75 years of age or older and pts below 75 years, no difference in ORR (96.8% vs. 96.3%, p=1), ≥VGPR (67.7% vs. 81.5%, p=0.3678) and PFS was found (ITT group: 22.3 months vs. not reached, p=0.926; PP group: 22.3 months vs. not reached, p=0.895). Likewise, OS did not differ in both age groups (data not shown). Outcome was also similar between pts with and without high-risk cytogenetics: ORR 100% vs.97.1%, p=1; ≥VGPR 80% vs. 71.4%, p=1; PFS not reached vs. 22.3 months, p=0.342; OS at 24 months was 85% for high-risk and 67% for standard-risk pts. In a safety evaluation with 66 patients, the most frequent grade 3/4 hematologic adverse events were anemia (4.5%), leukopenia (1.5%), and thrombocytopenia (6.0%). The non-hematologic grade 3/4 AEs were infections (21.2%), cardiac failure, gastrointestinal disorders, and renal impairment (6.0% each), neurologic disorders, hypertension, and rash (3.0% each), and hepatic failure, SPM, VTE, and psychiatric disorders (1.5% each). Conclusion: Once weekly carfilzomib 56mg/m² in combination with either lenalidomide or thalidomide resulted in high response rate and deep responses including MRDneg status in 47.1% of tested elderly patients with NDMM. Results were similar in very elderly pts (³75 years) and in those aged <75 years. Treatment was associated with an acceptable tolerance profile. Adverse events (mostly infections, and less frequently GI-toxicities, cardiac failure, and renal impairment) resulting in treatment discontinuations occurred mostly during cycle 1 or 2, when the twice weekly regimen was administered as run in phase. Disclosures Ludwig: Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; PharmaMar: Consultancy; Celgene: Speakers Bureau. Zojer:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hartmann:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: sponsoring of educational seminars; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of educational seminars. Gunsilius:Amgen: Honoraria. Podar:Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding; Takeda: Consultancy; Celgene: Consultancy, Honoraria; Amgen Inc.: Honoraria. Egle:Celgene: Honoraria, Other: Advisory board and Travel support. Willenbacher:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commission: Research Funding; Abbvie: Consultancy, Honoraria; Tirol Program: Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Fujimoto: Consultancy, Honoraria; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Petzer:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Personal fees; Takeda: Membership on an entity's Board of Directors or advisory committees. Machherndl-Spandl:Celgene: Other: Advisory board. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Greil:Eisai: Honoraria; Boehringer Ingelheim: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sandoz: Honoraria; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Honoraria. OffLabel Disclosure: Carfilomib 56mg/m2 in weekly dosing in combination with either Lenalidomide and low dose dexamethasone (KRd), or with thalidomide and low dose dexamethasone (KTd) was evaluated for first line treatment in TNE NDMM patients. After 9 cycles pts were randomized to K biweekly maintenance therapy for 12 months or to observation.
16
Eichhorst, Barbara, Carsten Niemann, Arnon P. Kater, Moritz Fürstenau, Julia Von Tresckow, Can Zhang, Sandra Robrecht, et al. "A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments (RVe, GVe, GIVe) Vs Standard Chemoimmunotherapy (CIT: FCR/BR) in Frontline Chronic Lymphocytic Leukemia (CLL) of Fit Patients: First Co-Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) Trial." Blood 138, Supplement 1 (November 5, 2021): 71. http://dx.doi.org/10.1182/blood-2021-146161.
Full textAbstract:
Abstract Background: For fit CLL patients (pts), continuous BTK inhibitor treatment is replacing CIT as standard of care in frontline setting, particularly in pts with unfavorable prognostic factors. The time limited combinations venetoclax plus obinutuzumab (GVe) and venetoclax plus rituximab (RVe) have produced high rates of undetectable minimal residual disease (uMRD), which strongly associates with long progression-free survival (PFS) both in frontline and relapsed setting. For frontline therapy GVe is approved in this setting based on data from the CLL14 trial in an unfit population. However, data from a fit cohort are not yet available. The GAIA (CLL13) trial evaluated the efficacy and safety of three Ven+CD20 antibody-based regimens in comparison to CIT as a frontline treatment for fit pts with CLL and without TP53 mutation/deletion. Methods: Treatment-naïve fit (CIRS ≤6, normal creatinine clearance with ≥ 70ml/min) CLL pts requiring therapy were eligible. Based on known poor response to CIT, pts with TP53 aberrations were excluded. Pts were randomized in a 1:1:1:1 ratio to receive six courses of CIT (FCR for pt ≤65 years: fludarabine 25 mg/m² d1-3, cyclophosphamide 250 mg/m² d1-3, rituximab 375 mg/m² d1 cycle 1 and 500 mg/m² d1 cycle 2-6; BR for pt >65 years: bendamustine 90mg/m² d1-2, rituximab) or one of three venetoclax (V) combinations (standard ramp-up from cycle 1 d22, 400 mg/d cycle 2-12): V and rituximab (375/500mg/m² d1 cycle 1-6) [RVe], V and obinutuzumab (1000 mg d1, 8, 15 cycle 1 and d1 cycle 2-6) [GVe], or V, obinutuzumab and ibrutinib (420 mg/d cycle 1-12, if MRD-detectable continued until cycle 36) [GIVe] . Pts were stratified according to country, Binet stage and age (≤ 65/> 65 years). The co-primary endpoints of the trial are (1) the rate of uMRD (<10-4) by flow in peripheral blood (PB) at month 15 (MO15, GVe vs CIT) and (2) PFS (GIVe vs CIT), each with a significance level of 2.5%. The co-primary endpoint PFS will be analyzed within a pre-planned interim analysis as soon as 138 (65%) PFS events will have been reported in the GIVe and CIT arm. The co-primary endpoint analysis of uMRD per protocol was performed after the last MO15 MRD sample had been collected. In addition, comparisons regarding uMRD for all study arms were performed using a pre-specified hierarchical test sequence. Bone marrow (BM) was evaluated 3 months after end of treatment (MO9 for CIT, MO15 for all others arms) in pts with clinical CR. Key secondary endpoints as investigator-assessed responses according to iwCLL 2008 guidelines and safety were analyzed. Trial is registered at ClinicalTrials.gov (NCT02950051). Results: A total of 926 pts (CIT: 229 (150 FCR, 79 BR), RVe: 237, GVe: 229, GIVe: 231) with a median age of 61 years (range 27-84) were accrued between 12/2016 and 09/2019. The majority of pts were in advanced Binet stage (B: 37.8%, C: 35.6%) and unmutated IGHV status was present in 56%. Fourteen pts did not receive study treatment (13 FCR, 1 GVe) and were not included in the safety population. The data cut for the first co-primary endpoint analysis was February 28, 2021. The median observation time was 27.9 months. The co-primary endpoint uMRD in PB at MO15 was met as the rate of uMRD in ITT population was significantly higher in GVe compared to CIT: 86.5% (97.5% CI 80.6-91.1) vs 52.0% (CI 44.4-59.5; p<0.0001), respectively. GIVe also showed a superior uMRD rate of 92.2% (CI 87.3-95.7) compared to CIT (p<0.0001), while RVe (57.0%, CI 49.5-64.2) did not (p=0.317) (Figure 1A). Corresponding BM uMRD rates in ITT population were 37.1% (CIT), 43.0% (RVe), 72.5% (GVe) and 77.9% (GIVe), respectively. MO15 overall response rates and complete response rates (CRR) are shown in Figure 1B. The most common grade 3-5 treatment-emergent AE were neutropenia (50.5% of all pts), thrombocytopenia (12.2%), tumor lysis syndrome (7.5%), infusion-related reaction (7.2%), febrile neutropenia (6.5%) and pneumonia (5.3%)). Atrial fibrillation and bleeding events occurred more frequently in GIVe while infusion-related reactions were most common in the GVe arm (Table 1). The absolute numbers of second malignancies were 33, 19, 22 and 21 for CIT, RVe, GVe and GIVe. Fatal AEs occurred in 5, 7, 6 and 9 of the patients. Conclusions: The time-limited therapies of GVe and GIVe provided superior uMRD rates in PB at MO 15 compared to CIT. In addition, uMRD rates in BM and CRR were higher in GVe and GIVe in particular than in CIT. All arms showed a good safety profile in this fit pt population. Figure 1 Figure 1. Disclosures Eichhorst: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Von Tresckow: Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant; AbbVie: Honoraria, Other: advisory board, travel grant. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Sanofi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: Roche: Speakers Bureau; Abbvie,: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Jaeger: Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Hebart: Roche: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Kreuzer: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ritgen: Abbvie: Consultancy, Other: Travel support, Research Funding; Chugai: Consultancy; MSD: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Hallek: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: Ibrutinib in combaintion with Venetoclax + Obinutuzumab is not approved.
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Widiantara, Ida Bagus Gde, and I. Wayan Suastawa. "Warm Water Pool System Simulation: Design and Manufacture." Logic : Jurnal Rancang Bangun dan Teknologi 20, no. 3 (November 30, 2020): 205–9. http://dx.doi.org/10.31940/logic.v20i3.2136.
Full textAbstract:
Human development and national competitivenes is one of the flagship programs from The Indonesian Government. Bali as one of the best tourist destination in the world is required to have an international standard tourism infrastructure. A swimming pool in a tourism accomodation is a standard facility in a tourist infrastructure. There are several types of swimming pools i.e. public swimming pools and private pools. During its development and demand, private pools develop into swimming pools with additional facilities such as warm water, which is often called a jacuzzi. Another additional facility is added pressure to the water in completing massage, fragrance and foam. The swimming pool is one of facilitity designed to hold water to allow swimming or other recreational activities. Pools can be built in the ground or on the ground as a free construction or as a part of structure and also with a common feature or a free style design. In-ground pools are the most common pools made and constructed from materials such as concrete, natural stone, metal, plastic, or fiberglass. To support comfort and satisfaction when using the swimming pool, the adequate water level in the swimming pool will be maintained by system with several supporting devices such as pumps, dirt filters and maintained at a certain level. Other things that support water quality include temperature, water turbidity, color, odor, pH, chlorine content etc.
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Bartle, John, Agustí Bosch, and Lluís Orriols. "The policy mood in Spain: the thermostat in a warm climate, 1978–2017." European Political Science Review 12, no. 2 (February 14, 2020): 133–53. http://dx.doi.org/10.1017/s175577392000003x.
Full textAbstract:
AbstractRepresentative democracies are supposed to be uniquely virtuous in that they ensure that public preferences drive public policy. Dynamic representation is the outcome of a recurring interaction between electorate and parties that can be observed at the macro level. Preferences can shape government policy via two possible mechanisms. ‘Policy accomodation’ suggests that governments respond directly to the electorate’s preferences. ‘Electoral turnover’, on the other hand, assumes that preferences shape policy indirectly. Parties pursue their ideological goals, and public preferences respond ‘thermostatically’ by moving in the opposite direction to policy. This causes voters to switch votes and eventually leads to a turnover of power from one ‘side’ to ‘the other’. In this paper, we estimate preferences for government activity (‘the policy mood’) in Spain between 1978 and 2017. We show that mood responds ‘thermostatically’ to policy. Variations in mood are associated with support for parties. Policy is driven by party control but is not thermostatically responsive to mood. It appears that in Spain – like Britain – dynamic representation can only be achieved by electoral turnover. We consider the implications of this for our understanding of how representation works.
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El Hafizah, Nafilah, Ervina Ahyudanari, and Valeriana Lukitosari. "Tourist Response as Water-based Seaplane Purposes for Island Tourism: A Literature Review." E3S Web of Conferences 434 (2023): 02021. http://dx.doi.org/10.1051/e3sconf/202343402021.
Full textAbstract:
In a journal review, the conclusion of the statistical and mathematic model was presented to illustrate the impact of various factors on tourist preferences, facilities and infrastructure available as tourism support facilities. On of the most important sectors that drives the national economic is tourism sectors. This literature review covers a lot of research conducted on sustainable tourism, especially regarding transport facilities and other aspects. Other aspects of tourism, namely facilities, accomodation, sosial-culture, environment, and economy, are also considered. The main determinants of tourism are assessed using a scientific approach to evaluate the attractiveness of tourist sites by considering many aspects. Several results have indicated that natural resources, island culture, and access infrastructure are important determinants of tourism demand in various countries. This discussion may be useful for the authorities involved in tourism development and sustainability in the future. The study primarily focused on accessibility, tourism attraction, environment, etc. With these results, important tourist sites can be prioritized for enhanced accessibility and promoted as major tourist destination in the country. Research mapping to establish the basic model can be based on simulation approach and statistical analysis, such as a system dynamic model and other relevant analysis.
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Bernard, Sophie, Hervé Ghesquieres, Rene-Olivier Casasnovas, Maria Gomes Da Silva, Pierre Feugier, Franck Morschhauser, Judith Trotman, et al. "Lenalidomide As Maintenance Therapy after R-CHOP Has No Protecting Effect for Central Nervous System Relapse in Frontline Treatment of Diffuse Large B-Cells Lymphoma. an Ancillary Studies of the Remarc Study." Blood 136, Supplement 1 (November 5, 2020): 22–23. http://dx.doi.org/10.1182/blood-2020-136912.
Full textAbstract:
Background. Central Nervous System (CNS) relapse is a rare and usually fatal event in diffuse large B-cell lymphoma (DLBCL). Prophylaxis of CNS relapse is currently based on high-dose methotrexate (HD MTX), a strategy associated with significant toxicity in elderly pts. Lenalidomide (LEN), an immunomodulatory agent, has shown activity in DLBCL, but also in association with rituximab in R/R PCNSL. In this analysis we explore the potential role of LEN given as maintenance for 2 years after R-CHOP to decrease the risk of CNS relapse Methods. The REMARC study is an international multicentre double-blind randomized phase III trial that assessed lenalidomide (LEN) maintenance therapy (n=323) versus placebo (PBO) (n=327) in 650 DLBCL patients aged 60-80, responding to R-CHOP (NCT01122472). CNS prophylaxis was permitted including either 4 intrathecal (IT) MTX; or 2 intraveinous (IV) HD MTX: MTX 1.5g/m² 3 weeks and 6 weeks after the D1 of the last cycle of R-CHOP. The primary objective was to analyze the CNS relapse risk comparing LEN and PBO arms. Secondary objectives were to determine the clinical and biological risk factors associated with the CNS relapse risk. Results . Median age was 68 (58-80), 392 pts (63%) had elevated LDH, 575 pts (89%) presented disseminated disease and 374 pts (60%) an elevated aaIPI (2-3). 333 pts (51%) received CNS prophylaxis during the R-CHOP induction phase. In LEN arm, 168 (52%) pts received a CNS prophylaxis: IT alone in 164 pts (98%) and HD MTX in 4 patients (2%). In PBO arm, 165 (50%) pts received a CNS prophylaxis with 160 pts (97%) with IT alone, 2 pts (1%) with HD MTX and 3 pts (2%) with both IT MTX and HD MTX. We retrospectively classified patients into groups of low- (n= 30, 5%), intermediate- (n= 377, 61%), and high-risk (n=215, 35%) CNS-IPI. MYC, MYC/BCL2, MYC/BCL2/BCL6 rearrangements were present in 10, 5 and 1 pts respectively. MYC expression alone, double expressor (DEL) (MYC/BLC2) were present in 79 pts (40%) and 71 pts (34%), respectively. 180 pts (46%) were GC, and 213 pts (54%) non-GC according to Hans score. Using Nanostring, 202 pts (50%) were classified GC-like DLBCL, 144 (36%) ABC-like DLBCL and 57 (14%) unclassified. With a median follow-up at 81.1 months, 274 (42%) patients presented a relapse. Among them, 22 pts presented a CNS relapse (3.4%). Median time for CNS relapse was 12.2 months (95%CI: 7-48) compared to 24 months (95%CI: 19-26) for relapse other than CNS. Median OS for the group with CNS relapse was 18 months (95%CI: 11-62) compared to 64 months (95%CI: 53-75) for the group with relapses other than CNS. Pts with a CNS relapse presented an aaIPI 2-3 and were classified as intermediate-risk (n=12, 54.5%) or high-risk CNS-IPI (n=10, 45.5%). Among them, 10/16 pts (63%) were ABC. MYC rearrangement, DHL and THL were not detected. DEL was found in 45% of data available patients. According to the maintenance arm, 16 CNS relapses (73%) occurred in LEN group and 6 (27%) in placebo group. Risk factors significantly associated with CNS relapses compared to no relapse were ABC profile (63% vs 28%, p=0.037), IPI 3-5 (91% vs 67%, p=0.028), and elevated LDH (38% vs 15%, p=0.012). Patients with high CNS-IPI were significantly associated with a worse PFS and OS in comparison with low-CNS-IPI (respectively HR=2.09, p = 0.035 and HR=2.70, p=0.032). In multivariable analysis, high CNS-IPI, age≥70, ABC profile assessed by NanoString and partial response at the end of R-CHOP were associated with poor OS. Conclusion LEN in maintenance for 2 years was not associated with a lower rate of CNS relapse. High CNS-IPI was confirmed as a poor prognosis factor for CNS-specific PFS, PFS and OS. The best strategy to decrease the risk of CNS relapses in DLBCL remains to be defined. Disclosures Bernard: Janssen: Other: Travel and accommodation . Ghesquieres:Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria. Casasnovas:Amgen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding. Gomes Da Silva:Janssen: Other: Travel and accommodation ; Abbvie: Other: Travel and accomodation ; Roche: Other: Travel and accommodation ; Gilead science: Other: travel and accomodation , Research Funding. Feugier:abbvie: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding; gilead: Consultancy, Honoraria, Research Funding; janssen: Consultancy, Honoraria, Research Funding; astrazeneca: Consultancy, Honoraria, Research Funding. Morschhauser:Genentech, Inc.: Consultancy; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Trotman:F. Hoffmann-La Roche: Research Funding; PCYC: Research Funding; Celgene: Research Funding; Takeda: Research Funding; BeiGene: Research Funding. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding. Caballero:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: travel; BMS: Other: travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel; Gilead: Other: travel; Roche: Other: travel. Haioun:Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Thieblemont:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).
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Anggoro, Rena Ratri, and Mochammad Bagus Qomaruddin. "ASSOCIATIVE SOCIAL INTERACTIONS OF EX-LEPROSY PATIENTS IN SUMBERGLAGAH VILLAGE OF MOJOKERTO REGENCY." Indonesian Journal of Public Health 14, no. 1 (July 5, 2019): 127. http://dx.doi.org/10.20473/ijph.v14i1.2019.130-140.
Full textAbstract:
Ex-leprosy patients still got stigma and discrimination from community although they had been cured. The stigma from community has been raising psychological and social problems that can affect their social interaction. This study aimed to describe associative social interactions of ex-leprosy patients in Sumberglagah Village of Mojokerto Regency based on the concept of social health aspect. The study employed descriptive qualitative method with the data collection techniques including observation, interview, and documentation. The instrument used in this study was interview guidelines. In this case, interview was conducted with 11 informants consisting of 8 ex leprosy patients as informants and 3 public figures as key informants. Informants were chosen based on characteristics that had been determined by the researcher. Besides, aspects examined in this study included cooperation, accommodation, and assimilation between ex-leprosy patients and other communities. Data were analyzed through several phases including reduction, data presentation, and drawing the conclusion. The results showed that first, the form of coorporation occurring between ex-leprosy patients and other communities was a bargaining process. Second, accomodation that occurred between ex-leprosy patients and other communities was tolerance. In this circumstance, ex-leprosy patients served the other communities with wrapped drinks and foods. Third, the assimilation aspect was marriage. It could be concluded from the study that the associative interactions that occurred couldrealize the patterns of good social interaction to support the realization of goodsocial health conditions for ex-leprosy patients in Sumberglagah Village.
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Anggoro, Rena Ratri, and Mochammad Bagus Qomaruddin. "INTERAKSI SOSIAL ASOSIATIF EKS PENDERITA KUSTA DI DUSUN SUMBERGLAGAH, KABUPATEN MOJOKERTO." Indonesian Journal of Public Health 14, no. 1 (July 5, 2019): 127. http://dx.doi.org/10.20473/ijph.v14i1.2019.127-137.
Full textAbstract:
Ex-leprosy patients still got stigma and discrimination from community although they had been cured. The stigma from community has been raising psychological and social problems that can affect their social interaction. This study aimed to describe associative social interactions of ex-leprosy patients in Sumberglagah Village of Mojokerto Regency based on the concept of social health aspect. The study employed descriptive qualitative method with the data collection techniques including observation, interview, and documentation. The instrument used in this study was interview guidelines. In this case, interview was conducted with 11 informants consisting of 8 ex leprosy patients as informants and 3 public figures as key informants. Informants were chosen based on characteristics that had been determined by the researcher. Besides, aspects examined in this study included cooperation, accommodation, and assimilation between ex-leprosy patients and other communities. Data were analyzed through several phases including reduction, data presentation, and drawing the conclusion. The results showed that first, the form of coorporation occurring between ex-leprosy patients and other communities was a bargaining process. Second, accomodation that occurred between ex-leprosy patients and other communities was tolerance. In this circumstance, ex-leprosy patients served the other communities with wrapped drinks and foods. Third, the assimilation aspect was marriage. It could be concluded from the study that the associative interactions that occurred couldrealize the patterns of good social interaction to support the realization of goodsocial health conditions for ex-leprosy patients in Sumberglagah Village.
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Dharawanij, Noppadol. "The Ways to Promote Wellness Tourism in Muang District, Chachoengsao Province." International Journal of Professional Business Review 8, no. 12 (December 18, 2023): e04009. http://dx.doi.org/10.26668/businessreview/2023.v8i12.4009.
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Purposes: There were many people travel for rest and relaxation, while a significant number of people also arrive in Thailand to address a medical need of varying urgency. Wellness tourism sits somewhere in between those two drivers of travel. It other locations, wellness tourism is often seen in the form of destination spas. This research aims to study wellness tourism in Muang district, Chachoengsao province, to study the government policy and support wellness tourism in Muang district, Chachoengsao province, and to study all private businesses which provide wellness tourism in Muang district, Chachoengsao province to increase the number of tourists and revenue to all businesses. Theoretical Referential: The research based on the definition of tourism, the 5 components of tourism (5As) which are attraction, accessibility, amenity, accomodation, the environment of tourist attrations. The composition of the potential tourist attractions, the image of tourist attractions, SWOT analysis and TOWS Matrix, and Health and Wellness Tourism which represented the government policy cooperated with private businesses and satisfy the needs of wellness touirsts around the world. Methodology: This research is a mixed methods: Quantitative and Qualitative research. Researcher used questionaire as a tool for quantitative research by accidental sampling 400 Thai tourists and 100 foreign tourists, 5 managers at least 5 years experinced in tour operators business and 10 tour operators staffs, 5 managers and 5 hotel staffs in hotel accomodation business, and 5 managers and 5 staffs of related service provider business. Qualitative research used interview as a tool by purposive sampling 5 heads of community in Muang district, a supervisor of Tourism Authority of Thailand and 1 staff, a director of Tourism Authority of Thailand, Chachoengsao province, and a director of tourism and sport, Chachoengsao office. Findings: The findings a of this research were as the follows: Firstly, there are 2 main types of wellness tourism in Muang district, Chachachoengsao province which is physical and spiritual. For the physical wellness tourism is aromatherapy, healthy food, massage, and spa; the spiritual wellness tourism is monk’s chat and meditation in the temple which can relieve their tension and mind. Secondly, the government policy support both physical and spiritual wellness tourism, and the 5’A of factors represent the essential requirements of successful tourism: Attractions (x̅ = 4.33), Access (x̅ = 4.52), Accommodation (x̅ = 4.37), Amenities (x̅ = 4.23), and Activities (x̅ = 4.63) were very well to serve all tourists. Lastly. all tourists want to come for their relaxation and get the healthy both physical wellness which increasing the number of tourists and revenue to the businesses. SWOT and TOWS matrix also supported the strengths and opportuinties which challege the growth of wellness tourism of the province. Value: These results served the need of many people travel for resting and relaxation, while a significant number of people also arrive in Thailand to address a medical need of varying urgency and wellness. Wellness tourism sits somewhere in between those two drivers of travel. Wellness tourism in Chachoengsao province not only challenge all of the top ten destinations because most of the resorts and hotels provide the wellness service in lower cost and the distance of travel from Bangkok is also very short distance but also can become the new wellness destination both physical and spiritual in Thailand.
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Brauneck, Franziska, Brit Fischer, Jasmin Wellbrock, Carsten Bokemeyer, Julian Schulze zur Wiesch, Friedrich Haag, Christin Ackermann, and Walter Fiedler. "Blockade of Tigit on AML-Derived M2 Macrophages Results in Reprograming into the M1 Phenotype and Enhances CD47-Mediated Phagocytosis." Blood 138, Supplement 1 (November 5, 2021): 3351. http://dx.doi.org/10.1182/blood-2021-148075.
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Abstract Background: Bidirectional interactions between the tumor microenvironment (TME) and AML cells lead to disease progression through induction of angiogenesis, migration, cancer stemness and local immunosuppression. Leukemia-associated macrophages (LAM) constitute an important cell population within the TME, but little is known about the phenotype, function, and plasticity of these cells. In the present study we provide an extensive characterization of the macrophage population in patients with AML. Methods: The phenotype and expression of co-regulatory receptors was assessed on different bone marrow-derived CD68 +CD14 + LAM populations, in comparison to corresponding CD3 + T-cells and CD117 +CD34 + AML cells (n=35), as well as peripheral blood monocytes from healthy donors (HD, n=16) using multi-parameter flow cytometry. The expression of surface markers and the distribution of LAM subpopulations was correlated with clinical parameters. The effect of a blocking anti-TIGIT antibody on the in vitro plasticity on primary LAMs and monocyte-derived macrophages from healthy donors was investigated. Furthermore, we analyzed if the treatment with blocking anti-TIGIT and anti-CD47 antibodies could increase the anti-leukemic phagocytosis of AML cell lines and in vitro polarized monocyte-derived M2 macrophages. Results: Phenotypic analysis of M1 and M2 macrophages in AML and HD revealed that the predominant macrophage population in patients with AML is made up of immunosuppressive alternatively activated M2 LAMs defined by expression of CD163 and CD86 (M1 AML vs. HD p<0.01 and M2 AML vs. HD p=0.02). These M2 LAMs contained significantly higher frequencies of cells expressing the immune checkpoint receptors TIGIT and TIM-3 than M1 LAMs (TIGIT + M2 vs. M1 p<0.01 and TIM-3 + M2 vs. M1 p<0.01, respectively). Regarding co-expression of multiple co-inhibitory receptors, the frequency of macrophages co-expressing TIM-3 or LAG-3 with TIGIT was higher in samples from AML patients in comparison to HDs (p=0.01 and p<0.01, respectively). This difference was caused by the significant up-regulation of TIM-3 and LAG-3 on TIGIT + M2 LAMs in comparison to their corresponding M1 LAMs (p<0.01and p<0.01, respectively). Importantly, in vitro blockade of TIGIT in primary LAMs of AML patients or differentiated PB-derived M2 macrophages of HDs resulted in a change in polarization from the M2 towards the M1 phenotype after 24 hours (AML: anti-TIGIT vs. IgG2a p<0.01, n=7 and HD: anti-TIGIT vs. IgG2a p=0.02, n=3). Moreover, the additional blockade of TIGIT on PB-derived M2 macrophages augmented the anti-CD47-mediated phagocytosis of the AML cell lines MOLM-13 and MV4-11 after 4 hours (MOLM-13: anti-CD47 vs. IgG1a 31% vs. 10.9%, p=0.04; anti-CD47 vs. combined anti-CD47 + anti-TIGIT 31% vs. 46.4%, p<0.01 and combined anti-CD47 + anti-TIGIT vs. IgG1a + IgG2a 46.4% vs. 13.6%, p<0.01, n=3 and for MV4-11: anti-CD47 vs. IgG1a 14.4% vs. 7.345%, p=0.03; anti-CD47 vs. combined anti-CD47 + anti-TIGIT 14.4% vs. 28.6%, p=0.03 and combined anti-CD47 + anti-TIGIT vs. IgG1a + IgG2a 28.6% vs. 12.85%, p=0.04, n=2). Next, we correlated the phenotypic data with clinical parameters. AML patients of the intermediate risk group according to ELN criteria exhibited a significantly higher frequency of M2 LAMs co-expressing TIGIT and LAG-3 than those in the favorable group (p=0.04 and p=0.01). Moreover, the frequency of TIM-3 + M2 LAMs was significantly increased in patients with adverse and intermediate risk in comparison to those with a favorable risk (p=0.01, p=0.0053). Furthermore, TIGIT + M2 LAMs were significantly more frequent in patients with the FLT3 ITD mutation in comparison with the wilde type (p=0.03). Conclusions: Our findings suggest that the proven clinical effect of monoclonal antibodies against TIGIT and TIM-3 in cancer may be due in part to their action on macrophages and depend on macrophage polarization. Our study identifies TIGIT + M2 LAMs co-expressing TIM-3 and LAG-3 as a promising effector population in AML. Further experiments should be conducted to investigate macrophage-mediated cytotoxicity in AML. Disclosures Brauneck: Daiichi Sankyo: Consultancy, Honoraria, Other: meeting attendance; Servier: Consultancy, Honoraria, Other: meeting attendance; Jazz Pharmaceuticals: Other: meeting attendance; Novartis: Other: meeting attendance. Bokemeyer: BMS: Honoraria, Other: Travel accomodation, Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel accomodation; Merck Serono: Consultancy, Other: Travel accomodation ; Bayer Schering Pharma: Consultancy; GSO: Consultancy; AOK Health insurance: Consultancy; Abbvie: Research Funding; ADC Therapeutics: Research Funding; Agile Therapeutics: Research Funding; Alexion Pharmaceuticals: Research Funding; Amgen: Research Funding; Apellis Pharmaceuticals: Research Funding; Astellas: Research Funding; BerGenBio: Research Funding; Blueprint Medicine: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Gilead Sciences: Research Funding; Gylcotope GmbH: Research Funding; GlaxoSmithKline: Research Funding; Inside: Research Funding; IO Biotech: Research Funding; Isofol Medical: Research Funding; Janssen-Cilag: Research Funding; Karyopharm Therapeutics: Research Funding; Lilly: Research Funding; Millenium: Research Funding; MSD: Research Funding; Merck KGaA: Honoraria; Bayer: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; AstraZeneca: Honoraria, Research Funding; Lilly/ImClone: Consultancy; Nektar: Research Funding; Rafael Pharmaceuticals: Research Funding; Springworks Therapeutics: Research Funding; Taiho Pharmaceutical: Research Funding; Pfizer: Other. Fiedler: Celgene: Consultancy; Servier: Consultancy, Other: support for meeting attendance; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: support for meeting attendance; Jazz Pharmaceuticals: Consultancy, Other: support for meeting attendance; Stemline: Consultancy; Novartis: Consultancy; ARIAD/Incyte: Consultancy; Amgen: Consultancy, Other: support for meeting attendance, Patents & Royalties, Research Funding.
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Seymour, John F., Jenny Qun Wu, Relja Popovic, Barbara Eichhorst, Peter Hillmen, Thomas J. Kipps, Anton W. Langerak, et al. "Assessment of the Clonal Dynamics of Acquired Mutations in Patients (Pts) with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Treated in the Randomized Phase 3 Murano Trial Supports Venetoclax-Rituximab (VenR) Fixed-Duration Combination Treatment (Tx)." Blood 138, Supplement 1 (November 5, 2021): 1548. http://dx.doi.org/10.1182/blood-2021-147731.
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Abstract Introduction: In the MURANO trial (NCT02005471), fixed-duration VenR (2 yrs Ven + R for the first 6 mo) improved survival and rates of undetectable minimal residual disease (MRD) over bendamustine (Benda)-R in pts with R/R CLL. Novel recurrent mutations in BCL2 and family genes (eg BAX and PMAIP1 [encoding Noxa]) have been linked to Ven resistance. We analyzed MRD+ samples from VenR-treated pts in MURANO to assess the nature and frequency of acquired mutations in BCL2 family genes (marker of emergent Ven resistance) and TP53 (may negatively impact response to re-Tx). We also analyzed the impact of these mutations on time to next CLL Tx (TTNT) and subsequent response. Methods: Pts included in this analysis received up to 2 yrs of VenR and had, at any time, ≥1 CLL cell per 100 leukocytes (high MRD+) in peripheral blood. Deep next generation sequencing (NGS) was performed without cell selection using a custom targeted NGS panel, encompassing 87 cell death related genes (coding regions and selected promoters). A CD19-enriched pre-Tx sample, analyzed by whole-exome sequencing, was available for all pts for comparison. Data cutoff was May 8, 2020, for the MURANO main study and Oct 13, 2020, for the substudy (where pts received next-line VenR following progression after initial VenR Tx). TTNT was calculated using the main study Ven completion/discontinuation date and the date of the first subsequent CLL Tx. Results: 107 samples from 42 pts, collected 21-42 mo post-Tx initiation, were evaluable. No BCL2 mutations were identified (limit of detection - variant allele frequency [VAF] 1%). Acquired BAX and PMAIP1 mutations were seen in 4 and 2 pts, respectively. Discordance between VAF and CLL MRD, and lack of proportionality in results with serial testing, suggested presence of BAX mutations in the non-CLL compartment in some pts, with further testing of sorted populations needed to clarify the source. All BAX mutations identified have been predicted to lead to loss of protein function, including 4 frameshift mutations. PMAIP1 mutations included a frameshift mutation (T86fs) and a mutation affecting gene splicing, both suggesting a loss-of-function effect. Nineteen TP53 mutations in 15/42 pts were observed across longitudinal samples (8/19 mutations in 6 pts present at baseline, 11/19 in 11 pts newly acquired, and 2 pts with both baseline and acquired mutations). Co-occurrence of TP53mut with BAXmut or PMAIP1mut was observed in 3/15 and 1/15 pts, respectively; based on VAF and assuming heterozygosity, these were likely in different clones. After Ven cessation, 28/42 (66.7%) had received an additional anti-CLL Tx by the cutoff; 19 pts received Ven-based regimens (15 in the substudy; 4 received other Ven-containing regimens per investigators' choice), 8 pts received ibrutinib (Ibr) monotherapy and 1 pt received Benda. Of the 19 pts who received Ven-based regimens (median 22.6 mo [range 11.9-38.1] post-main study end of Tx), 8 had TP53mut (5 acquired, 3 baseline), with 5/8 (63%) responding (complete response, 3 pts; partial response [PR], 2 pts). Six/11 pts (55%) with TP53-wild-type (WT) responded, all PRs. Two pts with TP53mut received Ibr as next Tx (one responded) vs 6 TP53-WT pts (all responded). The one pt treated with Benda without response had coexisting TP53mut and BAXmut. One patient with BAXmut received Ven re-Tx without response, while in pts with BAXmut and PMAIP1mut, responses to Ibr were 100% (2/2 pts) and 50% (1/2 pts), respectively (Table). No association was apparent between acquired TP53mut and TTNT, median 784 days (d; range 248-1051) vs 617 d (range 302-1142) in TP53-WT pts. Pts harboring BAXmut (n=5) had a shorter median TTNT (305 d; range 248-874) than BAX-WT pts (678 d; range 302-1142). Conclusion: No acquired BCL2 mutations were found in this analysis of pts from MURANO who received fixed-duration VenR Tx and subsequently manifest high MRD+. This suggests that fixed-duration Tx may reduce the propensity for selection of BCL2 resistance mutations, although confirmation using orthogonal methodology with higher sensitivity is required. Acquired TP53 mutations, noted in ~40% of pts, did not preclude response to subsequent Tx (primarily Ven-based regimens). Consistent with the TP53-independent mechanism of Ven, Ven re-Tx may be effective for pts with MRD+ disease who have relapsed following initial fixed-duration VenR Tx. More data are needed to better understand the significance of BAX or PMAIP1 mutations. Figure 1 Figure 1. Disclosures Seymour: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Wu: Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Genentech, Inc.: Current Employment. Popovic: AbbVie: Current Employment, Current equity holder in publicly-traded company. Eichhorst: Consultant Department I for Internal Medicine: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; University Hospital of Cologne: Current Employment. Hillmen: University of Leeds: Current Employment; Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Research Funding; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria. Kipps: European Research Initiative on CLL (ERIC): Honoraria; DAVA Pharmaceuticals: Speakers Bureau; Bionest Partner: Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Genetech: Honoraria, Other; Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Genentech/Roche: Honoraria; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding. Langerak: Janssen: Speakers Bureau; Gilead: Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Research Funding; Erasmus MS, University Medical Center: Current Employment. Owen: Incyte: Honoraria; AbbVie: Honoraria, Research Funding; Merck: Honoraria; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Servier: Honoraria; Pharmacyclics: Research Funding; Genentech: Research Funding; Gilead: Honoraria. Dubois: Abbvie: Research Funding; Genentech: Research Funding; Roche: Research Funding. Mellink: Cytogenetic Field: Consultancy; Genome Diagnostics Laboratory, AUMC: Current Employment; Financial support related to microarray analysis of Murano samples: Research Funding. Van Der Kevie-Kersemaekers: Amsterdam University Medical Centers: Current Employment. Dunbar: AbbVie: Current Employment. Jiang: Genentech, Inc./F.Hoffmann-La Roche Ltd: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Boyer: Roche: Current Employment. Thadani-Mulero: Roche: Current Employment, Current equity holder in publicly-traded company. Lefebure: Roche: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Harrup: AstraZeneca: Other: Advisory board. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding.
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Bottoni, Stefano. "Talking to the System: Imre Mikó, 1911–1977." East Central Europe 44, no. 1 (June 23, 2017): 47–75. http://dx.doi.org/10.1163/18763308-04401002.
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Taking a cue from an intelligence file produced by the Romanian political police on Transylvanian Hungarian intellectual Imre Mikó (Cluj, 1911–1977), the article analyzes the various patterns of accomodation with the political system, which represents a key to the understanding of how social legitimacy was built and maintained by the communist regimes of Eastern Europe. The framework in which this story takes place is especially interesting due to the Romanian context. On the one hand, the analysis of an unconventional collaboration established during the 1970s between the security organs of a national communist system and a prominent conservative intellectual stimulates us to rethink the state-society relationship in Ceaușescu’s Romania in more dynamic terms. Among the multiple reasons that led Mikó to accept the role of informer, one finds the communitarian ideology of “serving the people”, but also his belief that cooperation with the state security on relevant issues to the Transylvanian Hungarian community did not represent a betrayal of national ideals but the only way to achieve certain political goals, such as informing the Western public opinion on the worsening condition of the Hungarian minority. The case of Mikó can be compared with other files unveiled in Romania during the last years, and shows that often uncritically accepted definition of “collaboration” require serious conceptual reshaping. During the last decades of the communist regimes, significant parts of the formerly persecuted elite came to work together with the state security organs. They did not “talk to the system” with the purpose of spying on fellow citizens, but seeked to push forward their own cause with the infrastructural support of the state security, in a context where non-party members had been denied any access to the political sphere, and they regarded personal contact with a high-raking state security officer as a counterbalance of their marginality.
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Clement-Filliatre, Lauriane, Lotfi Benboubker, Anne-Marie Stoppa, Philippe Rodon, Kamel Laribi, Laure Vincent, Philippe Collet, et al. "Real-Life-Setting Effectiveness of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma: The Remix Study." Blood 136, Supplement 1 (November 5, 2020): 25–26. http://dx.doi.org/10.1182/blood-2020-133807.
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Background Ixazomib (IXA) is an orally-administered proteasome inhibitor approved in Europe in November 2016 for relapsed and/or refractory multiple myeloma (RRMM). It became available in France in May 2017 via a compassionate use program (CUP) and from October 2018 via the classical market access (non-CUP). In addition to pivotal clinical trials, real-world evidence (RWE) is required to evaluate effectiveness and safety in clinical routine practices. A non-interventional study, has been conducting in France to evaluate IXA use in combination with lenalidomide and dexamethasone (IRD) in real life. Methods REMIX is a non-interventional, multicentric study to assess IRD effectiveness and safety, conducted in 59 sites (public and private) in patients with RRMM. IRD was initiated in second line or more during the CUP and afterwards. After inclusion, patients were assessed every 3 months (mo) during 24 mo then every 6 mo as per standard practice. This interim analysis assessed IRD effectiveness (median Progression Free Survival (mPFS), 12 and 24-mo overall survival (OS) rates and tolerance in the CUP patients initiating IXA concomitantly to RD (patients who started lenalidomide more than 6 weeks before IXA were excluded). The analysis was conducted globally and per subgroups (age, number of lines of treatment, frailty as defined by Facon T & al.in Leukemia 2020). The CUP-patient median study follow-up was 17.4 mo for this interim analysis. Results The 198 eligible CUP patients were 47% of males, with a median age of 69 years (26% ≥75y). Out of them, 45% were frail and 7% had renal failure (CrCl ≤30 ml/min). Comorbidities were reported in 64% of patients including diabetes (9%), renal disease (10%), solid tumor (9%). At diagnosis, the cytogenetic risk was standard, high or unknown in respectively 46%, 13% and 41% of patients; 11% presented a plasmacytoma. 41% had multiple or severe bone lesions and 25% peripheral neuropathy. MM was diagnosed at a median of 4 years before IRD initiation. IXA was initiated after one (L2) / two (L3) / three or more lines of treatment (L4+) in respectively 58%, 18% and 24% of patients. Of them, 38% had received lenalidomide during prior line(s), mainly in patients with L3 and L4+ (78%, 65/84) vs L2 (8%, 9/114). The median washout period between lenalidomide discontinuation and IRD start was 18 mo 95%CI [17.6 - 29.6]. The mPFS was 19.2 mo 95%CI [13.3; 21.9] for the CUP cohort. mPFS was 21.5 mo 95%CI [13.3; 21.9] for L2 (104 patients), 17,8 mo 95%CI [12.2; 26.7] for L3 (29 patients) and 5.6 mo 95%CI [4.1; 8.8] for L4+ (38 patients) (c.f. Figure1). mPFS was similar in <75 YO (19.2, mo 95%CI [12.3; 24.8]) and in ≥75 YO patients (19.2 mo, 95%CI [1.7; 21.5]). In the subgroup with available frailty score (n= 124), mPFS was 21.5 mo 95%CI [12.5; -] in non-frail and 13.3 mo 95%CI [5.6 ; 19.8]) in frail patients. 12mo and 24mo-OS rates were 84% 95%CI [78%; 89%] and 73% 95%CI [65%; 80%] for the global group. Among the 166 patients with available response according to investigators, overall response rate (ORR) was 68% (66% in <75 YO and 71% in ≥75 YO patients) and very good partial response (VGPR) 35% (38% in<75 YO and 27% in ≥75 YO patients). The 187 followed-up CUP patients received a median of 14 IRD cycles. IXA discontinuation was reported in 50% of patients (n=92), related to AE in 13% of cases (n= 24). Serious adverse events were reported in 34% (n=69), including 14 (7%) patients with SAE considered related to IXA. Most frequent (>10%) AE were thrombocytopenia (30%), diarrhoea (28%), asthenia (20%), anaemia (18%), neutropenia (15%), nausea (14%) and peripheral neuropathy (10%). Conclusion Few RWE data have been published for IXA use in Europe. In this first interim analysis, estimated mPFS is consistent with MM1 results or data reported in MM1 study (19,2 mo vs 20.6 mo) even though CUP patients in REMIX were globally elder, frailer and more frequently treated in advanced lines (24% of L4+ in REMIX vs 11% of L4 in MM1). Reported adverse events were in line with known safety IXA profile. Figure 1 Disclosures Laribi: abbvie: Honoraria, Research Funding; amgen: Research Funding; novartis: Honoraria, Research Funding; takeda: Research Funding. Vincent:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; janssen: Membership on an entity's Board of Directors or advisory committees, Other: Congress support. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Macro:sanofi: Honoraria; gsk: Honoraria; janssen: Honoraria, Other: travel accomodation, Research Funding; takeda: Honoraria, Other: travel accomodation, Research Funding. Karlin:Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees; Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Texier:Kappa Santé: Other: employee of the CRO in charge of REMIX. Chouaid:pfizer: Honoraria, Research Funding; GSK: Honoraria, Research Funding; novartis: Honoraria, Research Funding; pfizer: Honoraria, Research Funding; takeda: Honoraria, Research Funding; bms: Honoraria, Research Funding; msd: Honoraria, Research Funding; astra zeneca: Consultancy, Honoraria, Research Funding; amgen: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding. Leleu:GSK: Honoraria; Amgen: Honoraria; BMS-celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Oncopeptide: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; Karyopharm: Honoraria.
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Killaspy, Helen, Stefan Priebe, Michael King, Sandra Eldridge, Paul McCrone, Geoff Shepherd, Maurice Arbuthnott, et al. "Supported accommodation for people with mental health problems: the QuEST research programme with feasibility RCT." Programme Grants for Applied Research 7, no. 7 (September 2019): 1–82. http://dx.doi.org/10.3310/pgfar07070.
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Background Across England, around 60,000 people live in mental health supported accommodation: residential care, supported housing and floating outreach. Residential care and supported housing provide on-site support (residential care provides the highest level), whereas floating outreach staff visit people living in their own tenancies. Despite their abundance, little is known about the quality and outcomes of these services. Objectives The aim was to assess the quality, costs and effectiveness of mental health supported accommodation services in England. The objectives were (1) to adapt the Quality Indicator for Rehabilitative Care (QuIRC) and the Client Assessment of Treatment scale for use in mental health supported accommodation services; (2) to assess the quality and costs of these services in England and the proportion of people who ‘move on’ to less supported accommodation without placement breakdown (e.g. to move from residential care to supported housing or supported housing to floating outreach, or, for those receiving floating outreach, to manage with fewer hours of support); (3) to identify service and service user factors (including costs) associated with greater quality of life, autonomy and successful move-on; and (4) to carry out a feasibility trial to assess the required sample size and appropriate outcomes for a randomised evaluation of two existing models of supported accommodation. Design Objective 1 – focus groups with staff (n = 12) and service users (n = 16); psychometric testing in 52 services, repeated in 87 services (adapted QuIRC) and with 618 service users (adapted Client Assessment of Treatment scale). Objectives 2 and 3 – national survey and prospective cohort study involving 87 services (residential care, n = 22; supported housing, n = 35; floating outreach, n = 30) and 619 service users followed over 30 months; qualitative interviews with 30 staff and 30 service users. Objective 4 – individually randomised, parallel-group feasibility trial in three centres. Setting English mental health supported accommodation services. Participants Staff and users of mental health supported accomodation services. Interventions Feasibility trial involved two existing models of supported accommodation: supported housing and floating outreach. Main outcome measures Cohort study – proportion of participants who successfully moved to less supported accommodation at 30 months’ follow-up without placement breakdown. Feasibility trial – participant recruitment and withdrawal rates. Results The adapted QuIRC [QuIRC: Supported Accomodation (QuIRC-SA)] had excellent inter-rater reliability, and exploratory factor analysis confirmed its structural validity (all items loaded onto the relevant domain at the > ± 0.3 level). The adapted Client Assessment of Treatment for Supported Accommodation had good internal consistency (Cronbach’s alpha 0.89) and convergent validity (r s = 0.369; p < 0.001). Supported housing services scored higher than residential care and floating outreach on six out of seven QuIRC-SA quality domains. Service users had a high prevalence of severe self-neglect (57%) and vulnerability to exploitation (37%). Those in supported housing (25%) and floating outreach (20%) experienced more crime than those in residential care (4%) but had greater autonomy. Residential care was the most expensive service (mean cost per resident per week was £581 for residential care, £261 for supported housing and £66 for floating outreach) but supported users with the greatest needs. After adjusting for clinical differences, quality of life was similar for users of supported housing and residential care (mean difference –0.138, 95% confidence interval –0.402 to 0.126; p = 0.306), whereas autonomy was greater for supported housing users (mean difference 0.145, 95% confidence interval 0.010 to 0.279; p = 0.035). Qualitative interviews showed that staff and service users shared an understanding of service goals and what constituted effective support. After adjusting for clinical differences, those in floating outreach were more likely to move on successfully at 30 months’ follow-up than those in residential care [odds ratio (OR) 7.96; p < 0.001] and supported housing (OR 2.74; p < 0.001), and this was more likely for users of supported housing than residential care (OR 2.90; p = 0.04). Successful move-on was positively associated with scores on two QuIRC-SA domains: the degree to which the service promoted ‘human rights’ (e.g. facilitating access to advocacy) and ‘recovery-based practice’ (e.g. holding therapeutic optimism and providing collaborative, individualised care planning). Service use costs for those who moved on were significantly lower than for those who did not. Recruitment in the feasibility trial was difficult: 1432 people were screened but only eight were randomised. Barriers included concerns about accommodation being decided at random and a perceived lack of equipoise among clinicians who felt that individuals needed to ‘step down’ from supported housing to floating outreach services. Conclusions We did not find clear evidence on the most effective model(s) of mental health supported accommodation. Indeed, our feasibility study suggests that trials comparing effectiveness cannot be conducted in this country. A range of options are required to provide appropriate support to individuals with differing needs. Future work Future research in this field requires alternatives to trials. Service planners should be guided by the mental health needs of the local population and the pros and cons of the different services that our study identified, rather than purely financial drivers. Trial registration Current Controlled Trials ISRCTN19689576. Funding This programme was funded by the National Institute for Heath Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 7, No. 7. See the NIHR Journals Library website for further project information. The fundholders are Camden and Islington NHS Foundation Trust and the research is a collaboration between University College London, Queen Mary University of London, King’s College London, the University of Ulster and Durham University.
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Mina, Roberto, Alessandra Larocca, Maria Teresa Petrucci, Gianluca Gaidano, Stelvio Ballanti, Pellegrino Musto, Massimo Offidani, et al. "Long-Term Carfilzomib for High-Risk Patients with Newly Diagnosed Multiple Myeloma: A Pooled Analysis of Two Phase 1/2 Studies." Blood 132, Supplement 1 (November 29, 2018): 3240. http://dx.doi.org/10.1182/blood-2018-99-112075.
Full textAbstract:
Abstract INTRODUCTION: High-risk cytogenetic abnormalities, such as del(17p), t(4;14), and/or t(14;16), are associated to an unfavorable prognosis. Several trials investigating current approved regimens have shown that high-risk multiple myeloma (MM) patients have shorter progression-free survival (PFS) and overall survival (OS) as compared to standard-risk patients. Carfilzomib, a second generation proteasome inhibitor, demonstrated to be able to improve the survival of high-risk MM patients in the relapse setting. Here we present a pooled analysis of two phase 1/2 studies to investigate the role of carfilzomib in high-risk, newly diagnosed (ND) MM patients. METHODS: Transplant ineligible patients with NDMM enrolled in the IST-CAR 561 and IST-CAR 506 studies were pooled together and analyzed. All patients received 9 28-day induction cycles of carfilzomib, either 70 mg/m2 once weekly (IST-CAR 561) or 36 mg/m2 twice weekly (IST-CAR 506), combined with weekly cyclophosphamide (300 mg/m2) and dexamethasone (40 mg) (CCyd). After the induction phase, patients proceeded to maintenance with single-agent carfilzomib until progressive disease or intolerable toxicity. The primary objective was to compare response to treatment, PFS, PFS-2 and OS in standard versus high-risk FISH, defined by the presence of del(17p), t(4;14), and/or t(14;16). A 15% cut-off point was used for detection of translocation [t(4;14) and t(14;16)] and 10% for detection of del(17p). RESULTS: 121 NDMM patients were enrolled in the IST-CAR 561 (n=63) and in the IST-CAR 506 (n=58) study. Cytogenetic data were available in 94 patients: 37 (31%) had high-risk chromosomal abnormalities by FISH, including 10% of patients with t(4;14), 3% with t(14;16) and 18% with del(17p), while 57 patients (47%) were classified as standard-risk. After the induction phase, no difference in terms of overall response rate (ORR; 86% vs. 92%; p=0.52) and at least near complete response (39% vs. 41%; p=1) was observed between standard and high-risk patients. After a median follow-up of 39 months, median PFS from enrollment was NR in standard-risk patients and 27.8 months in high-risk ones (HR: 0.76; p=0.38) (Figure 1); at 3 years, 52% and 43% of patients, respectively, were alive and free from progression. The PFS benefit for the comparison between standard and high-risk patients was more pronounced in patients who received once weekly carfilzomib at 70 mg/m2, (median: NR vs. 39.6 months; HR: 0.78, p=0.63) as compared to those treated with twice weekly carfilzomib at 36 mg/m2 (median: NR vs. 24.2 months; HR: 0.52, p=0.12). Median PFS-2 from enrollment was NR in standard-risk patients and 44.1 months in high-risk ones (HR: 0.66; p=0.26), without significant differences in the once weekly (median, NR vs. 39.6; p=0.27) and the twice weekly group (median; NR vs. 44.1; p=0.63). Median OS from enrollment was NR in standard-risk patients and 47.5 months in high-risk ones (HR:0.71; p=0.36) (Figure 1). In patients who received once weekly carfilzomib, median OS was NR and 47.5 months (HR:0.66, p=0.48) in standard and high-risk patients, respectively, while median OS in the twice weekly group was NR in standard-risk patients and 44.1 months (HR:0.73; p=0.55) in high-risk ones. CONCLUSION: In transplant ineligible patients with NDMM, carfilzomib combined with cyclophosphamide and dexamethasone as initial treatment mitigated the poor prognosis of high-risk FISH in terms of PFS, PFS-2 and OS. The median PFS of high-risk patients treated with CCyd compares favorably with those reported with current standard of care. As compared to twice weekly carfilzomib at 36 mg/m2, once weekly carfilzomib, at the dose of 70 mg/m2, confirmed to be effective in high-risk patients. These data support the use of carfilzomib for the treatment of high-risk NDMM patients. Figure 1. Figure 1. Disclosures Larocca: Janssen-Cilag: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Petrucci:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Gaidano:AbbVie: Other: Advisory Board; Janssen: Other: Advisory Board, Speakers Bureau. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Offidani:Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caravita di Toritto:Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Amgen: Other: Advisory Board; Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding; Takeda: Other: Advisory Board. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.
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Blum, Sabine, Norbert Gattermann, Filipe Martins, Kathrin Nachtkamp, Andrea Kuendgen, Guido Kobbe, and Ulrich Germing. "Is the IPSS-R Useful for Patients with MDS Receiving Disease-Modifying Treatment?" Blood 128, no. 22 (December 2, 2016): 5526. http://dx.doi.org/10.1182/blood.v128.22.5526.5526.
Full textAbstract:
Abstract Introduction The IPSS-R (Greenberg et al, Blood 2012) achieved a more accurate definition of risk groups among patients with myelodysplastic syndromes (MDS) by using refined cytogenetic risk assessment and a more sophisticated categorization of bone marrow blast percentages and cytopenias. Like the original IPSS, the IPSS-R was developed from clinical data describing untreated MDS patients, i.e. patients receiving only best supportive care. Our investigation was conducted to see whether the IPSS-R can also predict the survival of patients receiving specific MDS treatment, as is now the case for the majority of patients. Methods We identified in the Duesseldorf MDS Registry 142 patients who completed treatment with either a hypomethylating agent, intensive chemotherapy, allogeneic stem cell transplantation, lenalidomide, or more than one of these therapies, and in whom the IPSS-R could be calculated at the time of diagnosis and at least once after therapy was completed. We used the product-limit method to estimate the probability of survival. Results At diagnosis, the 142 MDS patients were distributed among IPSS-R risk groups as follows: 3 very low risk, 41 low risk, 43 intermediate risk, 27 high risk and 28 very high risk. Figure 1 shows the Kaplan-Meier (KM) survival curves of these groups, which are statistically not significantly separate. In other words, the strong prognostic power of the IPSS-R, which has clearly been demonstrated for untreated patients, was lost in patients receiving disease-modifying treatment. We also applied the IPSS-R after finishing therapy or subsequent to stem cell transplantation. Patients were assigned to the IPSS-R risk groups based on clinical data obtained at least four weeks after treatment. This resulted in Kaplan-Meier survival curves that clearly separated IPSS-R risk groups again (Figure 2). Conclusion Since it was developed on a data base of untreated MDS patients, it is not surprising that, applied at the time of diagnosis, the IPSS-R is not an effective tool to assess the prognosis of patients proceeding to receive disease-modifying treatment. Nevertheless, at the time of diagnosis, the IPSS-R reliably predicts the natural course of disease and thus helps to make appropriate, risk-adapted treatment decisions. After treatment has exerted its influence, mirrored by changes in blood counts, bone marrow blast counts and karyotypes, these changes can lead to re-categorization of patients in the IPSS-R. We demonstrate that such re-assignment is clinically meaningful, as shown by the survival curves in Figure 2. In other words, after disease-modifying treatment the IPSS-R regains its prognostic power and may again be used as an effective tool to support clinical decision making. This does not obviate the need to develop, independent of the IPSS-R, multiple treatment-specific tools to predict the response to various therapies. Disclosures Gattermann: Novartis: Consultancy, Honoraria, Other: travel, accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Kobbe:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding.
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Belada, David, Katerina Kopeckova, Juan Miguel Bergua Burgues, Don Stevens, Marc André, Ernesto Pérez Persona, Petra Pichler, et al. "First-Mind: Primary Analysis from a Phase Ib, Open-Label, Randomized Study to Assess Safety of Tafasitamab or Tafasitamab + Lenalidomide in Addition to R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 3556. http://dx.doi.org/10.1182/blood-2021-148354.
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Abstract Introduction Tafasitamab is a humanized, Fc-modified, anti-CD19 monoclonal antibody (mAb) shown to enhance antibody-dependent cellular cytotoxicity and phagocytosis. It is approved by the FDA under accelerated approval (July 2020) in combination with lenalidomide (LEN) for treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in adult patients ineligible for autologous stem cell transplantation. To evaluate if newly diagnosed DLBCL patients would also benefit from this regimen, this Phase Ib study (First-MIND; NCT04134936) was designed to first assess the safety and tolerability of tafasitamab ± LEN in addition to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in newly diagnosed DLBCL patients. Methods Eligible patients were ≥18 years old, with treatment-naïve DLBCL, international prognostic index (IPI) 2-5 and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients with known double- or triple-hit and transformed lymphoma were excluded. Patients were randomized 1:1 to either six 21-day [D] cycles of R-CHOP (R-CHO, D1; P, D1-5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafasitamab + LEN (25 mg orally, D1-10) (Arm B). Granulocyte colony-stimulating factor and venous thromboembolism prophylaxis was mandatory. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs); secondary endpoints included overall response rate (ORR), positron emission tomography (PET)-complete response (CR) rate, and partial response (PR) rate at end of treatment (EOT). Tumor measurements by PET/CT or PET/MRI at EOT were performed according to Lugano 2014 criteria within 6±2 weeks after Day 21 of the last treatment cycle the patient started. Results From December 2019 to August 2020, 83 patients were screened in nine countries across 34 sites in Europe and the US; 66 were randomized (Arm A, n=33; Arm B, n=33). Data cut-off for this analysis: 13 March 2021. Median age was 64.5 years (range 20-86). Many patients had high-risk disease: IPI 2: 24/66 (36.4%), IPI 3: 29/66 (43.9%), IPI 4: 11/66 (16.7%), IPI 5: 2/66 (3.0%); ECOG PS ≥2: 6/66 (9.1%). Most patients had Stage III/IV disease 62/66 (93.9%); 29/66 (43.9%) had bulky disease. All patients experienced at least one TEAE. The most frequent Grade ≥3 TEAEs by system organ class were blood and lymphatic disorders (81.8% patients overall), experienced by 24 patients (72.7%) in Arm A and 30 patients (90.9%) in Arm B. Grade ≥3 neutropenia and thrombocytopenia occurred in 19/33 (57.6%) and 4/33 (12.1%) (Arm A), and 28/33 (84.8%) and 12/33 (36.4%) (Arm B) patients, respectively; Grade ≥3 febrile neutropenia was experienced by 6/33 (18.2%) patients in each arm. Grade ≥3 infusion-related reactions to both rituximab and tafasitamab occurred in no patients in Arm A and one patient (3.0%) in Arm B, and 7/33 (21.2%) (Arm A) and 9/33 (27.3%) (Arm B) patients had a Grade ≥3 infection and/or infestation (Figure 1). Serious TEAEs occurred in 14/33 (42.4%) patients in Arm A and 17/33 (51.5%) patients in Arm B. Two out of 33 (6.1%) and one out of 33 (3.0%) patients discontinued study treatment due to TEAEs in Arms A and B, respectively. There were four deaths unrelated to tafasitamab and/or LEN (COVID-19 pneumonia, sepsis, and urosepsis). The average relative dose intensity of R-CHOP in each cycle was maintained in both arms. ORR at EOT was observed in 25/33 patients (75.8%; 95% confidence interval [CI]: 57.7-88.9) in Arm A and 27/33 patients (81.8%; 95% CI: 64.5-93.0) in Arm B. Conclusion These data suggest that both regimens are tolerable and do not impair dosing and scheduling of R-CHOP. Toxicities were similar to those expected with R-CHOP with or without LEN. With tumor follow-up still ongoing, the ORR at EOT suggests that patients with treatment-naïve DLBCL may achieve clinically meaningful efficacy tafasitamab and LEN in addition to standard treatment. A Phase III, multicenter, randomized, double-blind, placebo-controlled trial will assess efficacy and safety of R-CHOP + tafasitamab + LEN vs R-CHOP in newly diagnosed patients with high intermediate and high risk DLBCL, and is currently recruiting (frontMIND study; NCT04824092). Funding: MorphoSys AG. Figure 1 Figure 1. Disclosures Belada: Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen-Cilag: Consultancy, Research Funding; Takeda: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MorphoSys AG: Consultancy, Research Funding; Debiopharm Group: Consultancy; Pharmacyclics: Research Funding; Archigen Biotech: Research Funding; Reddys: Research Funding. André: Johnson & Johnson: Research Funding; Roche: Other: Travel/accomodation/expenses, Research Funding; Incyte: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Research Funding; Celgene: Other: Travel/accomodation/expenses; AbbVie: Other: Travel/accomodation/expenses. Pérez Persona: Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; GSK: Consultancy; Incyte: Consultancy. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Trneny: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria. Brackertz: MorphoSys AG: Current Employment. Shah: MorphoSys AG: Current Employment. Sporchia: MorphoSys AG: Current Employment. Burke: MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; Bristol Myers Squibb: Consultancy; Kymera: Consultancy; X4 Pharmaceuticals: Consultancy; AbbVie: Consultancy; SeaGen: Consultancy, Speakers Bureau; Kura: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Beigene: Consultancy, Speakers Bureau. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. In combination with lenalidomide (LEN), it received accelerated approval in July 2020 for adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), including arising from lowâ€'grade lymphoma, who are ineligible for autologous stem cell transplant (ASCT). Following FDA approval, we are now evaluating the safety and efficacy of tafasitamab in combination with LEN as an add-on to first-line therapy with R-CHOP in newly diagnosed patients with DLBCL.
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Macro, Magaret, Cyrille Touzeau, Clara Mariette, Salomon Manier, Sabine Brechignac, Laure Vincent, Benjamin Hebraud, et al. "Ixazomib and Daratumumab without Dexamethasone (I-Dara) in Elderly Frail RRMM Patients. a Multicenter Phase 2 Study (IFM 2018-02) of the Intergroupe Francophone Du Myélome (IFM)." Blood 138, Supplement 1 (November 5, 2021): 83. http://dx.doi.org/10.1182/blood-2021-148152.
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Abstract Purpose: Frail patients with multiple myeloma have an inferior outcome, especially in the relapse setting. This adverse prognosis is mainly related to a high discontinuation rate due to treatment related adverse events. The aim of this phase 2 study is to evaluate efficacy and tolerability of Ixazomib-Daratumumab (I-Dara) without Dexamethasone in elderly frail patients with relapsed myeloma (NCT03757221). Methods: Fifty Ixa-Dara naïve RRMM patients (1-2 prior therapy) were planned to receive oral Ixa (4 mg: days 1, 8, 15), IV Dara (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Dara (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled if frailty score was ≥2 by IMWG score and FIRST proxy score (Facon T et al, Leukemia, 2020). The primary endpoint was ≥very good partial response rate at one year. Secondary endpoints included ORR, PFS, OS & toxicity according to NCI-CTCAE version 5.0. Results: Among 52 patients screened during this ongoing trial, 44 were included between 03/2018 and 05/2021. Patient were at first (n=28) or second relapse (n=16). Thirty -eight patients (86%) were previously exposed to bortezomib and 8 (18%) were previously refractory to lenalidomide. Median age was 82 (80-84). All patients had a frailty score ≥2. In 22 patients ISS was stage I (n=5), II (n=10) or III (n=7). Eleven (32%) patients harbored high-risk cytogenetic, including t(4;14) (n=3) or del17p (n=8). The median duration of Tx among 23 pts with ongoing Tx was 6 months [0-27] at data cutoff (July 19)]. The median duration of Tx among 21 pts who stopped Tx was 7 months [0-21]: 13 had progressive disease. Six patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2); progressive disease (C2 & C4), sepsis (C1 & C2). Regarding toxicity, 28 ≥grade 3 AE occurred amongst 24 pts (54%). The most common grade 3-4 toxicities were thrombocytopenia (n=5), other cytopenias (n=4), infection (n=4) and gastrointestinal disorders (n=2). Fourteen out of 28 were SAE including 1 bronchospasm, 1 acute respiratory failure and 2 ixazomib overdoses. Overall response rate, including minimal response, was 86 % in pts with ongoing treatment and 71% in pts who stopped Tx; ≥VGPR rate was 33% and 6% respectively. Conclusions: These preliminary results show a favorable safety profile of ixazomib and daratumumab combination, without dexamethasone, in this specific population of very elderly frail patients with RRMM and high risk cytogenetic for almost one third of them. Efficacy results will be analyzed when the 50 patients will be enrolled in the study and evaluable for the primary endpoint. Disclosures Macro: GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Takeda: Honoraria, Other: Travel accomodation, Research Funding. Manier: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vincent: Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. OffLabel Disclosure: Ixazomib and Daratumumab association is not approved in NDMM or in RRMM
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Bringhen, Sara, Roberto Mina, Maria Teresa Petrucci, Lorenzo De Paoli, Stelvio Ballanti, Pellegrino Musto, Massimo Offidani, et al. "Once Weekly Versus Twice Weekly Carfilzomib in Combination with Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma: A Pooled Analysis of Two Phase 1/2 Studies." Blood 132, Supplement 1 (November 29, 2018): 1990. http://dx.doi.org/10.1182/blood-2018-99-111252.
Full textAbstract:
Abstract INTRODUCTION: Twice weekly carfilzomib is approved at two different doses, 27 mg/m2 in combination with lenalidomide and dexamethasone, and 56 mg/m2 with dexamethasone, for the treatment of relapsed and/or refractory multiple myeloma (MM). To reduce the treatment burden, the phase 3 A.R.R.O.W. study compared once weekly (70 mg/m2) to twice weekly (27 mg/m2) carfilzomib in relapsed/refractory MM patients, showing that once weekly carfilzomib increased the overall response rate (ORR) and prolonged progression-free survival (PFS) as compared to the twice weekly schedule. Here we present a pooled analysis of two phase 1/2 studies to compare once vs. twice weekly carfilzomib in newly diagnosed (ND)MM patients. METHODS: Transplant ineligible, NDMM patients enrolled in the single-arm IST-CAR 561 and IST-CAR 506 studies were pooled together. All patients received 9 28-day induction cycles of carfilzomib, either 70 mg/m2 once weekly on days 1,8,15 (IST-CAR 561) or 36 mg/m2 twice weekly on days 1,2,8,9,15,16 (IST-CAR 506), combined with cyclophosphamide (300 mg/m2 on days 1,8,15) and dexamethasone (40 mg on days 1,8,15,22). After induction, patients received maintenance with single agent carfilzomib at the same dose and schedule as induction phase, administered until progressive disease or intolerable toxicity. The primary objective was to compare PFS and overall survival (OS) from induction and maintenance, responses and rates of adverse events (AEs) with once vs. twice weekly carfilzomib. RESULTS: 121 NDMM patients (63 from IST-CAR 561 and 58 from IST-CAR 506) were analyzed. Median age at diagnosis was 72 years (IQR 68-74 years); baseline characteristics, ISS, cytogenetics by FISH and frailty status according to the IMWG frailty score, were balanced between the two groups (Table 1). After a median follow-up of 39 months, in the overall population, median PFS, PFS-2 and OS from start of induction were 36 months, 49 months and NR, respectively. No difference was observed in terms of median PFS (35.7 vs. 35.5 months; p=0.26), PFS-2 (48.6 vs. 48.5; p=0.51) and OS (49 vs. NA months; p=0.50) between patients who received once vs. twice weekly carfilzomib, irrespective of age, ISS, FISH status and frailty score (Figure 1). At cycle 9, no significant difference in the rate of ≥ partial response (PR; 87% vs. 90%; p=0.78) and ≥ near complete response (nCR; 30% vs. 47%; p=0.09) was reported in the two groups. Furthermore, the rates of patients who reduced (13% vs. 24%) or discontinued carfilzomib (27% vs. 28%) were comparable in the once vs. twice weekly carfilzomib, as were the rates of ≥1 grade 3-4 hematological (24% vs. 27%) and non-hematological (30% vs. 32%) AEs. After the induction phase, 90 patients started carfilzomib maintenance, 47 in the once weekly group and 43 in the twice weekly group. Overall, median PFS from start of maintenance was 31 months, while median PFS-2 and OS were NR. At 3 years, no difference was observed in terms of PFS (47% vs. 51%; p=0.92), PFS-2 (65% vs. 74%; p=0.74) and OS (72% vs. 73%; p=0.71) between patients who received once vs. twice weekly carfilzomib, irrespective of age, ISS, FISH status, frailty score and best response at induction. Among patients who received maintenance, 17% of patients deepened their response. Similar rates of ≥nCR (49% vs. 60%, p=0.30) and ≥CR (30% vs. 37%; p=0.51) were observed between the once vs. twice weekly groups. During maintenance, 26% and 16% of patients required ≥1 dose reduction of carfilzomib in the once and twice weekly carfilzomib, while 27% and 30% of patients discontinued carfilzomib due to AEs or death, respectively. The rates of ≥1 grade 3-4 hematological (0% vs. 5%) and non-hematological (19% vs. 23%) AEs were comparable within the two groups. CONCLUSION: In patients with NDMM, once weekly carfilzomib at 70 mg/m2 and twice weekly carfilzomib at 36 mg/m2 combined with cyclophosphamide and dexamethasone compared favorably with current standard of treatment. Moreover, once weekly carfilzomib administered both in the induction and maintenance phase resulted in similar PFS, PFS-2 and OS as compared to a lower (36 mg/m2), twice weekly infusion. The once weekly schedule at 70 mg/m2 was well tolerated and did not increase the risk of dose reduction or discontinuation in comparison with the twice weekly schedule at 36 mg/m2. These data support the use of triplet regimen including once weekly schedule of carfilzomib as initial treatment of MM patients in future trials. Disclosures Bringhen: Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria. Petrucci:Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. De Paoli:Gilead: Other: Advisory Board; Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Offidani:Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caravita di Toritto:Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Amgen: Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Takeda: Other: Advisory Board; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Palumbo:Takeda: Employment. Boccadoro:Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Larocca:Janssen-Cilag: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria.
34
Pleyer, Lisa, Michael Leisch, Alexandra Kourakli, Eric Padron, Jaroslaw P. Maciejewski, Blanca Xicoy, Jennifer Kaivers, et al. "Effects of the Therapeutic Armamentarium on Survival and Time to Next Treatment in CMML Subtypes: An International Analysis of 950 Cases Coordinated By the AGMT Study Group." Blood 134, Supplement_1 (November 13, 2019): 844. http://dx.doi.org/10.1182/blood-2019-123941.
Full textAbstract:
Background Chronic myelomonocytic leukemia (CMML) is an ultrarare stem cell disorder defined by the presence of monocytosis (≥1.0 G/l, ≥10%). Depending on white blood cell (WBC) count, CMML can be divided into a myelodysplastic (MD) (WBC ≤13 G/l) and a myeloproliferative (MP) variant (WBC >13 G/l). Although hypomethylating agents (HMA) have been shown to prolong overall survival (OS) in MDS patients (pts) in prospective, randomized phase III trials, only 6-14 MD-CMML pts were included, and MP-CMML pts were excluded [Silverman 2002; Kantarjian 2006; Fenaux 2009]. EMA approval of azacitidine (AZA) in CMML is thus based on limited experience and restricted to MD-CMML with 10-29% bone marrow blasts (BMB), whereas decitabine (DAC) is not approved for treatment (trt) of CMML in the EU. Smaller analyses and single-arm trials of HMA in CMML exist [Wijermans 2008; Ades 2013; Pleyer 2014; Zeidan 2017; Duchmann 2018; Santini 2018; Coston 2019; Diamantopoulos 2019], but it is still unclear whether HMA provide a benefit in CMML (subgroups) compared with other trts. Aim Evaluate the impact of HMA and hydroxyurea (HU) trt on OS and time to next trt (TTNT). Methods Data were collected from 7 European study groups and 2 US MDS Centers of Excellence; database lock 27.05.19; Assign Data Management and Biostatistics GmbH performed statistical analyses with SAS® 9.3. Of 1657 CMML pts, only those who received trt (n=950), with documented WBC and BMB at 1st line, were included in these analyses (n=845, cohort 1). Pts were stratified according to the EMA approved AZA indication, and inclusion/exclusion criteria of the GFM-DAC-CMML trial assessing DAC +/- HU vs HU (NCT02214407) (diagnosis of CMML, no prior trt [except supportive care, erythropoietin or ≤6 weeks HU], WBC ≥13 G/l and ≥2 of the following: BMB ≥5%, clonal cytogenetic abnormality [other than -Y], hemoglobin <10 g/dL, neutrophil count >16 G/l, platelet count <100 G/L, splenomegaly; pts with ECOG>2 excluded) (n=486; cohort 2). Results In cohort 1, pts receiving HMA 1st line (n=375) had longer OS (19.8 vs 16.3 months [mo], P=0.0102) and TTNT (13.2 vs 6.7 mo, P=0.0001) than pts treated with non-HMA 1st line (n=470). Survival benefit was longer when comparing pts who received HMA (any time) (AZA [n=442], DAC [n=37], both [n=27]) with those that never received HMA (never HMA; n=339) (23.0 vs 13.0 mo, P<0.0001). Median OS was longer for MD-CMML (n=294) vs MP-CMML pts (n=551) (25.5 vs 15.0 mo, P<0.0001). OS was shorter for all pts with 1st line HU preceding any 2nd line trt (9.4 vs 19.6 mo; P<0.0001; Fig A), for MP-CMML pts separately (8.7 vs 15.6 mo, P=0.0001), and for the subset with HU preceding 2nd line HMA (11.6 vs 19.8 mo; P=0.0016; Fig B). The following were significantly less common in pts treated with HMA vs those that were not: diagnosis in the pre-HMA era (8 vs 43%), MP-CMML (48 vs 66%), splenomegaly (27 vs 36%), ECOG≥2 (12 vs 24%), 1 trt line (43 vs 74%). WHO subtype, karyotype, transfusion dependence, LDH, CPSS score, AML transformation and therapy-related CMML were comparable between cohorts. HMA are not approved in the EU for CMML pts with <10% BMB. In this subgroup (n=588), median OS was longer for MD-CMML vs MP-CMML (28.1 vs 17.0 mo, P<0.0001) and for pts who received HMA vs never HMA (26.5 vs 14.8 mo, P=0.0003). Pts with <10% BMB and MD-CMML (n=206) did not seem to benefit from HMA vs non-HMA trt (median OS 28.4 vs 25.3 mo, P=0.9908; Fig C), whereas the MP-CMML subgroup (n=382) did (24.4 vs 13.0 mo, P<0.0001; Fig D). HMA are also unapproved in the EU for MP-CMML pts with ≥10% BMB. In pts with ≥10% BMB (n=257), median OS was longer for MD-CMML vs MP-CMML (19.4 vs 11.2 mo, P=0.0023) and for pts who received HMA vs never HMA (18.3 vs 7.0 mo, P<0.0001). Both MD-CMML (OS 21.7 vs 10.9 mo, p=0.0134; Fig E) and MP-CMML pts (15.6 vs 6.3 mo, P<0.0001; Fig F) benefited from HMA trt vs never HMA. In cohort 2, 1st line trts were HU (n=214), HMA (n=187) and others (n=85). Comparing HMA vs HU 1st line, median OS was 15.6 vs 14.5 mo (P=0.0307) and median TTNT was 8.8 vs 6.5 mo (P=0.0452; Fig G). OS and TTNT were comparable for HU vs other trts (Fig G). Similar observations were made in the larger cohort 1 (Fig H). Conclusions HMA show promising results with survival benefits of +11.4, +10.8 and +9.3 mo in pts with MP-CMML <10%, and MD- or MP-CMML ≥10% BMB. In MP-CMML pts fulfilling GFM-DAC-CMML trial inclusion criteria, survival and TTNT were longest in pts receiving HMA 1st line as compared to HU or other trts. Preceding HU portends poor prognosis (-10.2 mo). Disclosures Pleyer: Abbvie: Other: Advisory board; Novartis: Other: Advisory board; Inflection Point Biomedical Advisors: Other: Advisory board; Celgene: Other: Advisory board; Agios: Other: Advisory board. Leisch:Novartis: Honoraria, Other: Travel support; Bristol-Myers-Squibb: Honoraria; Celgene: Other: Travel support. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Heibl:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Honoraria; Daiichi Sankyo: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geissler:Novartis: Honoraria; Roche: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria; AOP: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Ratiopharm: Honoraria. Valent:Blueprint: Research Funding; Pfizer: Honoraria; Deciphera: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Medina de Almeida:Novartis: Speakers Bureau; Celgene: Speakers Bureau. Jerez:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanz:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding. Greil:Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding. OffLabel Disclosure: Azacitidine is not approved for the treatment of MP-CMML or CMML with <10% BM blasts, decitabine is not approved for treatment of CMML in the EU, hydroxyurea is not approved for the treatment of CMML in the EU.
35
Zaccaria, Gian Maria, Andrea Capra, Maria Teresa Petrucci, Massimo Offidani, Vittorio Montefusco, Francesco Di Raimondo, Annalisa Bernardini, et al. "Predictive Model of Early Relapse in Newly Diagnosed Multiple Myeloma: Analysis from a Pooled Dataset." Blood 134, Supplement_1 (November 13, 2019): 2130. http://dx.doi.org/10.1182/blood-2019-125640.
Full textAbstract:
Background. Despite the improvement of therapeutic regimens, a relevant proportion of multiple myeloma (MM) patients (pts) experience early relapse (ER) [Majithia, Leukemia 2016] and represents an unmet medical need. It is therefore of high clinical interest to identify baseline factors that may predict ER. Aims To design models predictive of ER (defined as pts with a time-to-progression ≤18 or ≤ 24 months). To assess the accuracy of every model on an independent validation set. To build a score to predict ER. Methods Data were obtained from 2326 pts enrolled in 8 multi-center clinical trials: NCT01093196, NCT01346787, NCT01857115, NCT01190787, NCT00551928, NCT01091831, NCT01063179 and 2005-004730-41. Here, we included 14 baseline features (fts): age, creatinine, albumin (alb), b2microglobulin (b2m), bone marrow plasma cell (PCbm) were evaluated as continuous variables; free light chain (FLC, λ vs K), M-component subtype (IgA vs others), Revised International Staging System (R-ISS stage II/III vs I), lactate dehydrogenase levels >/≤ upper limit of normal (LDHULN), presence vs absence of chromosomal abnormalities detected by FISH [del17p, t(4;14), t(14;16), t(11;14)], and presence of plasmacytomas as categorical values. Trials were assigned to training and validation set to have a superimposed median (μe) age and follow-up in the two subsets. From the training set, a univariate analysis (UV) on outcome was performed according to both Chi-square and Kruskal tests, as appropriate. Features with p<0.05 were then tested in a multivariate (MV) logistic regression model. Each MV model was based on pts with complete data available. We performed and compared 2 MV models, one including R-ISS and one including fts (LDHULN, alb, b2m and chromosomal abnormalities) defining the R-ISS considered individually. Secondly, each model was tested on the validation set assessing the area under the curve (AUC). From the most accurate model, a score defined low (L), intermediate (I) and high (H) chances of ER. Statistical analysis was performed via R (v.3.5.2). Results ER≤18 models. 10/14 fts were selected based on UV analysis: age, FLC, PCbm, del17p, t(4/14), t(14/16), alb and b2m, LDHULN and R-ISS stage. Pts with complete data were included in the training set (n=923; μe age =66 years [y]; ER=35%) and the validation set (n=313; μe age=67 y; ER=36%), respectively. In the MV incorporating the R-ISS, the R-ISS II/III vs I (OR=1.75, 95% CI:1.26-2.44) and increased PCbm (OR=1.05, 95% CI:1.02-1.08) increased the risk of ER. When the MV analysis was performed including single fts instead of R-ISS, increased PCbm (OR=1.05, 95% CI:1.02-1.08), λ FLC (OR=1.34, 95% CI:1.01-1.79), LDHULN (OR=1.80, 95% CI:1.16-2.81), presence of both del17q (OR=1.58, 95% CI:1.07-2.33) and t(4/14) (OR=2.01, 95% CI:1.36-3.01) increased the probability of ER; increased alb (OR=0.75, 95% CI:0.61-0.94), reduced the risk of ER (table 1). ER≤24 models. 8/14 fts were selected based on UV analysis: FLC, PCbm, del17p, t(4/14), alb and b2m levels, LDHULN and R-ISS stage. Pts with complete data were included in the training set (n=1009; μe age=67 y; ER=45%) and in the validation set (n=352; μe age=67 y, ER=45%). In MV analysis, including R-ISS, both R-ISS (OR=1.88, 95% CI:1.39-2.55) and PCbm (OR=1.04, 95% CI:1.02-1.06) impacted on outcome. When the MV analysis was performed including single fts, λ FLC (OR=1.31, 95% CI:1.01-1.69), PCbm (OR=1.04, 95% CI:1.02-1.07), del17p (OR=1.86, 95% CI:1.30-2.65) and t(4/14) (OR=2.00, 95% CI:1.38-2.88) retained their impact on outcome (table 1). Validation. Each MV model was tested on the validation set. Among the 4 MV models, the ER≤18 incorporating individual fts resulted in the highest AUC (0.66) and was therefore used to build up a prognostic score. Score. The ER score was calculated as 0.047 × PCbm + 0.589 × LDHULN + 0.459 × del17q (IF present) + 0.705 × t(4/14) (IF present) + 0.293 × FLC (IF FLC =λ) - 0.284 × alb. The ER score was calculated as 3 groups of pts with different risks of ER: L (42% of pts; risk of ER18=23%), M (33% of pts; risk of ER18=39%) and H (26% of pts; risk of ER18 =55%). Discussion. This is the first analysis proposing a score that includes standard baseline fts and aims at identifying pts at high risk of ER in the context of novel agent-based therapy. Based on our score, 26% of pts can be defined at high risk. To improve the clinical applicability, the construction of a simplified model with categorized variables is ongoing. Disclosures Petrucci: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Offidani:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy. Liberati:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Omedé:Janssen: Membership on an entity's Board of Directors or advisory committees. Mannina:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Caravita di Toritto:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation costs, Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation costs; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation costs; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Patriarca:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Benevolo:Novartis Pharmaceuticals: Consultancy. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Sunesys: Consultancy, Honoraria. Hajek:Amgen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Celgene: Honoraria, Other: Consultant or advisory relationship, Research Funding; AbbVie: Other: Consultant or advisory relationship; Bristol-Myers Squibb: Honoraria, Other: Consultant or advisory relationship, Research Funding; Novartis: Other: Consultant or advisory relationship, Research Funding; PharmaMar: Honoraria, Other: Consultant or advisory relationship; Takeda: Honoraria, Other: Consultant or advisory relationship, Research Funding; Janssen: Honoraria, Other: Consultant or advisory relationship, Research Funding. Spencer:Sanofi: Other: Consulting/advisory role; Specialised Therapeutics Australia: Consultancy, Honoraria; Amgen: Other: Consulting/advisory role, Research Funding; AbbVie: Other: Consulting/advisory role, Research Funding; Haemalogix: Other: Consulting/advisory role; Janssen Oncology: Other: Consulting/advisory role, Research Funding, Speakers Bureau; Servier: Other: Consulting/advisory role; Secura Bio: Other: Consulting/advisory role; Takeda: Other: Consulting/advisory role, Research Funding; Celgene: Other: Consulting/advisory role, Research Funding, Speakers Bureau. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding. Boccadoro:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Gay:AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.
36
Perrot, Aurore, Valerie Lauwers-Cances, Titouan Cazaubiel, Thierry Facon, Denis Caillot, Lauriane Clement-Filliatre, Margaret Macro, et al. "Early Versus Late Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the IFM 2009 Trial." Blood 136, Supplement 1 (November 5, 2020): 39. http://dx.doi.org/10.1182/blood-2020-134538.
Full textAbstract:
Introduction The IFM 2009 study prospectively evaluated the combination of 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) versus (vs) 3 cycles of RVd plus high dose (HD) melphalan with autologous stem cell transplantation (ASCT) plus 2 consolidation RVd cycles, followed by lenalidomide maintenance for 12 months (mo) in newly diagnosed multiple myeloma (NDMM) patients (Attal M et al, NEJM 2017). RVd with transplant was associated with significantly longer progression-free survival (PFS) (primary endpoint) compared to RVd alone. Overall survival (OS) at 4 years was similar in both groups. In order to evaluate the long-term outcome in the 2 arms and the impact of 2nd line treatments on PFS2 and OS, we performed an extension of patient follow-up (FU) of the IFM 2009 study over a period of 4 years (DB-FU-IFM 2009 / NCT03679351). Methods 700 NDMM patients (pts) (median age 59 years [range, 28.0-65.0]) were randomized between the 2 arms after stratification by ISS stage and FISH analysis. Patient characteristics were well-balanced, notably age, gender, ISS3, and high risk cytogenetics (defined by t(4;14), t(14;16), del(17p)). 100 patients (50 from each arm) who experienced 1st progression were included in the IFM 2009-02 PCD trial (NCT02244125, Garderet L et al, Blood 2018). The choice of 2nd line treatment and decision to perform an ASCT at relapse was based on investigator's discretion. PFS2 was defined as the time from randomization to progression on next line therapy or death from any cause; second PFS as the time from date of 1st progression to progression on next line therapy or death. This trial was previously reported with a median FU of 44 mo (Attal M et al, NEJM 2017). Results As of March 2020, median FU was 93 mo [range, 88-98]. As previously reported, median PFS was significantly longer in the transplant group (TG), at 47.3 mo compared to 35.0 mo in the RVd alone group (RG) (HR (95CI) 0.70 [0.59-0.83] p<0.001). 497/700 pts experienced disease progression, 270 (77.1%) pts in the RG and 227 (64.9%) pts in the TG; 262 and 217 of them respectively initiated a 2nd line. Among these pts, 76.7% (201/262) in RG and 22.6% (49/217) in TG received an ASCT at 1st relapse; 40.1% (105/262) and 46.5% (101/217) respectively received a pomalidomide-based 2nd line. Only 14 and 12 pts received carfilzomib- and daratumumab-based 2nd line regimens. Median PFS2 was similar in both groups, at 95 mo in the RG and not reached (NR) in the TG (HR [95CI] 0.96 [0.76-1.21] p=0.76). This estimate was homogeneous across ISS stage (p-value for interaction 0.26) and cytogenetic group (p-value for interaction 0.90). Median PFS2 in ISS3 and high-risk cytogenetic pts was 73 and 75 mo, and 48 and 47 mo, in the RG and TG, respectively. Second PFS was significantly increased in the RG, at 36 vs 25 mo in TG (HR [95CI] 1.41 [1.11-1.79] p=0.003). Median OS was NR in either group. At 8 years, the OS rate was 60.2% in the RG and 62.2% in the TG (HR [95CI] 1.03 [0.80-1.32] p=0.81). Minimal residual disease (MRD) was a strong predictor of outcome: PFS (HR [95CI] 0.28 [0.22-0.36] p<0.001), PFS2 (HR [95CI] 0.27 [0.20-0.37] p<0.001) and OS (HR [95CI] 0.35 [0.25-0.49] p<0.001) were longer in pts achieving MRD negativity, in comparison with those who did not. The incidence of invasive 2nd primary cancer was not significantly different between the 2 groups (p=0.38); of note, 2nd hematological malignancies were reported in 5/350 and 7/350 pts in RG and TG respectively. Conclusion RVd before and after HD melphalan and ASCT followed by one-year of lenalidomide maintenance is associated with a significantly longer PFS than RVd alone, without a significant increase of 2nd primary malignancy. At 1st relapse, before the systematic use of daratumumab- or carfilzomib-based combinations, almost half of the pts received pomalidomide-based treatment and about 3 quarters of pts who had not received frontline ASCT underwent delayed transplant. With a FU of almost 8 years, median OS was NR and there was no difference between the 2 strategies with respect to PFS2 and OS. MRD appears to predict outcome and might be used after induction to identify those pts who probably do not require a transplant. Quadruplets with anti-CD38 monoclonal antibodies combined with the selective use of HD therapy and transplant, followed by extended maintenance, should be considered in the future to further improve outcome. Such an approach could potentially provide a functional cure for a significant proportion of NDMM pts. Disclosures Perrot: Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Clement-Filliatre:BMS/Celgene: Honoraria. Macro:gsk: Honoraria; janssen: Honoraria, Other: travel accomodation, Research Funding; sanofi: Honoraria; takeda: Honoraria, Other: travel accomodation, Research Funding. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Touzeau:Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding. Leleu:AbbVie: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Oncopeptide: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; BMS-celgene: Honoraria. Munshi:C4: Current equity holder in private company; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Anderson:Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Moreau:Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Attal:BMS/Celgene, Sanofi: Consultancy, Honoraria, Research Funding.
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Boquoi, Amelie, Soraya Magdalena Banahan, Judith Strapatsas, David Lopez y Niedenhoff, Guido Kobbe, Norbert Gattermann, Ulrich Germing, Rainer Haas, Thomas Schroeder, and Roland Fenk. "Therapy-Related Myeloid Neoplasms Following Treatment for Multiple Myeloma : A Single-Center Analysis." Blood 134, Supplement_1 (November 13, 2019): 4261. http://dx.doi.org/10.1182/blood-2019-122598.
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Introduction Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) comprise late complications following mutagenic treatment. Limited data is available on the outcome of patients (pts) developing therapy-related MDS and AML (tMDS, tAML) after treatment for multiple myeloma (MM). Methods From 1976 to 2011, 3814 pts were entered into the Düsseldorf MDS registry. We identified 200 pts with tMDS or tAML. Of those, 41 pts had also been diagnosed with multiple myeloma (mm-MDS/AML). We compared these 41 pts to pts with de novo MDS (n=3614) and to pts with tMDS with other underlying diseases (n=159, 55 pts with other hematological diseases (34.5%), 93 with solid tumors (58.5%) and 11 with other diseases (7%)). Patient characteristics Median time between MM diagnosis and the onset of MDS was 5.5 years (range 0-28.5 years). Median age at the time of diagnosis of mm-MDS/AML was 67.8 years (range 32.5-84.6 years). Of all 41 mm-MDS pts, 13 developed AML (32%). Median time to progression from MDS to AML was 5 months (range 0.5-68 months). According to the WHO classification of 2016, there were 7 MDS-SLD, 10 MDS-MLD, 1 MDS-RS SLD, 13 MDS-RS MLD, 7 MDS-EB I, 2 EB-2, 1 MDS del(5q). 58% of mm-MDS pts had a complex karyotype, mostly affecting chromosomes 5 (22%) and 7 (17%), less often affected were chromosomes 17 (13%), 20 (13%) and 21 (13%). At MDS diagnosis, 11 MM pts were in complete remission (22%), 29 pts showed partial remission (58%), and 10 pts a stable disease (20%). 84.4% of pts with mm-MDS/AML had received conventional chemotherapy, mostly anthracyclines and alkylating agents. 94.4% had received melphalan. 15% of pts had received novel agents including immunomodulatory drugs and proteasome inhibitors. Results Both mm-MDS pts and tMDS pts were significantly younger than de novo MDS pts, however, there was no age difference between mm-MDS and tMDS (mm-MDS: mean 67.8 years, range 32-85, tMDS: mean 64.3 years, range 21-85, p<0.05, de novo MDS: 71,9 years, range 18-105; p<0.05). Both mm-MDS pts and de novo MDS pts showed significantly more males than females (mm-MDS 67% male versus 33% female, de novo MDS 57% versus 43%, p<0.05) while tMDS pts showed an equal ratio (48% versus 52%). When we compared risk group distribution according to IPSS-R we found significantly fewer mm-MDS pts to be in the lower risk categories (p<0.05 for both mm-MDS versus t-MDS and mm-MDS versus de novo MDS). Both mm-MDS and tMDS pts had a significantly worse karyotype when compared to de novo MDS (p<0.05). More cell lineages were affected in mm-MDS and tMDS pts than in de novo MDS (p<0.05). 50% of mm-MDS pts were pancytopenic versus 26% of de novo pts (p<0.05). Hemoglobin levels were significantly lower in mm-MDS and tMDS pts than de novo MDS pts (p<0.05). mm-MDS pts showed significantly higher blast counts in the bone marrow than all tMDS (p<0.05). Progression to AML occurred significantly more often in mm-MDS pts. At 12 months we discovered 12% of de novo MDS pts to have transformed to AML, 19% of tMDS and 24% of mm-MDS. At 36 months, 20% of de novo MDS pts had transformed to AML, 34% of tMDS and 39% of mm-MDS (p<0.05). When mm-MDS pts transformed to AML their survival was very poor, however, not significantly different compared to mm-MDS without AML transformation (7 months versus 11 months, p>0.05). Median survival of de novo MDS pts was 32 months (CI 29.940 - 34.192, range 1-345 months). In contrast, median overall survival of both mm-MDS and all other t-MDS was significantly shorter with 13 months in both groups (p<0.05, mm-MDS: CI 5.262 - 20.692, range 1-99 months; tMDS: CI 10,016 - 15,939, range 0-160 months). Myeloma remission status had no impact on survival: pts in complete remission showed a median survival of 6 months (95% CI, range 0 - 35 months), pts with partial remission 7 months (95% CI, range 5 - 9 months) (p>0.05). Conclusion Pts developing a myeloid neoplasm after treatment for multiple myeloma present with biological characteristics similar to those seen in pts with other tMDS. However, both clinical and molecular features are more severe with higher bone marrow blast counts, worse karyotypes, a more unfavourable IPSS-R score, and a significantly higher rate of transformation to AML. Yet despite a more aggressive phenotype, prognosis is equally poor and independent of myeloma remission status in mm-MDS/AML pts suggesting secondary myeloid neoplasia to govern the stem cell niche independent of previous disease or treatment. Disclosures Boquoi: Celgene: Other: Travel, Accommodation, Expenses; Janssen: Other: Travel, Accommodations, Expenses; BMS: Honoraria; Amgen: Honoraria, Other: Travel, Accommodations, Expenses. Kobbe:Takeda: Honoraria, Other: Travel support; Novartis: Honoraria, Other: Travel support; Medac: Honoraria, Other: Travel support; Jazz: Honoraria, Other: Travel support; Roche: Honoraria, Other: Travel support; MSD: Honoraria, Other: Travel support; Neovii: Honoraria, Other: Travel support; Abbvie: Honoraria, Other: Travel support; Pfizer: Honoraria, Other: Travel support; Biotest: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding; Amgen: Honoraria, Other: Travel support, Research Funding. Gattermann:Takeda: Research Funding; Novartis: Honoraria; Alexion: Research Funding. Germing:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria. Schroeder:Celgene Corporation: Consultancy, Honoraria, Research Funding. Fenk:Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria, Other: Travel, Accomodation, Expenses; Amgen: Honoraria; Celgene: Honoraria, Research Funding.
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Kreissl, Stefanie, Helen Goergen, Bastian von Tresckow, Karolin Behringer, Jana Markova, Andreas Lohri, Julia Meissner, et al. "Primary Progressive Disease in Hodgkin Lymphoma Patients: A Retrospective Analysis from the German Hodgkin Study Group." Blood 126, no. 23 (December 3, 2015): 3941. http://dx.doi.org/10.1182/blood.v126.23.3941.3941.
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Abstract Background: Primary progressive disease still remains an unmet medical need in Hodgkin Lymphoma (HL). Due to missing data on treatment effects and survival there is no established standard of care. We thus performed a retrospective analysis using the German Hodgkin Study Group (GHSG) database to improve the knowledge on the course of primary progressive HL patients. Methods: Patients aged between 18 and 60 years treated within the GHSG first-line trials HD13-HD15 were screened for primary progressive HL. Primary progression was defined as progressive disease during ongoing therapy, within 3 months after the end of treatment, or up to 6 months after the end of treatment in patients with partial response or stable disease in the final restaging. We investigated types and outcome of second-line treatment approaches and overall survival, which was calculated from first diagnosis of HL (OS) and from diagnosis of first progression or relapse (OSp). Results: We analyzed 5,126 patients, of whom 112 (2.2%) were identified with primary progressive disease. Of those, 62 (55%) patients had initially been treated for advanced-stage HL with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) variants, 30 (27%) for early-stage unfavorable HL with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)- or BEACOPP-like regimens (24 and 6 patients, respectively) and 20 (18%) for early-stage favorable HL with ABVD variants. The median age at the time of progression was 33 years. 3 patients (3%) died before a salvage therapy was started. Second-line treatment strategies included reinduction with intensified salvage regimens (77%), conventional chemotherapy (14%), and radiotherapy (8%). Autologous stem cell transplantation (ASCT) was performed in 76% of the patients who had received intensified reinduction chemotherapy, and allogeneic stem cell transplantation in ten (9%) patients. After the first salvage therapy, 42% of all patients achieved a complete remission (CR) and did not require further treatment. In total, 66% of the patient cohort achieved a CR after one or more second-line approaches. Median duration of the first CR was 61 months. After a median observation time of 7 years, 55 of the patients with primary progressive disease (49%) had died, mostly from progressive or relapsed HL (n=36) or toxicity of salvage treatment (n=10). The majority of the 57 survivors was in CR at the time of analysis; 2 were under treatment for HL and there was no information available for one patient. Median OSp for the entire cohort was 83 months, 5-year OSp was 55.4% (95%-CI, 46% to 65%). Since OSp differed among patients of different initial stages and types of pre-treatment (early-stage favorable and unfavorable patients treated with ABVD variants, OSp 74.2% [61%-87%] vs. higher-stage patients treated with BEACOPP variants, OSp 42.9% [31% - 55%]), treatment groups were analyzed for survival separately. In both groups, patients responding to the first salvage therapy had a significantly better OSp compared to those not responding (each p<0.001). OS was significantly worse in patients with primary progressive disease when compared to the complementary study cohort in both treatment groups (each p<0.001). When comparing patients with primary progressive disease with those patients with a relapse of HL (n=272), there were significant advantages of the latter regarding OS and OSp within the BEACOPP-pre-treated subgroup (each p<0.001). In patients pre-treated with ABVD variants, there was also a significant difference in OS (p=0.007), but no detectable difference regarding OSp (5-year OSp 74% vs. 78%, p=0.3). Conclusion: Overall, the 5-year OSp in this unselected patient cohort of primary progressive HL patients is encouraging and supports the use of aggressive salvage regimens and consolidating high-dose chemotherapy in general. However, this approach is known to induce severe long-term toxicities and has limited efficacy in patients failing first-line treatment for advanced stage disease. We conclude that there is a need to develop different treatment approaches in primary progressive HL patients. Disclosures von Tresckow: Novartis: Consultancy, Other: Travel and accomodation, Research Funding; Amgen: Other: honoraria for preparation of scientific educational events; Celgene: Other: honoraria for preparation of scientific educational events; Takeda: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Engert:Takeda: Consultancy, Research Funding. Borchmann:Millennium: Research Funding.
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Beksac, Meral, Simona Iacobelli, Linda Koster, Didier Blaise, Jan J. Cornelissen, Péter Reményi, Xavier Leleu, et al. "A Novel Early Relapse Prediction Score Based on Age, ISS and Disease Status at the Time of Transplant in Patients with Newly Diagnosed Multiple Myeloma. a Study of the EBMT Chronic Malignancies Working Party." Blood 138, Supplement 1 (November 5, 2021): 3937. http://dx.doi.org/10.1182/blood-2021-147001.
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Abstract Rationale and Aim: In patients with Myeloma, early relapse following Autologous Haematopoietic Cell Transplantation (Auto-HCT) is a poor prognostic marker. Two groups have published scoring systems to predict early relapse. The CIBMTR score is based on cytogenetics, the bone marrow plasma cell percentage at the time of Auto-HCT and serum albumin. The GIMEMA Simplified early relapse in multiple myeloma (S-ERMM) score is a cumulative score based on a raised serum lactate dehydrogenase (LDH), t(4;14), del17p, low albumin, bone marrow plasma percentage >60%, and lambda light chain. The aim of the current study was to develop a scoring system to predict early relapse post-Auto-HSCT-1 using readily available variables. Study design and statistics: Within the EBMT database, there were 8,206 patients meeting the following eligibility criteria: First auto transplant 2014-2019, Known sex, ISS at diagnosis, cytogenetics analysis at diagnosis, disease status at Auto-HCT, Interval diagnosis-Auto-HCT > 1 month and <= 12 months, conditioning with Melphalan 200 mg/m2 and known information on relapse; tandem auto-allo patients were excluded. The analysis consisted of two steps: (1) Training: modeling based on 4,389 patients (611 events for PFS12) transplanted between 2014 and 2017, with internal validation carried out by bootstrapping; and (2) Testing: the models obtained were applied to 3,817 patients (346 events for PFS12) transplanted in 2018 and 2019 for external validation. The characteristics of the two cohorts are first reported separately and then together (Table 1). Possible adjustment factors analyzed for the prognostic model included Age at Auto-HCT, Known sex, ISS at diagnosis, disease status at Auto-HCT, and time from diagnosis to Auto-HCT. Complete cytogenetic information was not available at the time of this analysis and will be included in the later analysis. The shape of the effect of age and of time from diagnosis to Auto-HCT was investigated both by the analysis of residuals and by applying boot-strap backward selection among different alternatives. The final results were confirmed in a robustness analysis excluding patients undergoing tandem Auto-HCT. Results: Comparison of the training and validation cohorts revealed no relevant differences (Table 1). Importantly, OS and PFS of both cohorts were overlapping with the probability of PFS at 12 months being 83.3% and 86.8%, respectively. The cumulative incidence of relapse at 12 month was 15.7% and 12.1%, respectively. Among patients who relapsed early, this occurred at a median of 6.64 months (0.56-11.99) in the first cohort, and at 5.85 months (0.1- 11.99) in the second cohort. The final model included (1) disease status at Auto-HCT, (2) age at Auto-HCT, and (3) ISS at diagnosis. Considering the order of magnitude of the coefficients, the points attributed in the risk score were: 0 for CR or VGPR; 1 for PR or SD/MR; 3 for Rel/Prog; 0 / 1/ 2 respectively for ISS I / II / III and -1 for Age<=55 yrs; -2 for Age (55-75 yrs]; -3 for Age>=75 yrs. The Hazard Ratio for a +1 point is 1.52 i.e. the risk of early relapse/death increased on average by 52% for each additional point in the score. The distribution of risk scores was as follows: Score= -2 (n=757), -1 (n=1,481), 0 (n=1,358), 1 (n=647), and 2 (n=146). The score allows separation of the PFS12 curves (Figure 1), with the lowest risk group (N=757) having a PFS at 12 months of 91%, and the highest risk group (N=146) having a PFS at 12 months of 65%. Despite some minor differences in the risk factors between the training and validation cohorts, the score has a similar average effect (HR=1.48 i.e. + 48% hazard for each additional point) and worked well in separating the curves, in particular in identifying the patients at high risk of early relapse. Discussion and conclusion: The new EBMT score to predict early relapse post-Auto-HCT uses the easily available variables of age and ISS stage at diagnosis as well as the dynamic variable of response to induction. With this simple approach, we were able to clearly identify patients at high risk of early relapse. To our surprise, older age emerged as a protective factor against relapse. This may reflect a relative selection bias in that older patients with higher risk disease may not have been selected for transplant. Impact of cytogenetics will be presented at the Congress. In conclusion, this novel scoring system is robust and easy to use in routine daily practice. Figure 1 Figure 1. Disclosures Beksac: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy. Blaise: Jazz Pharmaceuticals: Honoraria. Leleu: Karyopharm Therapeutics: Honoraria; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Oncopeptides: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Forcade: Novartis: Consultancy, Other: Travel Support, Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support. Rabin: Janssen: Consultancy, Honoraria, Other: Travel support for meetings; BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings; Takeda: Consultancy, Honoraria, Other: Travel support for meetings. Kobbe: Celgene: Research Funding. Sossa: Amgen: Research Funding. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Schoenland: Pfizer: Honoraria; sanofi: Research Funding; janssen,Prothena,Takeda,: Consultancy, Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.
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Perrot, Aurore, Valérie Lauwers-Cances, Cyrille Touzeau, Olivier Decaux, Cyrille Hulin, Magaret Macro, Anne-Marie Stoppa, et al. "Daratumumab Plus Ixazomib, Lenalidomide, and Dexamethasone As Extended Induction and Consolidation Followed By Lenalidomide Maintenance in Standard-Risk Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM) Patients (IFM 2018-01): A Phase II Study of the Intergroupe Francophone Du Myélome (IFM)." Blood 138, Supplement 1 (November 5, 2021): 464. http://dx.doi.org/10.1182/blood-2021-146040.
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Abstract Introduction Induction therapy followed by autologous stem cell transplantation (ASCT) before maintenance is the standard of care for transplant eligible NDMM patients. The addition of daratumumab to bortezomib, thalidomide, and dexamethasone (VTD) improved response rates and reduced the risk of progression or death compared to VTD alone (Moreau et al, Lancet 2019). Other quadruplet combinations such as carfilzomib, lenalidomide, dexamethasone and daratumumab have also been evaluated, showing high response rates and high levels of MRD negativity (Landgren et al, JAMA Oncol 2021), which seems particularly suitable to high-risk patients. The replacement of bortezomib with ixazomib in an all-oral combination with lenalidomide and dexamethasone (IRD) has been demonstrated to be safe, convenient, and effective in induction and consolidation before and after ASCT (Moreau et al, Blood 2017). The more progressive response kinetics and the very safe profile of ixazomib led to consider daratumumab plus IRD (D-IRD) extended induction and consolidation in standard-risk NDMM patients. We evaluated its safety and efficacy before and after ASCT followed by lenalidomide maintenance as frontline therapy for patients with standard-risk NDMM younger than 66 years (NCT03669445). Methods Patients with standard-risk cytogenetic MM (defined by FISH at diagnosis according to IMWG criteria) received six 21 days-cycles of induction therapy with daratumumab 16 mg/Kg IV at days 1, 8, 15 (cycles 1-4) and days 1 and 15 (cycles 5-6) plus ixazomib 3 mg on days 1, 4, 8 and 11 plus lenalidomide 25 mg on days 1 through 14 and dexamethasone 40 mg on days 1, 8 and 15. Peripheral blood stem cells were collected after cyclophosphamide mobilization, followed by Melphalan 200 mg/m2 and ASCT. D-IRD consolidation started 2 to 3 months after ASCT and consisted in four 28 days-cycles with daratumumab at days 1 and 15, ixazomib 4 mg on days 1, 8 and 15, lenalidomide 25 mg on days 1 to 21 and dexamethasone 20 mg on days 1, 8, 15 and 22 (cycles 7-8) and days 1 and 15 (cycles 9-10). Single agent lenalidomide maintenance was administrated at 10 mg on days 1 through 21 of a 28 days-cycle during 26 cycles. The primary endpoint was the MRD-negativity after consolidation and before maintenance. MRD-negativity was assessed using NGS method with a sensitivity threshold of detection of MM cells up to 10 -6. Secondary objectives were toxicity according to NCI-CTCAE version 5.0, MRD-negativity rates at other timepoints, response rates according to 2016 IMWG criteria as well as PFS, TTP and OS. Results From 12/2018 to 09/2019, 45 patients were enrolled in 10 IFM centers. Median age was 57 years [28-65] and 66.7% were male. Since it was an eligibility criteria, there was no t(4;14), t(14;16) or del(17p). The distribution of ISS scores 1, 2 and 3 was as follows: 40.9%, 38.6% and 20.5%. On 45 patients who initiated the treatment, 43 completed induction, ASCT and consolidation and 42 started maintenance. All patients responded (ORR 100% [CI 92.1-100.0]) and the best response was sCR or CR in 53.4%, VGPR in 40% and PR in 6.7% of the patients. For the primary endpoint 38 patients were evaluable at 10 -6 after consolidation and the MRD-negativity rate was 39.5% ([CI 26.1-54.1]; p=0.137). At a sensitivity of 10 -5 (IMWG criteria) the MRD negativity rate was 51.4% ([CI 36.8-65.7]; p=0.005). Response rates deepen with time, regarding IMWG categories as well as MRD-negativity rates (Figure). After a median follow up of 23.6 months, 2 patients experienced disease progression. The PFS rate at 24 months was 95.2% [CI 82.1-98.8]. Serious adverse events occurred in 15 (33.3%) patients and grade 3/4 event in 28 (62.2%). The most common grade 3-4 toxicities were neutropenia (28.9%), thrombocytopenia (11.1%) and infections (15.6%). Moderate peripheral neuropathy (35.6%; no grade 3-4), gastrointestinal disorders (4.4% grade 3-4) and rash (28.9%; no grade 3-4) were also described. No deaths or secondary primary malignancies were reported to date. Conclusion D-IRD as extended induction prior to, and as consolidation following ASCT was safe and allows gradually deepening responses in standard-risk MM, with 39.5% of patients with MRD negativity at 10 -6 after consolidation, 2-year PFS at 95.2% and 2-year OS at 100%. MRD-negativity rates are lower than those obtained with D-VTD or D-KRD; more follow-up is needed to confirm PFS and OS data. Figure 1 Figure 1. Disclosures Perrot: Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria. Hulin: Janssen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; abbvie: Honoraria. Macro: Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding. Karlin: Abbvie: Honoraria; Takeda: Honoraria, Other: member of advisory board; Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; GSK: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Janssen: Honoraria, Other: member of advisory board, travel support; oncopeptide: Honoraria. Roussel: Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; BMS: Honoraria; Takeda: Consultancy; Amgen: Consultancy. Guillemot: Takeda: Honoraria. Avet-Loiseau: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: Janssen: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria. OffLabel Disclosure: The quadruplet Dara-Ixa-Len-Dex is not approved in newly diagnosed multiple myeloma.
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Rücker, Frank G., Mridul Agrawal, Andrea Corbacioglu, Daniela Weber, Silke Kapp-Schwoerer, Verena I. Gaidzik, Nikolaus Jahn, et al. "Measurable Residual Disease (MRD) Monitoring in Acute Myeloid Leukemia (AML) with t(8;21)(q22;q22.1) RUNX1-RUNX1T1 Identifies Patients at High Risk of Relapse: Results of the AML Study Group (AMLSG)." Blood 134, Supplement_1 (November 13, 2019): 2740. http://dx.doi.org/10.1182/blood-2019-125584.
Full textAbstract:
Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1) resulting in the RUNX1-RUNX1T1 gene fusion is considered favorable in the 2017 genetic risk stratification by the European LeukemiaNet (ELN). After intensive chemotherapy most patients (pts) achieve complete remission (CR), but relapse occurs in about 50% and is associated with poor prognosis. In this AML subgroup monitoring of measurable residual disease (MRD) has been shown to identify pts at higher risk of relapse. Aims: To assess the prognostic impact of MRD monitoring in bone marrow (BM) and peripheral blood (PB) in a large cohort of 155 clinically well-annotated t(8;21)-AML pts enrolled in one of six AMLSG treatment trials. Methods: RT-qPCR was used to quantify RUNX1-RUNX1T1 transcript levels (TL) reported as normalized RUNX1-RUNX1T1 values per 106 transcripts of the housekeeping gene B2M. Samples were analyzed in triplicate, the sensitivity was up to 10-6. Results: While pretreatment RUNX1-RUNX1T1 TL did not impact prognosis, both reduction of RUNX1-RUNX1T1 TL and achievement of MRD negativity (MRDneg) at end of treatment (EOT) were of significant prognostic importance in BM as well as in PB: MR2.5 (>2.5 log reduction) after treatment cycle 1 and MR3.0 after cycle 2 were significantly associated with a reduced relapse risk (MR2.5, BM: P=.034; PB: P=.008 and MR3.0, BM: P=.028; PB: P=.036, respectively). After completion of therapy, MRDneg was an independent favorable prognostic factor for cumulative incidence of relapse (CIR) (4-year CIR BM: 17% vs 36%, P=.021; PB: 23% vs 55%; P=.001) and overall survival (OS) (4-year OS rate BM: 93% vs 70%, P=.007; PB: 87% vs 47%; P<.0001). Moreover, maximally selected Gray´s statistic defined specific MRD cut-offs at EOT associated with a lower relapse risk: <83 RUNX1-RUNX1T1 TL in BM and <5 in PB predicted for superior 4-year CIR (BM: 18% vs 61%; P<.0001; PB: 23% vs 65%; P<.0001). During follow-up serial MRD analyses allowed prediction of relapse in 77% of pts exceeding an arbitrary cut-off of 150 RUNX1-RUNX1T1 TL in BM and in 84% of pts with >50 TL in PB, respectively. KIT mutation observed in 28% of pts predicted for lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TL during treatment. To determine whether PB could provide similar prognostic information as BM, we compared 680 paired samples (diagnosis, n=125; after cycle 1, n=80; after cycle 2, n=86; at EOT, n=78; during follow-up, n=311). At diagnosis RUNX1-RUNX1T1 TL tended to be slightly higher in BM than in PB (P=.072), but were significantly higher after cycle 1 (P=.008), cycle 2 (P<.001), at EOT (P=.002), and during follow-up (P<.001). RUNX1-RUNX1T1 TL in BM and PB correlated well (r=.87; P<.0001) with on average 1-log lower values in PB. However, 2.5%, 26.7%, 26.9%, and 24.8% of all pairs were discrepant (BMpos/PBneg or BMneg/PBpos) after cycle 1, cycle 2, at EOT, and during follow-up. Of 104 PBneg samples obtained during treatment, 46 (44%) were still BMpos. In the post-treatment period, this fraction decreased to 28% (77 BMpos/276 PBneg pairs) (P=.003). Of note, RUNX1-RUNX1T1 TL in all but four of the 77 (5.2%) BMpos samples were below the cut-off of 150 TL. Virtually all relapses occurred within one year after EOT with a very short latency from molecular to morphologic relapse strongly suggesting to perform MRD assessment at short intervals during this period. Based on our data we refined the practical guidelines for MRD assessment in RUNX1-RUNX1T1-positive AML: i) along with the current ELN MRD recommendations, BM and PB should be analyzed after each treatment cycle; ii) during the follow-up period, in particular the first year after EOT, MRD monitoring in PB should be performed monthly; in pts with TL >50 in PB, increase of MRD TL >1-log, and/or conversion from MRDneg to MRDpos a complementary BM samples should be analyzed timely. Summary: RUNX1-RUNX1T1 MRD monitoring allows for the discrimination of pts at high and low risk of relapse. MRDneg in both BM and PB after completion of therapy was the most valuable independent favorable prognostic factor for relapse risk and OS. During follow-up, serial MRD analyses allowed the definition of cut-offs predicting relapse. Moreover, considering that virtually all relapses occurred within the first year after EOT with a very short latency from molecular to morphologic relapse MRD assessment in PB at shorter intervals during this period is indispensable. Disclosures Weber: Celgene Corporation: Research Funding. Schroeder:Celgene Corporation: Consultancy, Honoraria, Research Funding. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Fiedler:Amgen, Pfizer, Abbvie: Other: Support in medical writing; Amgen, Pfizer, Novartis, Jazz Pharmaceuticals, Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Amgen, Jazz Pharmaceuticals, Daiichi Sanchyo Oncology, Servier: Other: Support for meeting attendance. Greil:Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sandoz: Honoraria. Krauter:Pfizer: Honoraria. Bullinger:Amgen: Honoraria; Astellas: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Hexal: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Menarini: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Bayer: Other: Financing of scientific research; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria. Paschka:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Other: Travel expenses, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel expenses; Janssen: Other: Travel expenses; Abbvie: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Astellas: Membership on an entity's Board of Directors or advisory committees. Döhner:AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; Celgene, Novartis, Sunesis: Honoraria, Research Funding; AROG, Bristol Myers Squibb, Pfizer: Research Funding. Döhner:Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria; Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria.
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Neukirchen, Judith, Pia Arat, Charlotte Teutloff, Celina Gerrlich, David Lopez y Niedenhoff, Amelie Boquoi, Ingrida Savickaite, et al. "Favourable Outcome of Elderly Patients with Multiple Myeloma Treated with Tandem Melphalan 100 High-Dose Therapy, Autologous Stem Cell Transplantation and Novel Agents - a Single Center Experience." Blood 128, no. 22 (December 2, 2016): 3460. http://dx.doi.org/10.1182/blood.v128.22.3460.3460.
Full textAbstract:
Abstract Introduction: High-dose therapy (HDT) with autologous peripheral blood (PB) stem cell transplantation (SCT) is currently standard of care in patients with multiple myeloma (MM) who are younger than 65 years. In patients older than 65 years, HDT compared to thalidomide-containing chemotherapy had no advantage in one phase III trial and up to date no further phase III trials comparing HDT with other novel agents in elderly patients have been published. As a transplant center we believe that HDT is still benefitting elderly patients, despite an increasing number of new alternative drugs for the treatment of patients with MM. As we treated elderly patients with HDT and autologous SCT since 2000 on a regular basis, we wanted to analyze the impact of this treatment strategy on outcome in elderly patients over the time. Methods: We retrospectively analyzed 437 patients who received first-line HDT and autologous PBSCT at our institution between Feb 2000 and Feb 2014 in order to compare the outcome of patients according to age. Eligibility for HDT in our center was not based on chronological age but on general biological fitness as reflected by comorbidities. Results: Median age was 54 years (range: 30-65) in 345 patients categorized as "young", and 68 years (range: 66-75) in 92 "elderly" patients. In young vs elderly patients, the prevalence of ISS stage 3 was 17% and 26%, respectively (p=0.02), and the frequency of high-risk FISH cytogenetics was 40% and 38%, respectively (p=0.5). Treatment consisted of conventional (62% vs 47%) or bortezomib-containing (38% vs 53%) induction therapy, 1-2 cycles of cyclophosphamide-containing stem cell mobilization, and HDT with melphalan 200 in young and tandem melphalan 100 in elderly patients, followed by autologous SCT. In both groups, 8.5% of patients received single melphalan 140 due to renal insufficiency or other toxicity concerns. Maintenance treatment with lenalidomide was given in 32% of the young and 44% of elderly patients, respectively (91 and 34 patients). There was no significant difference between young and elderly patients of treatment-related mortality (3.0% vs 2.2%, p=0.5) or response rates at 100 days after HDT (16% vs 20% CR, p=0.8). After a median follow-up of 50 months, there was no difference in median PFS (38 vs 44 months, p=0.4) and median OS (95 vs 85 months, p=0.8). The same was true for subgroup analysis of patients with either good or poor prognostic markers, like ISS stage or FISH. Interestingly, looking at the time periods 2000-2007 and 2008-2014, we found a more pronounced improvement of median PFS over time in elderly (28 vs 58 months, p<0.0001) than in young patients (34 vs 41 months, p=0.04). Of note, the difference in PFS between elderly and younger patients was significant before the year 2007 (p=0.004) and became undetectable with increasing use of novel agents in combination with HDT (p=0.2). There was a trend for an improvement of median OS before and after 2007 from 70 to 84 months for the elderly group (p=0.3), and from 83 to 116 months for the younger patients (p=0.2). Looking at defined treatment protocols instead of time periods, we could observe that patients treated with HDT preceded by bortezomib-containing induction therapy and followed by lenalidomide maintenance were no longer subject to an influence of age on treatment outcome. The 4-year-PFS was 70% and 77% (p=0.7) and the 4-year-OS was 87% and 90% (p=0.9) in young and elderly patients, respectively. Conclusion: In our single center experience, we could demonstrate a significant improvement of PFS and a trend for OS especially in elderly patients aged 66-75 years treated with first-line tandem melphalan 100 HDT and autologous SCT from 2000 to 2014. Two factors did not change over time, namely selection of appropriate candidates for HDT, based on comorbidities and performance score, and toxicity of HDT in terms of TRM. In our view our results are based on the addition of novel agents to HDT regimen such as bortezomib for induction therapy and lenalidomide as maintenance treatment. The combination of novel agents and HDT had an equalizing effect with regard to the prognostic impact of age. Further, treatment outcomes with a HDT regimen including bortezomib and lenalidomide seems to be superior to other standard therapies for elderly patients such as VMP or Ld. We conclude that, despite the availability of several new drugs, HDT is still a useful treatment option for selected patients beyond the age of 65. Disclosures Neukirchen: Celgene: Other: Travel support. Gattermann:Novartis: Consultancy, Honoraria, Other: travel, accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Kobbe:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding. Fenk:Celgene: Honoraria, Other: travel support, Research Funding; Jansen: Honoraria, Other: travel support.
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Kvasnicka, Hans Michael, Juergen Thiele, Carlos E. Bueso-Ramos, William Sun, Ahmad Naim, Smitha Svaraman, Jessy Gao, et al. "Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients with Myelofibrosis (MF) Enrolled in the COMFORT-I Study." Blood 128, no. 22 (December 2, 2016): 1949. http://dx.doi.org/10.1182/blood.v128.22.1949.1949.
Full textAbstract:
Abstract Background: MF is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, cytopenias, debilitating symptoms, and progressive BM fibrosis The 2 phase 3 COMFORT studies have shown that RUX, an oral Janus kinase (JAK) 1/JAK2 inhibitor, improves splenomegaly, constitutional symptoms, and overall survival in patients with MF. Accumulating evidence suggests that RUX may also modulate the BM microenvironment. Aims: We evaluated the effects of long-term RUX treatment on changes in BM fibrosis in patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who were enrolled in the phase 3 COMFORT-I study. Methods: BM biopsies were obtained at baseline (BL), Weeks 48 and 72, and approximately every 48 weeks thereafter for up to 5 years of RUX treatment. Biopsies were reviewed independently in a blinded fashion (blinded for patient and treatment) by 3 hematopathologists (HMK, JT, and CEB-R). The final grading was based on consensus; no disagreements were recorded. The WHO grading system was used to grade BM fibrosis density based on a scale of 0-3 (Thiele et al, Haematologica 2005;90). Other details on the patient population and study design for the COMFORT-I study have been published previously (Verstovsek et al, N Engl J Med 2012;366). Biopsies from 59 patients were included in this exploratory analysis; patients who failed screening or received only 1 BM measurement were excluded. Three subgroups were defined for the analysis: 1) originally randomized to RUX (n=36); 2) randomized to placebo with BM measurements at BL and Week 48 (n=15); and 3) crossover to RUX with BM measurements at BL and ≥1 post-BL measurement after crossover (n=21). Changes from BL in BM fibrosis grades at various time points were categorized for each patient as improvement (-1 to -3), stabilization (0), or worsening (1 to 3). Patients with a BL score of 0 for improvement and 3 for worsening were excluded from the analysis. Patients who received placebo for ≥36 weeks were included in the crossover group, with Week 48 used as the BL BM measurement. RUX and crossover groups were combined for evaluation of RUX effect. Placebo effect in the crossover group was assessed by analyzing change from BL to Week 48. Change from BL was evaluated using a signed rank test. Change from BL to last grade, and time to the first occurrence of a ≥1 grade improvement from BL was assessed for RUX and crossover groups. KM analysis was used to estimate time to improvement in BM fibrosis for a subgroup of patients who had a BM fibrosis grade of ≥1 at BL. Results: BL characteristics for age, gender, International Prognostic Scoring System risk, spleen volume, hemoglobin, and platelet counts were similar between the 3 groups. At BL, of 36 patients originally randomized to RUX, 17% (n=6) presented with WHO-defined fibrosis grade 1, 39% (n=14) with grade 2, and 36% (n=13) with grade 3 (3 patients were grade 0). Of the 15 patients randomized to placebo, 20% (n=3) presented with grade 1, 40% (n=6) with grade 2, and 27% (n=4) with grade 3 WHO-defined fibrosis at BL (2 patients were grade 0). Mean exposure to RUX in the RUX and crossover groups was 136.0 (SD, 67.4) weeks and 129.1 (SD, 67.7) weeks, respectively. The proportion of evaluable patients with an improvement in BM fibrosis from BL to Week 48 was 26% (n=27) in the RUX group and 15.4% (n=13) in the placebo group. When evaluating all patients who received RUX (including placebo crossover), a significant shift was observed from BL to the last change in BM fibrosis grade (P=0.0119; signed rank test). For all RUX-treated patients (n=57), 33% (grade -1, n=11; -2, n=7; -3, n=1) had an improvement, 49% had no change or stabilization, and 18% had a worsening in BM fibrosis from BL to the last grade (Figure). At the final grading, 82% (n=47) of patients had improvement or stabilization while on RUX. Median time to a ≥1 grade improvement in BM fibrosis grade was approximately 3.5 years (95% CI, 2.5 to 4.5; n=51). Conclusions: This analysis from the COMFORT-I study showed that treatment with RUX was associated with improvement and stabilization in WHO-defined BM fibrosis in the majority of patients with MF in this study cohort. These results support evidence from other studies, suggesting that RUX treatment may contribute to disease-modifying effects in MF. The clinical effect of improvement and stabilization in BM fibrosis requires further study. Disclosures Kvasnicka: Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; AOP Pharma: Consultancy, Honoraria. Thiele:Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria. Sun:Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Svaraman:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dao:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Winton:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek:AstraZeneca: Research Funding; Roche: Research Funding; Celgene: Research Funding; Lilly Oncology: Research Funding; Galena BioPharma: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Geron: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Genentech: Research Funding.
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Thieblemont, Catherine, Loïc Chartier, Ulrich Dührsen, Umberto Vitolo, Sally F. Barrington, Laetitia Vercellino, Jan Zaucha, et al. "The Combination of High Total Metabolic Tumor Volume and Poor ECOG Performance Status Defines Ultra-High Risk Diffuse Large B-Cell Lymphoma. Validation across Multiple Cohorts of Large Clinical Trials and in Real World." Blood 136, Supplement 1 (November 5, 2020): 30–31. http://dx.doi.org/10.1182/blood-2020-136544.
Full textAbstract:
Background. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is currently considered as the standard of care for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, three-year progression-free survival (PFS) and overall survival (OS) rates remain at 60% and 70%, respectively. We recently reported a new tool to help the early identification of ultra-high risk DLBCL patients1. This tool was identified in a cohort of 301 patients included in the REMARC study, responders to R-CHOP, and was based on a combination of 2 factors at baseline: 1/ total metabolic tumor volume (TMTV) above 220cm3 measured on baseline 18FDG-PET and 2/ elevated ECOG PS ≥2. Here, we validated this combination in multiple cohorts including two large clinical trials and in real world. Methods: We evaluated the combination TMTV-PS in a series of 2306 patients with DLBCL including patients treated in clinical trials in Europe and the United States; PETAL (n= 510) and GOYA (n=1315) and 481 patients treated in Real world (RW) across multiple centers in Europe (France, Poland, Portugal, UK). All patients were treated with a combination of immuno-chemotherapy with curative intent (Rituximab (R) or Obinutuzumab (0)-CHOP (R-CHOP n= 70%%, O-CHOP n= 29 %, and intensified regimen n=1%). Patients in PETAL were treated by a PET-guided strategy. Associations of TMTV and ECOG PS at baseline were explored with the International Prognostic Index (IPI) and outcome. Results. For the PETAL, GOYA, and RW series, the median age was 62 (18-80), 62 (18-86), and 65 (17-92), and 55%, 58%, 60%, were > 60y respectively. ECOG PS>2 was present in 11%, 12%, 23% of the patients; IPI 3-5 in 38%, 44%, 51%; TMTV>220 in 45%, 61%, 44%, respectively. The combination of TMTV>220cm3 and ECOG PS>2 defined in PETAL, GOYA, and RW, patients with no risk factor representing 53%, 37% and 49% of the patients, one risk factor (either TMTV> 220cm3 or ECOG PS>2) representing 38%, 53.5%, 35% of the patients, and two risk factors representing 9%, 10%, and 16%, respectively. Patients with 2 risk factors had a significantly worse PFS than patients with 0 or 1 risk factor in the PETAL, GOYA and RW series, HR=3.32 (95% CL: 2.0-5.5); HR=2.68 (95% CL: 2.0-3.6), HR=4.06 (95% CL : 2.7-6.1), respectively. Overall survival was also significantly worse in patients with 2 risk factors than patients with 0 or 1 risk factor, HR=3.85 (95% CL: 2.2-6.8); HR=3.16 (95% CL: 2.2-4.5), HR=5.23 (95% CL: 3.4-8.1), respectively. The combination of TMTV-PS performed better than IPI with a positive C-Index for PFS and OS across all the series, PETAL, GOYA, and RW (figure 1) Conclusion. The combination of TMTV and ECOG PS improves risk stratification for patients with DLBCL treated in frontline by standard treatment or intensified immuno-chemotherapy. This observation meets an unmet need for early and better identification of ultra-high risk DLBCL patients. Disclosures Thieblemont: Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Dührsen:Gilead/Kite: Consultancy, Honoraria; Alexion: Honoraria; CPT: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: travel, accomodations, expenses; Janssen: Consultancy, Honoraria, Other: travel, accomodations, expenses. Vitolo:Roche: Honoraria, Other: travel, accomodations, expenses; Jansen: Honoraria. Zaucha:Cellgene: Other: travel, accomodations, expenses; Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses; Takeda: Consultancy, Honoraria, Other: travel, accomodations, expenses; BMS: Consultancy; Novartis: Consultancy. Maria:Gilead: Consultancy, Other: travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Other: travel, accomodations, expenses; MSD: Consultancy; BMS: Consultancy; Roche: Consultancy, Other: travel, accomodations, expenses; Abbvie: Consultancy, Other: travel, accomodations, expenses. Decazes:Bayer: Other: travel, accomodations, expenses. Tilly:BMS: Honoraria. Casasnovas:MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Amgen: Consultancy, Honoraria. Hüttmann:University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Lead Discovery Center GmbH: Consultancy; Gilead: Honoraria; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Seattle Genetics: Research Funding; Roche: Other: Travel expenses. Schmitz:Abbvie: Other: travel. Paulson:F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Meignan:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).
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Landgren, Ola, Melissa Alsina, Noa Biran, David H. Vesole, Paul K. Wallace, Belle Fang, Gregory Arnold, Amy Kimball, and David S. Siegel. "Assessment of Minimal Residual Disease in a Phase 1b Study of Once-Weekly Carfilzomib Combined with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 28. http://dx.doi.org/10.1182/blood-2020-133803.
Full textAbstract:
Introduction: While minimal residual disease (MRD) negativity is not yet an established regulatory surrogate for a clinical endpoint in multiple myeloma (MM), it does have value as a prognostic biomarker and in assessing disease status. Previously we reported results from a phase 1b trial that described the safety and efficacy of the triplet regimen carfilzomib (given weekly), lenalidomide, and dexamethasone (KRd) in patients with relapsed and/or refractory MM (RRMM) or newly diagnosed MM (NDMM) (Biran et al, Am J Hematol 2019;94:794-802; Alsina et al, Clin Lymphoma Myeloma Leuk 2019;19:Suppl E52). Here, we evaluate MRD status by flow cytometry after treatment with weekly KRd in this trial. Methods: A total of 56 patients with RRMM and 51 with NDMM were enrolled and treated with weekly KRd. Treatment was given in 28-day cycles. Carfilzomib was given on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, and 15 (also day 22 for cycle 1-8). In the NDMM cohort, patients were enrolled regardless of transplant eligibility, and treatment interruption for mobilization and collection with or without autologous stem cell transplant was allowed after cycle 4. Per the protocol, aspirate was collected for flow cytometry evaluation at two separate endpoints: at cycle 8 day 1 (C8D1); and at the time when laboratory data supported a response of complete response (CR) or better (on the basis of negative immunofixation on serum and urine). Sample quality was assessed by several measures (including the presence of mast cells, erythroid precursors, and immature B cells), and viability was determined using a flow assay. Adequate samples were tested for MRD using 8-color flow cytometry in two tubes, with a sensitivity of 10-5. MRD was reported as positive when a minimum of 2 x 106 CD138+ cells per tube were evaluated, and ≥ 20 abnormal events detected. Results: Overall, 58 of 79 (73.4%) study-specified samples were obtained and evaluated by flow cytometry. Of the NDMM patients, 15 had bone marrow aspirate evaluable for MRD at C8D1 (in total 22 patients were treated to C8D1), and 12 had bone marrow aspirate evaluable for MRD at the time of CR (14 patients achieved CR). At C8D1, 53% (8/15) of NDMM patients with flow data achieved MRD negativity, and at time of CR, 83% (10/12) of NDMM patients were MRD negative (the remaining patients with flow data were determined to be MRD positive). Among the 12 NDMM patients evaluated for MRD at time of CR, 17% had high-risk cytogenetics, 58% had standard-risk cytogenetics, and 25% had unknown cytogenetic risk status. Of the RRMM patients, 26 had bone marrow aspirate evaluable for MRD at C8D1 (30 patients were treated to C8D1), and five had bone marrow aspirate evaluable for MRD at the time of suspected CR or better (in total 13 patients achieved CR). Of RRMM patients with available flow data at time of CR, 40% (2/5) achieved MRD negativity, and of those with flow data at C8D1, 50% (13/26) achieved MRD negativity. Of all patient samples evaluated for MRD, 67% of NDMM and 48% of RRMM samples were MRD negative. The results reported here are directionally comparable to the rates of MRD-negative CRs observed in previous studies of twice-weekly KRd in NDMM (Jasielec J et al, Blood 2014;124:2127; Kazandjian D et al, JAMA Oncol 2018;4:1781-1783; Zimmerman T et al, Blood 2016;128:675). Our findings are limited by incomplete acquisition of samples to support a full MRD analysis per protocol (approximately 73% of the intended time point samples were acquired). Additionally, we reported MRD status without censoring for missing MRD data, as would be required to analyze MRD for a randomized controlled trial to eliminate acquisition bias. A robust comparison of MRD-negative CR rates between regimens would require an RCT with full MRD sampling, and sensitivity analyses that treat missing MRD data as MRD-positive (Chari A et al, Blood 2017;130:974-981; Voorhees PM et al, Blood 2020). Conclusions: We have previously shown that once-weekly KRd is active and has acceptable toxicity in both the RRMM and NDMM settings. We found that among MRD-evaluable patients who had a CR or better, MRD negativity rates were impressive in both the NDMM setting (83%) and in the RRMM setting (40%), suggesting that the weekly KRd regimen can induce MRD-negative CRs in both settings. Disclosures Landgren: Adaptive: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Merck: Other; Cellectis: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Other; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Seattle Genetics: Research Funding. Alsina:Janssen: Honoraria, Speakers Bureau; BMS: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Honoraria, Speakers Bureau. Biran:Janssen: Consultancy, Honoraria, Other: reimbursement of travel and accomodation, Research Funding, Speakers Bureau; KAryopharma: Research Funding; Sanofi: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: reimbursement of travel and accomodation, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: reimbursement of travel and accommodation, Research Funding, Speakers Bureau. Vesole:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Speakers Bureau; Janssen: Speakers Bureau; BMS: Speakers Bureau. Fang:Amgen: Current Employment, Current equity holder in publicly-traded company. Arnold:Amgen: Current Employment, Current equity holder in publicly-traded company. Kimball:Amgen: Current Employment, Current equity holder in publicly-traded company; WindMIL Therapeutics: Current equity holder in private company. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. OffLabel Disclosure: Carfilzomib is a proteasome inhibitor that can be used for the treatment of relapses/refractory multiple myeloma
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Hrusak, Ondrej, Valerie De Haas, Ales Luks, Iveta Janotova, Ester Mejstrikova, Kirsten Bleckmann, Anja Moricke, et al. "Acute Leukemia of Ambiguous Lineage: A Comprehensive Survival Analysis Enables Designing New Treatment Strategies." Blood 128, no. 22 (December 2, 2016): 584. http://dx.doi.org/10.1182/blood.v128.22.584.584.
Full textAbstract:
Abstract Acute leukemia (AL) of ambiguous lineage (AMBI-L) comprises up to 5% of AL cases in both children and adults. Although several definitions exist, a general treatment guideline has been missing. Single country studies usually report fewer than 50 cases of children or adults. Accordingly, the international iBFM AMBI2012 Study/Registry collected 275 AMBI-L cases in patients <18y from Australia, Austria, Brazil, Czechia, Germany, Greece, Israel, Italy, Netherlands, NOPHO (Denmark, Estonia, Finland, Norway, Sweden, Iceland, Latvia and Lithuania), PINDA (Chile), Poland, SAHOP (Argentina), Slovakia, St. Jude's Children Research Hospital (USA), Texas Children's Cancer Center (USA), Ukraine and United Kingdom. Each center/country reported all consecutive patients with AMBI-L from a 2 to 13 year period ending May 31, 2015. Apart from the study itself, the central database served also as a basis for consulting individual patients during the diagnostic workup. Preliminary results of this study were first introduced in ASH 2015 and now the complete detailed analysis of updated findings including significance of immunophenotype, molecular genetics, blast clearance and transplant are shown. In total, 275 patients were included in the study. Of these, 240 fulfilled the definitions of biphenotypic/mixed phenotype AL, partially overlapping with cases in whom two clones had been identified (n=68) and 15 cases presented with undifferentiated AL. Most patients started their treatment with an ALL-type protocol (n=161), 79 with AML therapy, 27 with a combined regimen, including the Interfant protocols, 2 patients were not treated, 2 received other treatment, and in 4 patients such information was missing. The 5yEFS of the entire cohort was 56±3.7% and 5y overall survival was 67±3.3%. Patients treated by ALL-type protocols had superior 5 year event free survival (5yEFS) (70±4.6%, n=158) compared to those who started AML-type treatment (5yEFS: 40±6.4%, n=78) or hybrid ALL/AML treatment (5yEFS: 50±11%, n=27). Although protocol selection was likely biased, we recommend ALL treatment, when diagnostic findings, including molecular genetics, fail to indicate AML therapy. Although myeloperoxidase (MPO) has been used as the ultimate marker of myeloid lineage, patients who started with ALL-type treatment demonstrated a better prognosis even among cases classified as MPOpos/part pos (Fig. 1). These differences by initial choice of treatment are most prominent when CD19pos/part pos cases are analyzed regardless of the overall lineage (Fig. 2). This shows that at least for CD19pos/part pos cases in the absence of RUNX1/RUNX1T1 fusion, treatment should not start with current AML-type protocols. Until week 12, patients with higher leukemia burden were slightly overrepresented compared to non-AMBI ALL patients (data not shown). In addition, patients with higher residual disease had a much poorer prognosis. Thus, Prednisone poor and good responders (based on day 8 blood blast counts) had a 5yEFS of 50±9.7%, n=38 and 81±5.8%, n=82, respectively (p=0.005). By day 15 bone marrow (BM), only cutoffs of 10-4 and 10-3 were analyzed and neither showed significant associations with EFS. At the end of induction, patients with BM residual disease ≥10-3 had a 5yEFS of 51±10%, n=49 compared to 90±4.3% for those with lower levels, n=75 (p=0.0002). Especially higher residual disease at week 12 was associated with an extremely poor EFS (Fig. 3). Early identification of patients with inadequate response and designing alternative treatment for them is our important challenge. No overall benefit of transplantation was seen in patients who started on ALL treatment or hybrid ALL/AML treatment. Again, this may be caused by a biased selection of more severe cases for transplant. In patients who started with AML treatment, transplant appeared to improve prognosis (Fig. 4). This study provides the basis for improved treatment of future patients with AMBI-L, with more accurate diagnostics. OH, AL, IJ, EM and JS were supported by Czech Health Research Council 15-28525A. Disclosures Bleckmann: JazzPharma: Other: financial support of travel costs. Moricke:JazzPharma: Honoraria, Other: financial support of travel costs. Inaba:Arog: Research Funding. Kattamis:Novartis: Honoraria, Research Funding; ApoPharma: Honoraria. Reinhardt:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharma: Other: Travel Accomodation; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.
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Muriawan Putra, Agus, and Ida Bagus Ketut Astina. "The Development of Local Accommodation to Support Subak Jatiluwih Tourism in Tabanan Regency." Udayana Journal of Social Sciences and Humanities (UJoSSH) 1, no. 1 (February 28, 2017): 1. http://dx.doi.org/10.24843/ujossh.2017.v01.i01.p01.
Full textAbstract:
The aim of research to develop local accommodations Jatiluwih, so tourists can stay longer in Jatiluwih and the community direct can interacts with tourists and direct benefit also from the tourists who stay. In this research, using qualitative descriptive analysis and the determination of sampling is quota sampling method and method of sampling taking with Slovin method. This research took place in JatiluwihVillage, Penebel District, Tabanan Regency. Key research findings show that there are still many obstacles the development of local Jatiluwih accommodations, such as: human resources, supporting facilities, the presence of the Holy Place, a large family does not agree, and promotions. In addition, in the development of local Jatiluwih accommodations there are several criteria that must be filled according the community, such as: obey with the rules in the village, not allowed in the Holy Place, keep hygiene, improved facilities, the easy of working capital, the coaching routine of related parties and criteria according tourists, such as: hospitality, cleanliness and security, mastery of English, supporting facilities, the willingness to interact with tourists, and the easy of information. Also, some programs in the development of local Jatiluwih accommodations, such as: dissemination to the public, collect data on houses to be used as a local accomodations, training, funding, establish a local accommodations management, preparing tourism package and tourism product of Jatiluwih, and promotions.
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Avet Loiseau, Herve, Pieter Sonneveld, Philippe Moreau, Fritz Offner, Vincent H. J. van der Velden, Denis Caillot, Cyrille Hulin, et al. "Daratumumab (DARA) with Bortezomib, Thalidomide, and Dexamethasone (VTd) in Transplant-Eligible Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM): Analysis of Minimal Residual Disease (MRD) Negativity in Cassiopeia Part 1 and Part 2." Blood 138, Supplement 1 (November 5, 2021): 82. http://dx.doi.org/10.1182/blood-2021-147897.
Full textAbstract:
Abstract Introduction: The 2-part phase 3 CASSIOPEIA study (NCT02541383) investigated the combination of DARA with VTd (D-VTd) in transplant-eligible NDMM pts. D-VTd induction/consolidation (ind/cons) led to increased rates of MRD negativity and prolonged progression-free survival (PFS) compared with VTd (Moreau P, et al. Lancet. 2019;394(10192):29-38). In Part 2, DARA as post-autologous stem cell therapy (ASCT) maintenance significantly improved PFS in pts who received VTd ind/cons. Most common (≥2.5%) grade 3/4 adverse events included pneumonia (DARA: 2.5%; observation [OBS]: 1.4%), lymphopenia (3.6%; 1.8%), and hypertension (3.0%; 1.6%; Moreau P, et al. J Clin Oncol. 2021;39(no. 15_suppl):8004). Here, we present results from a detailed analysis of MRD negativity. Methods: Eligible pts were 18-65 years of age, had NDMM and were ASCT eligible. Pts were randomized 1:1 to 4 (28-day) cycles of pre-ASCT induction and 2 (28-day) cycles of post-ASCT consolidation with D-VTd or VTd (bortezomib, 1.3 mg/m 2 SC on Days 1, 4, 8, 11; thalidomide, 100 mg PO daily; dexamethasone, 20-40 mg IV/PO; ± DARA, 16 mg/kg IV weekly (QW) in Cycles 1-2, Q2W in Cycles 3-6). Pts who completed consolidation and achieved partial response or better were re-randomized 1:1 to maintenance DARA at reduced intensity (DARA, 16 mg/kg Q8W) for a maximum of 2 years, or OBS. Samples were collected for MRD analysis at predefined timepoints from all pts regardless of response to ind/cons and in pts with very good partial response or better during maintenance. The primary MRD assessment methodology was multiparametric flow cytometry during ind/cons and next-generation sequencing during maintenance, each at the 10 -5 threshold. MRD negativity is reported here for pts who achieved complete response or better. Results: 1,085 pts were randomized to ind/cons (D-VTd, n=543 or VTd, n=542) and 886 pts were re-randomized for post-ASCT maintenance (DARA, n=442 or OBS, n=444). The rate of MRD negativity was higher with D-VTd than with VTd following induction (9.2% vs 5.4%; odds ratio [OR], 1.79; P=0.0150) and consolidation (33.7% vs 19.9%; OR, 2.06; P<0.0001). Sustained MRD-negativity was higher in the D-VTd group compared to VTd at 1-year (50.1% vs 30.1%; OR, 2.37; P<0.0001) and at 2 years (35.5% vs 18.8%; OR, 2.41; P<0.0001). Among pts who were at risk of progression 1 or 2 years after induction, those who achieved, respectively, 1- or 2-years sustained MRD negativity from post-induction, showed improved PFS over pts who did not, regardless of treatment (1yr sustained: HR, 0.20; P<0.0001; 2yr sustained: HR, 0.08; P<0.0001). D-VTd pts at risk who achieved 1- or 2-years sustained MRD negativity from post-induction showed improved PFS over D-VTd pts who did not (1yr sustained: HR, 0.20; P<0.0001; 2yr sustained: HR, 0.04; P<0.0001). VTd pts at risk who achieved 1- or 2-years sustained MRD negativity from post-induction showed improved PFS over VTd pts who did not (1yr sustained: HR, 0.40; P=0.0030; 2yr sustained: HR, 0.22; P<0.0046; Figure). During maintenance, the rate of MRD negativity significantly favored DARA over OBS (58.6% vs 47.1%; OR, 1.80; P=0.0001). In pts who received D-VTd ind/cons, the MRD-negativity rates with DARA and OBS were 64.2% and 57.6% respectively (OR, 1.43; P=0.1037). In contrast, pts who had received VTd ind/cons showed significantly higher MRD-negativity rates during DARA maintenance vs OBS (52.6% vs 35.8%; OR, 2.26; P=0.0002). The rates of sustained MRD negativity in the D-VTd group were not significantly different with DARA vs OBS (1yr sustained: 48.5% vs 41.0%; OR, 1.41; P=0.0885; 2yr sustained: 28.8% vs 21.8%; OR, 1.47; P=0.0789). In the VTd group, the 1-year sustained MRD-negativity rate was significantly higher with DARA vs OBS (35.7% vs 21.4%; OR, 2.22; P=0.0006) but no difference was observed in the 2-year sustained MRD rate (11.3% vs 13.0%; OR, 0.83; P=0.5481). Conclusion: In CASSIOPEIA, the highest and most durable rates of MRD negativity were achieved after D-VTd ind/ASCT/cons and DARA maintenance. Reduced intensity (Q8W) DARA maintenance did not significantly improve MRD negativity compared to OBS in patients treated with D-VTd. In patients treated with VTd, DARA maintenance did improve MRD negativity, but this effect was not long lasting. Longer follow-up is required to assess the potential long-term benefits of sustained MRD negativity for DARA vs OBS after D-VTd. Figure 1 Figure 1. Disclosures Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Moreau: Amgen: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. van der Velden: Janssen: Other: Service Level Agreement; BD Biosciences: Other: Service Level Agreement; Navigate: Other: Service Level Agreement; Agilent: Research Funding; EuroFlow: Other: Service Level Agreement, Patents & Royalties: for network, not personally. Hulin: abbvie: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Arnulf: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Karlin: Janssen: Honoraria, Other: member of advisory board, travel support; Abbvie: Honoraria; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Takeda: Honoraria, Other: member of advisory board; Celgene-BMS: Honoraria, Other: member of advisory board; GSK: Honoraria, Other: member of advisory board; oncopeptide: Honoraria. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Perrot: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van De Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy. Krevvata: Janssen: Current Employment. Rigat: Janssen: Current Employment, Current equity holder in publicly-traded company. Yang: Janssen: Current Employment. Vanquickelberghe: Janssen: Current Employment. de Boer: Janssen: Current Employment. Kampfenkel: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Broyl: Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria; Sanofi: Honoraria; Bristol-Meyer Squibb: Honoraria; Amgen: Honoraria. OffLabel Disclosure: The specific regimen combination is not yet approved in the maintenance setting.
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Avet-Loiseau, Herve, Romain Lannes, Aurore Perrot, Céline Mazzotti, Marion Divoux, Titouan Cazaubiel, Xavier Leleu, et al. "In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present from the Diagnosis in Tiny Undetectable Subclones." Blood 138, Supplement 1 (November 5, 2021): 77. http://dx.doi.org/10.1182/blood-2021-146869.
Full textAbstract:
Abstract In multiple myeloma (MM), among the anomalies associated with shorter survival, it should be noted recurrent copy number variations (CNV), such as del(17p13), del(1p32), or 1q gains. These abnormalities are considered secondary, thus acquired during the course of the disease. Although they can be observed from diagnosis, they are only detected at the time of relapses in some patients. It is now clearly demonstrated that MM is a molecular subclonal disease, with the coexistence of different subclones of varying size. As in other cancers, it has also been shown that these different subclones can vary in size according to the different relapses, suggesting that an unnoticed minor subclone at diagnosis could become the major one at the time of relapse. Although subclonality has been largely reported at the mutational level, little is known about this phenomenon at the CNV level. Since a few CNV are associated with a poor outcome, and assuming they will impact the disease course, it would be clinically highly valuable to track these abnormalities at the time of diagnosis in minor subclones. Here, we report the first analysis at the single cell level of CNV of tumor cells from 81 patients with MM analyzed at the time of diagnosis, relapse or pre-symptomatic stages. A total of 52,176 single MM cells were analyzed. The number of analyzable tumor cells was variable from patients to patients, due to heterogeneity in the sample cellularity, but also variability in cell capture rate for the single cell analysis. The mean number of analyzable cells was 656 MM cells per patient (range=83-5192). To avoid possible false positive cases, we arbitrarily defined a subclone by at least 10 cells presenting the same CNV. In these 81 patients, at least one subclone was detected in 74 of them (91%). In this cohort, a subclonal high-risk CNV (not detected on the routine assessment) was observed in 19 patients (23.5%). We had the opportunity to also analyze at single cell level residual MM cells from one patient at the end of induction therapy, and early relapse. This patient displayed a 1q gain subclone at diagnosis (16 % of the analyzed cells), not detected in the bulk analysis. At the post-induction time (thus before high-dose melphalan and autologous stem cell transplantation), 70 % of the 202 analyzable tumor cells presented this high-risk feature. This patient did relapse only 18 months after diagnosis and at this time, 92% of the cells harbored the 1q gain (Figure 1). To address the question whether these high-risk subclonal features may impact outcome as soon as diagnosis, we explored our database. We found that 1q gains are observed in 34.1% of patients (1891/5539) at the time of diagnosis. When analyzing patients at relapse, 46.3% of them displayed a 1q gain (622/1341), thus a 12% increase. This increasing frequency reflects clonal selection of minor subclones already present at diagnosis but not detectable by conventional technique (found in comparable proportions), rather than actual acquisition after diagnosis during evolution of the disease. We then looked at the prognostic impact of 1q gain in patients displaying this CNV at diagnosis versus those presenting it only at the time of first relapse. Interestingly, the PFS and OS) curves were totally superimposable, suggesting that this subclonal 1q gain present from diagnosis in these latter patients impacts survival, possibly through early expansion. In order to go further in the molecular consequences of these high-risk subclones, we did perform single cell RNA-sequencing in 63 of the 81 patients. 1q gains defined specific subclones in the MM cells expression analyses from affected patients. Based on the expression of CDC28 protein kinase regulatory subunit 1B (CKS1B), located at 1q21, we found that high expression was restricted to specific subclones. In conclusion, our study highly suggests that high-risk CNVs are not acquired after, but are present from the diagnosis, and selected by the treatment. These findings may have implications in high-risk definition and patient's management, by reinforcing the therapeutic strategy in these patients as soon as the first line therapy to prevent the clonal selection of these aggressive subclones. Whether this finding could be extended to cancer in general but also in some pre-malignant stages is possible, but needs to be explored. Figure 1 Figure 1. Disclosures Perrot: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leleu: Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Other: Non-financial support; AbbVie: Honoraria. Manier: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Mohty: Novartis: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Pfizer: Honoraria; Jazz: Honoraria, Research Funding. Munshi: Novartis: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Adaptive Biotechnology: Consultancy; Legend: Consultancy; Pfizer: Consultancy.
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Thieblemont, Catherine, Maria Gomes da Silva, Olivier Casasnovas, Hervé Ghesquieres, Gandhi Laurent Damaj, Judith Trotman, Pierre Feugier, et al. "Final Analysis of the International Double-Blind Randomized Phase III Study of Lenalidomide Maintenance in Elderly Patients with DLBCL in Response after R-CHOP, the Remarc Study from Lysa." Blood 136, Supplement 1 (November 5, 2020): 1–2. http://dx.doi.org/10.1182/blood-2020-136511.
Full textAbstract:
Background. R-CHOP is the standard first-line treatment for elderly patients (pts) with diffuse large B-cell lymphoma (DLBCL). However 30% of pts will relapse and 70% of relapsed pts will die within 2 years of diagnosis. The REMARC study (NCT01122472) is an international, multicenter, double-blind, randomized, placebo controlled, phase III trial that assessed the benefit of lenalidomide (LEN) maintenance in response after R-CHOP in pts aged 60 to 80 years with untreated DLBCL, FL3b or transformed lymphoma. The pts were randomized 1:1 to receive 2 years of LEN maintenance (25 mg/day for 21 of every 28 days) or placebo (PBO). The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints were safety, PR to CR conversion rate, and overall survival (OS). We present the final analysis with a median follow-up of 81 months. Methods. From May 2009 to May 2014, 794 pts were enrolled. After R-CHOP therapy, 650 pts were randomized to maintenance with LEN (n=323) or PBO (n=327), either in CR (n= 495) or in PR (n= 152). Median age at diagnosis was 68 y (range 58-80), 43.5% were older than 70 y, and 56% were male. aaIPI was low in 38.5% and high in 57.5% of pts (missing data 4%). COO analyses were performed by both Hans algorithm (n=393) and NanoString technology (n=403). MYC, BCL2, BCL6 rearrangements were assessed by FISH in 169, 161 and 143 pts respectively. Expression of MYC BCL2 and BCL6 by immunohistochemistry in 198 pts, 247 pts and 385 pts Results. The median PFS (according to independent centralized radiology review) was not reached in the LEN group versus 89 months in the PBO group (HR = 0.73 - 95% CL : 0.6-0.9; p=0.01)(See Figure). In the LEN group, 24 pts (35%) converted from PR to CR during maintenance compared to 22 pts (27%) in the PBO group (p=0.29) with a median time of 6.4 months and 5.6 months, respectively. Overall survival data did not show any benefit for LEN arm (HR =1.17, 95% CL: 0.9-1.6; p=0.29), a lack of difference not attributable to an excess of lymphoma relapse, secondary cancer or safety problems in LEN arm. Deaths generally occurred off study drug (median time from last dose of study drug to death was 18 months (range: 1-99) in LEN arm and 25.7 months (range:1-103) in control arm. During maintenance, the most common observed grade 3 or 4 AEs were neutropenia (57% vs. 22%), rash (5% vs. 1%), infections (8% vs. 6%), and thrombocytopenia (2.5% vs. 0.6%) in LEN and PBO arms, respectively. Dose adjustments were necessary in 72% of the LEN pts and 42% of PBO pts. 59% of pts stopped LEN and 39% stopped PBO for toxicity during maintenance. Median number of cycles was 15 in LEN and 26 in PBO arms. Secondary primary malignancies occurred in 56 pts receiving LEN and in 70 pts on PBO. Considering the cohort of pts with ABC profile (n=144), PFS and OS was similar in the LEN group (n=78) compared to the PBO group (n=66), p=0.15 and p=0.59, respectively. Among biological characteristics, GC profile was the only favorable parameter for PFS (HR=0.55, p=0.003) and OS (HR=0.47, <0.001) compared to ABC profile. Multivariate analysis identified PBO arm, age> 70, IPI 3-5, ABC profile, PR after R-CHOP as independent factors for an inferior PFS, and the same variables except treatment arm for OS. Conclusion. The final analysis of the REMARC study shows that 2 years of LEN maintenance in pts responding to R-CHOP significantly improved PFS (primary endpoint) regardless of COO, without a significant impact on OS Figure. Progression free survival - Follow-up : 81.1 months Figure 1 Disclosures Thieblemont: Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Cellectis: Speakers Bureau; Roche, Hospita: Research Funding. Gomes da Silva:Janssen: Consultancy; MSD: Consultancy; BMS: Consultancy; abbvie: Consultancy; roche: Consultancy; Gilead: Consultancy. Casasnovas:Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; abbvie: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Ghesquieres:Janssen: Honoraria; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; CELGENE: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Trotman:F. Hoffmann-La Roche: Research Funding; BeiGene: Research Funding; PCYC: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Feugier:janssen: Consultancy, Honoraria, Research Funding; astrazeneca: Consultancy, Honoraria, Research Funding; gilead: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding; abbvie: Consultancy, Honoraria, Research Funding. Haioun:Amgen: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Roche: Honoraria; Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria. Greil:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding. Caballero:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: travel; BMS: Other: travel; Roche: Other: travel; Gilead: Other: travel; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel. Lopez-Guillermo:roche: Consultancy, Research Funding; gilead: Consultancy, Research Funding; novartis: Consultancy; celgene: Consultancy, Research Funding. Snauwaert:abbvie: Other; janssen: Other: travel; roche: Other: travel. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Heibl:BMS/celgene: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria; AOP orphan: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Catalano:celgene: Other: travel. Cairoli:celgene: Other: travel; roche: Other: travel. Gaulard:innate pharma: Research Funding; takeda: Honoraria, Research Funding. Morschhauser:F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria; Epizyme: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Genentech, Inc.: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tilly:BMS: Honoraria.