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1
Robson, Mark. "Relative influence of contextual factors on deliberation and development of cooperation in community-based forest management in Ontario, Canada." Canadian Journal of Forest Research 44, no. 1 (January 2014): 64–70. http://dx.doi.org/10.1139/cjfr-2013-0294.
Full textAbstract:
Co-management of forests has been reported from more than fifty countries and stakeholder advisory committees have become central to forest planning in Canada. Scientists tend to agree that local users are capable of self-organising to manage resources more effectively than state agencies alone, whether jointly with governments or with considerable autonomy. Little, however, is known about how the network of contextual influences helps, hinders, or overrides the deliberation that facilitates the development of cooperation critical for co-management success. The objectives of the paper are to identify the relative influence of contextual factors, participants’ sense of control over contextual factors, and effects on performance. In a comparative case study of two stakeholder advisory committees in Ontario, Canada, the objectives are addressed by identifying and analysing advisory committee thinking about consensus building using network analysis of group cognitive maps. The paper concludes with three lessons regarding how the mix of hierarchical, market, and community institutions that influence community-based deliberation can be coordinated for effective forest management.
2
Rein, Lindsay A. M., and David A. Rizzieri. "A Phase I Trial of Incorporating Natural Killer (K-NK) Cells for Patients with Chronic Myeloid Leukemia (CML) and Molecular Residual Disease after Tyrosine Kinase Inhibitor (TKI) Therapy." Blood 136, Supplement 1 (November 5, 2020): 5. http://dx.doi.org/10.1182/blood-2020-142062.
Full textAbstract:
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML) ushering in an era where, in select patient populations, treatment planning goals have shifted towards the achievement of treatment free remission (TFR) after TKI cessation. Both duration and depth of response to TKI therapy are predictors of future success in achieving a lasting TFR and with improved outcomes independent of TKI cessation. Unfortunately, molecular residual disease (MRD) persists in many patients despite optimal therapy and predicts for worse outcomes over time and decreased ability to maintain a TFR after TKI cessation. Achievement of a major molecular response (MMR) and probability of TFR have been associated with increased numbers of NK cells, particularly mature cytolytic NK cells. Kiadis K-NK003 cells are off-the-shelf NK cells from a universal donor expanded using PM21, proprietary membrane particles modified to express membrane bound IL-21 and 4-1bb ligand. The resulting expanded K-NK003 cells have a hyperfunctional phenotype that are simultaneously highly cytotoxic with high release of perforin and Granzyme B, and potent producers of the cytokines IFN-γ, TNF-α and IL-2. This is an open label, non-randomized, prospective phase I pilot study designed to evaluate safety and to examine whether the addition of K-NK003 to ongoing TKI therapy for CML patients with persistent MRD will allow patients to achieve MRD negative status. Patients will be treated with K-NK003 on day 1 of each 14 day cycle, for a total of 6 cycles, in conjunction with their ongoing TKI therapy. The primary endpoint is safety. The efficacy objective is to estimate the rate of optimal molecular responses (negative to at least MR4.5). Secondary and exploratory endpoints include the proportion of patients with a reduction in BCR-ABL transcripts and NK cell number and function. Adult patients with chronic phase CML who have been on TKI therapy for at least 1 year prior to enrollment in the study will be eligible. Patients must have been on their most recent TKI consistently for at least 6 months prior to enrollment on study and must be expected to remain on current TKI for the duration of the study. Patients with current accelerated or blast crisis phase disease will be excluded. Disclosures Rein: Celgene: Consultancy; Blueprint Medicine: Consultancy; Novartis: Consultancy; Clinical Care Options: Consultancy, Other: Speaker. Rizzieri:Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; abbvie: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
3
Zhang, Jing, Matthew Hadfield, Helen Swede, Biree Andemariam, and George Lykotrafitis. "Increased Adhesiveness of Red Blood Cells from Sickle Cell Trait Carriers after Exposure to Daunirubicin Breast Cancer Chemotherapeutic Agent." Blood 136, Supplement 1 (November 5, 2020): 5–6. http://dx.doi.org/10.1182/blood-2020-143324.
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Introduction: African-Americans (AA) with breast cancer continue to experience worse morbidity and mortality than white patients. In addition to barriers to care, an active area of investigation has been the etiology of the increased risk adverse events (AEs) related to chemotherapy. An emerging question is if sickle cell trait (i.e., heterozygotes for hemoglobin beta gene), present in an estimated 1 in 12 of the AA population, confers increased susceptibility to chemotherapy-related complications. We posit that conditions of high physiological stress might be manifest during systemic treatment with toxic agents resulting in alterations of red blood cells (RBCs). Using an experimental biomechanical model system, we hypothesized that RBCs from SCT carriers would be prone to increased adhesiveness after exposure to a common systemic anti-cancer agent used in breast cancer. Increased adhesiveness of RBCs can be a precipitating factor of blocked vasculature and subsequent sickling crises, potentially leading to AEs during treatment. Methods: Our study testedex vivoRBCs from two groups of healthy female participants: 20 African-American sickle cell trait carriers (AA-SCT); and 15 white subjects with wild-type hemoglobin (W-WT). Isolated RBCs were treated with scaled Daunorubicin (DNR) doses. The unbinding forces between αvβ3 ligands and intercellular adhesion molecule-4 (ICAM-4) receptors are reported using the frequency distribution, which states the percentage of events whose unbinding forces are within each width of the bin. We then compared the median values of the forces measured in experiments without and with treatment for each drug. The collective frequency (CF%) is related to the population of active ICAM-4 receptors and is defined as the percentage of all unbinding events divided by the total number of measurements, which is 32 × 32 =1024 for each cell multiplied by the number of tested cells for each blood sample. Results: For AA-SCT RBCs, pre-treatment baseline CF of active ICAM-4 receptors was 4.88 ± 0.87%, which was significantly increased after administration of DNR (13.13 ± 2.30%, p<0.0001). In contrast, treatment of W-WT RBCs held the CF of active ICAM-4 receptors at a comparable level as untreated RBCs (9.54 ± 1.48%; 7.47 ± 1.07%, p=0.50, respectively). Conclusion: Our findings could support hypotheses for adhesion-related RBC clumping among AAs with SCT during systemic treatment with anti-neoplastic agents, and, putatively, resultant AEs. Given past studies showing African-American women with breast cancer have higher rates of self-withdrawal from treatment, further exploration with additional systemic agents are warranted. Our novel study is limited by a small sample size as well lack of potential confounding factors in analyses. Future studies are planned with additional agent(s) and AAs without SCT. Should it be confirmed that SCT carrier status predicts RBC alterations during systemic treatment for breast cancer, and are linked to subsequent adverse events, it could lead to precision treatment planning. Disclosures Andemariam: Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Hemanext:Membership on an entity's Board of Directors or advisory committees;Global Blood Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Vertex:Honoraria;Imara:Research Funding;Emmaus:Membership on an entity's Board of Directors or advisory committees;bluebird bio:Consultancy, Membership on an entity's Board of Directors or advisory committees;NovoNordisk:Consultancy, Membership on an entity's Board of Directors or advisory committees;CRISPR/Vertex:Consultancy, Membership on an entity's Board of Directors or advisory committees;CHNCT:Consultancy;Accordant:Membership on an entity's Board of Directors or advisory committees;Guidepoint:Honoraria;Sanofi Genzyme:Consultancy, Membership on an entity's Board of Directors or advisory committees;Terumo BCT:Consultancy, 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;Cyclerion:Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees.
4
Allan, John N., William G. Wierda, Krish Patel, Susan M. O'Brien, Anthony R. Mato, Matthew S. Davids, Richard R. Furman, et al. "Preliminary Safety, Pharmacokinetic, and Pharmacodynamic Results from a Phase 1b/2 Dose-Escalation and Cohort-Expansion Study of the Noncovalent, Reversible Bruton's Tyrosine Kinase Inhibitor (BTKi), Vecabrutinib, in B-Lymphoid Malignancies." Blood 132, Supplement 1 (November 29, 2018): 3141. http://dx.doi.org/10.1182/blood-2018-99-116382.
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Abstract Background: Vecabrutinib (formerly SNS-062, the succinate salt of vecabrutinib) is a reversible, noncovalent BTKi that has demonstrated in vitro activity in BTK wild-type and C481S mutated cells (Binnerts AACR-NCI-EORTC 2015; Fabian AACR 2017; Libre EHA 2018). Acquired mutations of BTK at C481 (BTK C481), the covalent binding site for ibrutinib, were reported prior to, and at, clinical progression in ibrutinib-treated patients (pts); therefore, vecabrutinib may have therapeutic potential in this setting. A phase 1a study of vecabrutinib in healthy subjects showed favorable safety pharmacokinetic (PK)/pharmacodynamic (PD) profiles, supporting twice-daily (BID) oral dosing (Neuman ASH 2016). Here we report preliminary results of the ongoing phase 1b/2 study of vecabrutinib in adult pts with relapsed/refractory (R/R) advanced B-cell malignancies. Methods: The phase 1b dose-escalation portion of the study employs a standard 3+3 design in pts with histologically confirmed R/R chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), diffuse large B-cell lymphoma, and follicular lymphoma who have received ≥2 prior lines of systemic therapy, including use of a covalent BTKi where approved for their disease. The objectives of this study are to assess safety, establish the maximum tolerated dose, and identify the recommended phase 2 dose of vecabrutinib. Pts aged ≥18 years with an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2 are eligible. Dose-limiting toxicity (DLT) is assessed over an initial 4-week period (1 treatment cycle). Molecular profiles, PK, and PD (inhibition of BTK phosphorylation [pBTK] and cytokine levels) are evaluated throughout Cycle 1. Vecabrutinib succinate dose levels from 25 to 500 mg BID were specified for evaluation. Early safety, PK, and PD data from pts treated to date at dose levels of 25 and 50 mg BID are reported. Results: Nine pts (CLL, n=6; MCL, n=2; WM, n=1) have been treated in the phase 1b portion of the study (25 mg BID, n=3; 50 mg BID, n=6). Median pt age was 66 years (range: 47-75), all had an ECOG PS of 0 or 1, 78% were male, and median number of prior regimens was 5 (range: 2-7). Prior therapies included ≥1 chemotherapy regimen (n=9), BTKi (ibrutinib, n=8; acalabrutinib, n=1), venetoclax (n=4), and chimeric antigen receptor T-cell therapy (n=2). At baseline, 67% (6/9) of pts had TP53 mutations or deletions. The CLL pts had 83% (5/6) unmutated IGHV, 83% (5/6) deleted or mutated TP53, 50% (3/6) detectable BTK C481 mutations by next-generation sequencing (C481S: n=2, variant allelic frequency [VAF]: 16%, 58%; C481R: n=1, VAF: 77%), and no mutations in PLCg2 were detected. No mutations in BTK 481 or PLCg2 were found in MCL or WM pts. The most common treatment-emergent adverse events (TEAEs) of any grade were anemia and night sweats (43%, 3/7 each), and leukopenia, neutropenia, thrombocytopenia, abdominal distension, constipation, fatigue, alanine aminotransferase levels (ALT) increased, aspartate aminotransferase levels increased, back pain, and pyrexia (29%, 2/7 each). In the second cohort, 1 pt experienced a DLT of an inadequate number of Cycle 1 doses administered due to a grade 3 ALT elevation. This resulted in expansion of the cohort to 6 pts. Grade ≥3 TEAEs considered related to study drug thus far occurred only in this 1 pt (anemia, neutropenia, and ALT levels increased). Three pts from the 50-mg cohort experienced disease progression prior to the end of Cycle 1 requiring replacement. Pts evaluable for DLT have remained on study up to 5 cycles (range: 1-5), but no responses have been observed to date. The vecabrutinib PK profile was consistent with the results from the phase 1a study (Figure 1). Vecabrutinib was rapidly absorbed (median time to maximum concentration [Tmax]: 2 hr [range: 1-6]), and exposure increased with dose. Decreased pBTK was observed in 2 CLL pts and 1 MCL pt; no consistent effect on chemokines has yet been observed. BTK C481S VAF appeared stable at end of treatment (EOT) in the two CLL pts with baseline mutations who provided EOT samples. Conclusions: These data show sustained vecabrutinib exposure throughout the dosing interval, and preliminary evidence of PD activity in pts with R/R B-lymphoid malignancies. The study (NCT03037645) continues enrollment in the dose-escalation phase. Planning is ongoing for subsequent phase 2 expansion cohorts in selected indications. Disclosures Allan: Acerta: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Patel:Genentech: Consultancy, Speakers Bureau; Sunesis Pharmaceuticals: Consultancy; Pharmacyclics/Janssen: Speakers Bureau; Juno Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy. O'Brien:Acerta: Research Funding; Pharmacyclics: Consultancy, Research Funding; Alexion: Consultancy; Abbvie: Consultancy; Kite Pharma: Research Funding; Sunesis: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy; Vaniam Group LLC: Consultancy; Aptose Biosciences Inc.: Consultancy; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Astellas: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Pfizer: Consultancy, Research Funding. Mato:Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy; Acerta: Research Funding; Celgene: Consultancy; Regeneron: Research Funding; TG Therapeutics: Research Funding; Prime Oncology: Speakers Bureau; Sunesis: Honoraria, Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding. Davids:Celgene: Consultancy; Surface Oncology: Research Funding; BMS: Research Funding; Astra-Zeneca: 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; Roche: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Research Funding; BMS: Research Funding; Roche: Consultancy; Merck: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Merck: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Surface Oncology: Research Funding. Furman:Gilead: Consultancy; Janssen: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; Loxo Oncology: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Acerta: Consultancy, Research Funding; Incyte: Consultancy, Other: DSMB. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Fox:Sunesis Pharmaceuticals: Employment; Amphivena Therapeutics: Employment. Ward:Sunesis Pharmaceuticals: Consultancy. Taverna:Sunesis Pharmaceuticals: Employment. Brown:Boehringer: Consultancy; Sunesis: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy; Verastem: Consultancy, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Sun Pharmaceutical Industries: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy; Loxo: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Gilead: Consultancy, Research Funding; TG Therapeutics: Consultancy; Janssen: Consultancy.
5
Imber, Brandon, M. Lia Palomba, Carl DeSelm, Connie Lee Batlevi, Parastoo B. Dahi, Sergio A. Giralt, Ariela Noy, et al. "MSKCC Early Experience Using Radiotherapy As a Bridging Strategy for Relapsed Diffuse Large B Cell Lymphoma before CD19 CAR T Therapy." Blood 134, Supplement_1 (November 13, 2019): 3238. http://dx.doi.org/10.1182/blood-2019-131449.
Full textAbstract:
Background: CD19-targeted chimeric antigen receptor T cell (CAR T) therapies have remarkable overall response rates (ORR) for relapsed diffuse large B cell lymphoma (DLBCL). There is strong rationale to use a radiotherapy (RT) bridge during the cell manufacturing process including palliation, local control and cytoreduction with limited count impact. Recent data from our institution suggests RT may augment an immune response and sensitize antigen negative cells to CAR-mediated death. This series details our early experience using RT conditioning. Methods: 13 patients (median age 64 years) with DLBCL (n=9) or transformed follicular lymphoma (n=4) were analyzed. Overall, patients had a median of 2 prior therapies (range 1-8) including 3 with autologous transplant, 3 with distant RT and 1 with CAR T infusion. Several CAR products were used, including axicabtagene ciloleucel (n=8), JCAR017 (n=3, per NCT02631044), tisagenlecleucel (n=1) and EGFRt/19-28z/4-1BBL "armored" CAR (n=1, per NCT03085173). Most patients (n=10) began RT post apheresis with median duration between RT and CAR infusion of 20d (range 13-80, Figure 2). The most common RT regimen (n=8) was 20 Gy in 5 fractions (range 20-47 Gy) but 2 received our pre-transplant regimen of 30 Gy in 20 BID fractions. None received concurrent chemotherapy with RT but one had a cycle post RT and pre CAR. All had cyclophosphamide and fludarabine lymphodepletion. PET response was evaluated by Lugano criteria. Results: Three patients had limited stage PET avid disease at RT and were treated comprehensively pre-CAR. The remaining 10 were advanced stage and were treated palliatively to limited sites. Irradiated sites included the pelvis/groin (n=4), neck (n=3), intraabdominal (n=2) and extremity (n=2). Most (n=10) had intensity modulated radiotherapy. RT fields were large (median planning treatment volume of 887 cc, range 163-1641). Post RT PET interpretation was challenging given a short interval since RT ended (median 11d) but of 11 evaluable patients, many (n=8, 73%) had partial response (PR). Though locally controlled, most (n=10, 91%) had out of field progressive disease (PD) pre-CAR. Post CAR T, no severe adverse events in the RT field were noted, 9/13 had cytokine release syndrome (n=1 grade 3, n=2 grade 2) and 4 had neurotoxicity (n=3 grade 3). At day 30, ORR was 90%; of 10 evaluable patients, 7 had complete response (CR) and 2 had partial response (PR). Of the 7 evaluable patients at day 90, 4 (57%) had continued CR and the other 3 (43%) had PD and subsequently died from DLBCL. One relapsed at 95d post armored CAR both in and out of the RT field, and the other relapsed at 64d post JCAR017 primarily out of field. Conclusions: Use of RT as a CAR T bridging strategy is feasible and associated with excellent pre-CAR local control and initial post CAR ORR in a cohort of heavily pre-treated DLBCL patients. We observed moderate serious CAR toxicity that did not appear to be augmented by RT. Future efforts should clarify the optimal RT timing/dose and assess the potential for incremental immunogenicity with combined therapy. Disclosures Palomba: Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding; NIH: Research Funding; Janssen: Consultancy. Park:Amgen: Consultancy; Autolus: Consultancy; AstraZeneca: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Allogene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Genmab: Consultancy; GSK: Consultancy; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding. Sadelain:Memorial Sloan Kettering Cancer Center: Employment; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy, Patents & Royalties. Perales:Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: 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, Research Funding; Nektar Therapeutics: 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; Omeros: 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; Merck: Consultancy, Honoraria; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding.
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Castellino, Alessia, Melissa C. Larson, Matthew J. Maurer, Susan L. Slager, Cristine Allmer, Jonathon B. Cohen, Andrew L. Feldman, et al. "Patterns of Care and Outcomes in Mantle Cell Lymphoma in the Modern Immunochemotherapy Era." Blood 132, Supplement 1 (November 29, 2018): 4140. http://dx.doi.org/10.1182/blood-2018-99-119595.
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Abstract Backgroud. The treatment landscape of mantle cell lymphoma (MCL) has significantly changed in last decades. Improvement in diagnosis and understanding of disease biology has been coupled with emergence of new therapeutic options, including targeted agents. While MCL outcome data comes primarily from clinical trials (CT), the impact of therapeutic advances on pattern of care (POC) and outcome in MCL in the general population is not well characterized. This study sought to characterize changes in pattern of care and outcomes of patients with MCL in a prospective observational series in the rituximab era. Methods. The study included consenting adult patients with newly diagnosed MCL that were prospectively enrolled into the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) Molecular Epidemiology Resource, from 09/01/2002 to 06/30/2015. Demographic, clinical and prognostic factors were abstracted, and all patients were actively followed for re-treatment, relapse and death. Since bendamustine-rituximab (BR) regimen starting to be used in 2010, we defined patients enrolled from 09/01/2002 to 12/31/2009 as era 1 and those enrolled 01/01/2010 to 06/30/2015 as era 2. Baseline characteristics and outcomes, evaluated in terms of event free survival (EFS), overall survival (OS) and cause of death, were analyzed and compared between the two eras identified. Results. 348 patients with newly diagnosed MCL were enrolled. Five patients had no available data for front-line treatment and were excluded. The analysis was thus conducted on 343 patients: 169 patients were diagnosed in era 1 with a median follow-up of 131.2 months vs. 174 in era 2 with a median follow-up of 58.9 months. Baseline clinical characteristics and MIPI score were similar across the two eras ( Table 1). Frontline induction treatment was significantly different in the two eras. BR use was 0 vs 49 (28.2% ), R-CHOP/CHOP like regimen in 89 (52.7%) vs 45 (25.9%), high-dose cytarabine (HiDAC)-based therapy in 1 (0.6%) vs 28 (16.1%), intensified regimens (HyperCVAD) in 16 (9.5%) vs 8 (4.5%), other regimens (including R-cladribine, R-fludarabine-mitoxantrone, rituximab monotherapy) in 35 (20.7%) vs 13 (7.5%) patients in era 1 vs era 2 respectively. Non-systemic treatment (observation, surgery or radiation only) was performed in 25 (14.8%) vs 31 (17.8%), while 9 (8%) vs 12 (7.7%) patients were enrolled in clinical trials, in era 1 vs era 2 respectively. Autologous stem cell transplantation (ASCT) as consolidation of first line treatment or use of Rituximab maintenance was not different between Era 1 and Era 2. Among the entire cohort of 343 MCL patients, 3y-EFS and 3y-OS were 51.9% (95% IC 46.7-57.6) and 73.5 (95% CI 68.8-78.4), respectively (Figure 1). 3y-EFS was 45.9% (95% CI 39.0-54.1%) vs 58.4 (95% CI, 51.2-66.6%) in Era 1 vs Era 2 (HR 0.69 (0.51-0.92), p=0.006), 3y-OS was 70.9% (95% CI, 63.4-78.1%) vs 76.1% (95% CI, 69.7-83.1%) in Era 1 vs Era 2 (HR 0.87 (0.61-1.24), p=0.26), respectively (Figure 1). In a univariate analysis, high risk simplified MIPI was prognostic of lower EFS and OS in both the era groups. Conclusion. The BR regimen entered front line therapy of MCL resulting in decline of R-CHOP use in the MER. While rates of ASCT remain similar over the two eras, high dose cytarabine usage in induction therapy has increased. While POC in MCL continue to evolve, the introduction of bendamustine and high-dose citarabine based regimens resulted in an improvement in EFS but not OS in this observational cohort-based analysis. Findings in this study are important for design and planning of future clinical trials incorporating novel agents in induction therapy of MCL. Figure 1. Figure 1. Disclosures Cohen: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.
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Merz, Maximilian, Isabelle Vande Broek, Manuel Pérez, Brigitte Kolb, Argiris Symeonidis, Emmanouil Nikolousis, Athanasios Zomas, Francisco Gonzalez, Lenka Kellermann, and Hartmut Goldschmidt. "Evolving Treatment Trends in Relapsed/Refractory Multiple Myeloma (RRMM) in Europe from 2016 to 2018: Analysis of a Multi-National Survey." Blood 134, Supplement_1 (November 13, 2019): 3115. http://dx.doi.org/10.1182/blood-2019-122706.
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Background Recently, treatment options for RRMM have increased substantially with multiple approvals of novel agents/combination, making the treatment algorithm increasingly complex, with changes driven chiefly by access to novel agents/regimens. Furthermore, patient (pt) and disease characteristics have a profound impact on treatment decisions. To understand the impact of recently approved novel regimens on real-world (RW) treatment patterns, we conducted a multi-national survey to investigate the management of RRMM across Europe. Methods Retrospective, anonymized data from RRMM pts, treated in academic or community hospitals/clinics in 8 countries were extracted from Jan 2016 to Dec 2018. Data were analyzed overall and for Germany, Austria, and Switzerland (DACH) vs other countries (Belgium, France, Greece, Spain and UK) due to differences in treatment access. Results The cumulative number of pts included was 2782 in 2016, 3902 in 2017, and 4658 in 2018. Of the pts enrolled in 2016, 2017 and 2018, 40%, 49% and 51%, respectively, were in 3rd+ line (≥3L), potentially reflecting the increasing availability of treatment options for RRMM and extended survival in MM. Median age at diagnosis in pts enrolling in 2016, 2017, and 2018, was 68, 69, and 70 years, respectively, with 23%, 24%, 26% aged >75 years, underlining the fact that MM remains a disease of the elderly. The data revealed a difficult-to-treat RW population: 31%-36% of pts had an ECOG PS ≥2 at 2nd line (2L) in 2016-2018; increasing to 44%-49% at 4th+ lines (≥4L). At 2L, 42%-45% of pts presented ≥1 treatment-dependent comorbidity in 2016-2018, including hypertension (23-27%) and renal impairment (9-10%). Cytogenetic risk, evaluated in 38%-42% of pts at initial diagnosis, was reported as high in 8%-10% of the total population. Treatment initiation due to biochemical relapse was reported in 33%/36% of pts at 2L/3L in 2016, and in 30%/28% in 2018, indicating that ~1/3 of pts manifested an asymptomatic rather than clinical relapse. The proportion of pts treated with triplet regimens increased from 26%, 26%, and 30% at 2L, 3L and ≥4L in 2016 to 43%, 40%, and 38% in 2018, reflecting the adoption of newly approved triplets in RRMM, particularly in DACH countries. Use of proteasome inhibitor (PI)-based regimens increased from 35%, 30% and 34% at 2L, 3L and ≥4L in 2016, to 43%, 37% and 37% in 2018, driven by increased/earlier use of novel PIs (carfilzomib and ixazomib). These trends were more obvious in DACH, highlighting the impact of earlier access to modern treatment in these countries. Similarly, the proportion of pts on daratumumab-based regimens increased from 0, 5%, and 20% at 2L, 3L and ≥4L in 2016, to 10%, 24% and 31% in 2018. From 2016 to 2018, prior IMiD exposure at 2L increased from 11% to 20% in DACH, but remained stable at 42% in other countries; at 3L, there was an increase from 77% to 82% in all countries reflecting the uptake of novel triplet combinations. Most pts were IMiD-exposed or IMiD-refractory at ≥4L. Regarding the treatment algorithm, the rate of PI-based treatment at 1L was 74%-75%. PI- to IMiD-based therapy was the commonest treatment sequence from 1L to 2L, at 64%-66%, while PI- to PI-based therapy at 1L to 2L increased from 22% in 2016 to 30% in 2018. Key disease/pt characteristics associated with the selection of regimens at 2L and 3L are summarized in the Table. Prior IMiD treatment limited the use of IMiD-based therapy in subsequent lines. The use of KRd, IRd and DRd was mostly associated with ISS stage III, while the use of KRd was less frequently reported in pts with cardiac comorbidities. In pts with prior PI treatment, KRd and IRd (but not Kd) were more common at 2L, while DRd was preferred at 3L. A higher proportion of fit, young, or prior-SCT pts were treated with KRd or DRd, while IRd was the preferred treatment in pts with biochemical relapse. Conclusions Multiple drug approvals for RRMM in Europe have resulted in marked changes in the treatment algorithm, with a more immediate impact in countries with earlier access to new treatment options. Multiple decision drivers such as age, fitness, comorbidities and prior treatment are associated with uptake of different novel regimens at 2L and 3L. The increasing range of treatment options has resulted in pts receiving more lines of therapy for RRMM, highlighting the need for cautious planning of treatment sequencing to optimize the use of available combinations according to pt characteristics and disease factors. Disclosures Merz: Janssen: Other: Travel grants; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Abbvie: Other: Travel grants; Celgene: Other: Travel grants; Takeda Vertrieb GmbH: Other: Travel grants, Research Funding. Pérez:Janssen: 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. Kolb:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: travel and registration for my participation to international medical congres (ASH). Symeonidis:Celgene: Honoraria, 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; 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; Gilead: 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. Zomas:Takeda: Employment. Gonzalez:Takeda: Employment. Kellermann:Amgen: Research Funding; BMS: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Takeda: Research Funding. Goldschmidt:Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; ArtTempi: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product.
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Krick, Eva, Johan Christensen, and Cathrine Holst. "Between ‘Scientization’ and a ‘Participatory Turn’. Tracing shifts in the governance of policy advice." Science and Public Policy 46, no. 6 (September 3, 2019): 927–39. http://dx.doi.org/10.1093/scipol/scz040.
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Abstract This study traces the claims of a ‘scientization’ and a ‘participatory turn’ in modern governance within the system of temporary policy advisory committees in Norway. It analyzes whether there is evidence of the two claims in these key governance institutions and to what extent these shifts are compatible with each other. As expressions of a participatory turn, a growing emphasis on citizen involvement and transparency in the committee system is searched for. A growing relevance of researchers and of science-based claims in the committees’ reports are taken as indicators of scientization. The longitudinal study shows an overall shift both towards science- and expertise-based governance and towards an increasing openness and public engagement, as well as some variation between policy fields.
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Hunt, Len M. "Monitoring changes in forest resource advisory groups’ composition and evaluations of perceptions of public participation effectiveness: a case of Ontario’s Local Citizens Committees." Canadian Journal of Forest Research 45, no. 12 (December 2015): 1866–72. http://dx.doi.org/10.1139/cjfr-2015-0241.
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Effective public participation is a key part of sustainable forest management on publicly owned lands. However, long-term monitoring data that seek to measure effectiveness of public participation in forest management planning is lacking. Here, measures based on attitudes and satisfaction ratings associated with suspected criteria of public participation effectiveness were developed and applied to forest resource advisory group members from Ontario, Canada. Using data from four social surveys (2001, 2004, 2010, and 2014), advisory group members were, on average, satisfied and held positive attitudes towards the advisory group, their participation in the group, and forest management planning. In many instances, these positive evaluations increased from 2001 to 2014, especially for statements related to fairness. One concern about Local Citizens Committees (LCCs) related to their composition. Advisory group members were male dominated (about 88%) and were increasingly overrepresented by individuals between 50 and 69 years old in 2014 (67%). Given that male and female LCC members held different perceptions of the effectiveness of some public participation criteria, these concerns suggest that composition of LCCs might impair the ability of the groups to consider all viewpoints related to forest management planning. Finally, the research illustrates the importance of designing and collecting long-term monitoring data to understand how evaluations of public participation and composition of participants changes over time.
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Lissat, Andrej, Despina Maniotis, Michael Nosswitz, Julia Alten, Silvia Jenni, Yi-Chien Tsai, Gunnar Cario, et al. "In Vitro Drug Response Profiling in BCP- and T-ALL Primary Samples Adds a Robust Functional Layer Enabling Optimized Guidance of Individualized Therapy in Relapsed and Refractory Pediatric Acute Leukemia Patients." Blood 136, Supplement 1 (November 5, 2020): 15–16. http://dx.doi.org/10.1182/blood-2020-142314.
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Despite progress with immunotherapy and targeted agents, treatment of refractory disease remains challenging, in particular for patients with T-ALL. Identification of genomic lesions defining actionable targets had limited impact on patient care so far. The complexity of biological systems highlights the need to develop complementary functional approaches. We and others have established platforms with a library of 120 drugs based on current treatment and (pre-)clinical development, to detect ex-vivo drug response phenotypes on leukemia samples at single cell resolution by high content image analysis. We demonstrated that drug response profiling (DRP) identifies dependencies not predicted by genetic alterations adding a functional information layer for clinicians. Here we report first correlations with clinical outcome using DRP in a non-interventional setting. From 2016 to 2019 we performed DRP in the framework of European ALL first- and second- line protocols upon request by treating centers. Here we analyze retrospectively treatment decisions and outcome for 23 T- and 50 BCP-ALL patients. To evaluate drug responses, we compared dose response curves of individual patients to data recorded for all patients. Sensitivity and resistance were defined based on the IC50 outlier analysis using cut-offs depending on distribution (normal gaussian vs. skewed). From 73 patients tested, clinical outcome data has been available for 36 BCP- and 15 T-ALL patients. NGS data provided by the INFORM registry has been available in 8 BCP- and 2 T-ALL patients. In first line BCP-ALL patients, ex-vivo Dexamethasone response predicted clinical response to prephase prednisone (d8) and minimal residual disease (MRD) reduction measured by flow cytometry at d15 of first line AIEOP BFM 2009 induction (Fig. 1). For refractory and relapsed ALL we observed an association of DRP and response to targeted agents in 14 out of 16 patients (87.5 %; Table 1). Data for the r/r BCP-ALL cohort is limited because most patients underwent CD19 and / or CD22-directed immunotherapy. Sensitivity and resistance to Calicheamicin correlated with clinical response to Inotuzumab, suggesting functional testing to be evaluated in future studies. In contrast, lack of correlation of ex-vivo sensitivity to MEK-inhibitors with presence of RAS-pathway alterations caution the exclusive use of molecular information to predict response to these agents. Most therapeutic decisions based on DRP information were made for patients with r/r T-ALL. Bortezomib ex-vivo sensitivity correlated with clinical responses in 5 T-ALL patients (Fig. 2). Both patients predicted to respond to Bortezomib and treated on Bortezomib + Venetoclax experienced good MRD response providing a bridge to stem cell transplantation (SCT). However, these patients relapsed after SCT emphasizing the need for additional consolidative therapeutic elements for heavily pretreated patients. In line with previous reports, we confirmed a T-ALL with high sensitivity to Dasatinib (IC50 1.9 nM; Fig. 3). Dasatinib monotherapy induced a molecular remission. A 2nd T-ALL showing an ex- vivo Dasatinib IC50 at 80 nM was refractory to treatment with Dasatinib + Daunoxome-FLAG. A 3rd ABL1-fusion positive T-ALL, ex-vivo resistant to Imatinib and Dasatinib, had only short- term response to Imatinib + chemotherapy. Finally, treating a T-ALL patient based on high sensitivity to the XPO1 inhibitor Selinexor as 4th line monotherapy led to significant decrease of PB blasts from d1 25 G/L to 0.7 G/L at d13 of treatment (Fig. 4). The patient experienced improved quality of life, minimizing need of hospitalization with stable disease for 3 months on maintenance with Selinexor. Given the promising preclinical data with this class of agents and current lack of established biomarkers, we propose that DRP should be evaluated for this class of agents. In conclusion, we established first associations between DRP and clinical response for various agents providing a rationale for the evaluation of DRP in prospective clinical trials. Integration of molecular and functional information may improve the selection of more specific treatment options for patients with resistant disease. The international BFM Study Group and ITCC Consortium are planning an international multiarm early clinical trial for treatment of r/r ALL patients that will include DRP for evaluation in order to improve selection of targeted therapy. Disclosures Cario: Jazz Pharmaceuticals: Consultancy, Other: travel support; Novartis: Consultancy, Other: travel support. Hrusak:Amgen: Other: MRD investigations funded by Amgen, Research Funding. Kulozik:Novartis: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. von Stackelberg:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau. Jacoby:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lonza: Membership on an entity's Board of Directors or advisory committees. Bourquin:Servier: Other: Travel Support.
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Bufton, Mark W. "Coronary heart disease versus BSE: characterising official British expert advisory committees." Science and Public Policy 28, no. 5 (October 1, 2001): 381–88. http://dx.doi.org/10.3152/147154301781781291.
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Berdeja, Jesus G., Melissa Alsina, Nina D. Shah, David S. Siegel, Sundar Jagannath, Deepu Madduri, Jonathan L. Kaufman, et al. "Updated Results from an Ongoing Phase 1 Clinical Study of bb21217 Anti-Bcma CAR T Cell Therapy." Blood 134, Supplement_1 (November 13, 2019): 927. http://dx.doi.org/10.1182/blood-2019-126660.
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Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 studies. Persistence of CAR T cells post infusion may be one determinant of duration of response. bb21217 is a next-generation anti-BCMA CAR T cell therapy based on investigational therapy idecabtagene vicleucel (bb2121) (Friedman 2018, Hum Gene Ther 29:585) that uses the same lentiviral CAR T design as bb2121, but adds the phosphoinositide 3-kinase inhibitor bb007 during ex vivo culture to enrich the drug product for memory-like T cells. Evidence suggests that CAR T cells with this phenotype may be more persistent and more potent than unselected CAR T cells. CRB-402 is a first-in-human study of bb21217 in patients with RRMM designed to assess safety, pharmacokinetics, efficacy and duration of effect. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 planning to enroll 74 patients with RRMM who received ≥ 3 prior regimens, including a proteasome inhibitor and an immuno-modulatory agent, or are double-refractory to both classes. During dose escalation, enrollment is restricted to patients with ≥ 50% BCMA expression by IHC on malignant plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for transduction, expansion and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive bb21217 as a single infusion. Planned dose levels are 150, 450, 800, and 1,200 x 106 CAR+ T cells and intermediate dose levels are allowed. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ T cells in blood. Results: Asof April 20, 2019, 22 patients (median age 63 [min;max 42 to 74]) have received bb21217 (12 at 150, 6 at 300 and 4 at 450). Eleven had high tumor burden, defined as ≥ 50% bone marrow plasma cells pre-infusion. Patients had a median of 7 (min;max 4 to 17) prior lines of therapy and 18/22 had prior autologous stem cell transplant; 7/22 had high-risk cytogenetics. Of the 22 patients, 19 received prior daratumumab, 13 received prior Bort/Len/Car/Pom/Dara. Median follow-up after bb21217 infusion was 23 weeks (<1 to 77 weeks). As of data cut-off, 13/22 patients developed cytokine release syndrome (CRS; 5 G1, 7 G2, 1 G3) and responded to supportive care, tocilizumab and/or corticosteroids. Five patients developed neurotoxicity [1 G1, 2 G2, 1 G3 (vertigo/dizziness), 1 G4 (encephalopathy, previously reported)]. For the 1 patient with G4 neurotoxicity, G3 CRS was also reported; both have resolved. A total of 18 patients were evaluable for response with ≥ 2 months of follow up or PD within 2 months. Fifteen (83%) patients demonstrated clinical response per IMWG criteria. Six of these subjects subsequently progressed. Nine patients remained in response, including 2 patients with ongoing response at months 15 and 18. MRD negative results at 10-5 nucleated cells or better were obtained by NGS in 10/10 evaluable responders at month 1. Overall, 6/8 patients evaluable at 6 months and 2/2 patients evaluable at 12 months had detectable CAR T cells in blood. Updated data from this study will be presented, including extended follow-up on the initial patients treated and early clinical and CAR T cell persistence data from at least 15 additional patients treated with up to 450 x 106 CAR+ T cells. Conclusions: The adverse events observed to date were manageable and consistent with known toxicities of CAR T therapies. Initial efficacy results with bb21217 CAR T therapy in heavily pretreated RRMM are encouraging, with 83% of patients demonstrating clinical response. Emerging data demonstrate long-term persistence of CAR T cells in long-term responders. Updated data to be presented will help determine whether treatment with bb21217 results in sustained CAR T cell persistence and durable clinical responses, and whether bb21217 is tolerated at higher doses. Disclosures Berdeja: AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. Shah:Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jagannath:Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Merck: Consultancy. Madduri:Abbvie: Consultancy; Celgene: Consultancy; Takeda: Consultancy; undation Medicine: Consultancy. Kaufman:Janssen: Honoraria; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Celgene: Consultancy. Munshi:Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Abbvie: Consultancy. Rosenblatt:BMS: Other: Advisory Board ; Parexel: Consultancy; Imaging Endpoint: Consultancy; Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; BMS: Research Funding; Amgen: Other: Advisory Board; Celgene: Research Funding; Merck: Other: Advisory Board. Turka:bluebird bio: Employment. Lam:bluebird bio: Employment. Massaro:bluebird bio: Employment. Campbell:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees. Petrocca:bluebird bio: Employment. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.
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Landre, Betsy K., and Barbara A. Knuth. "Success of citizen advisory committees in consensus‐based water resources planning in the great lakes basin." Society & Natural Resources 6, no. 3 (July 1993): 229–57. http://dx.doi.org/10.1080/08941929309380823.
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Journeycake, Janna M., Michael Recht, Christine Guelcher, Ellis J. Neufeld, Margaret V. Ragni, Robert F. Sidonio, Cliff Takemoto, et al. "Dosing, Patient Satisfaction and Other Patient-Reported Outcomes after Switching to Rurioctocog Alfa Pegol in Athn 2: A Longitudinal, Observational Study of Previously Treated Hemophilia Patients Switching Coagulation Replacement Factor Products." Blood 136, Supplement 1 (November 5, 2020): 17–18. http://dx.doi.org/10.1182/blood-2020-138898.
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Introduction: It is anticipated that many patients with hemophilia are likely to switch from one coagulation factor product to a newer agent within the next few years. New replacement factor formulations have been developed using several approaches that have theoretical benefit. However, except for pharmacokinetic properties, it may be difficult to determine whether they are superior to current clinically successful preparations. Rurioctocog alfa pegol (Adynovate®), a pegylated, extended half-life factor VIII (FVIII) concentrate, received United States Food and Drug Administration approval in 2015. Its efficacy and safety for the treatment of hemophilia A have been demonstrated in multiple studies (Konkle et al. 2015; Gruppo et al. 2019; Mullins et al. 2017). The ATHN 2: Factor Switching Study provided the opportunity to longitudinally observe previously treated hemophilia patients switching to rurioctocog alfa pegol to identify dosing regimens, patient satisfaction with the change in therapy, impact on health states and productivity. Methods: The ATHN 2: Factor Switching Study is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at ATHN-affiliated sites in the US. This multi-center, longitudinal, observational study enrolled male and female children and adults with moderate or severe congenital hemophilia A or B (factor VIII or IX clotting activity ≤5% of normal) who were previously treated with plasma-derived or recombinant factor replacement products with ³50 exposure days. Patients receiving care from one of 30 hemophilia treatment centers were enrolled into 2 arms: 1) a prospective arm including those switching factor replacement products who were followed for <1 year; and 2) a retrospective arm including those who had switched factor replacement products within the past 50 weeks at the time of enrollment. Patients were assessed retrospectively or followed prospectively for <1 year. Treatment administered in ATHN 2 was at the discretion of the patient's provider. Each patient was seen during a study visit or contacted by telephone at least once every 3 months. A product-specific module developed for rurioctocog alfa pegol included assessment of dosing and treatment satisfaction vs prior therapy; adherence to therapy assessed using Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS-Pro), a validated instrument with 6 subscales (timing, dosing, planning, remembering, skipping, communication); health states measured by the EQ-5D-DL; work productivity assessed by the Work Productivity Activity Impairment Questionnaire (WPAI); and overall satisfaction with therapy. Results: Patients (n=59) with hemophilia A were enrolled into the rurioctocog alfa pegol sub-study by May 1, 2020. Mean (± standard deviation [SD]) age was 25 ± 18 years (range = 4-77 years); 72.9% (n=43) were in the prospective arm and 27.1% (n=16) in the retrospective arm; 11.9% (n=7) had moderate hemophilia A and 88.1% (n=52) had severe disease. All were taking rurioctocog alfa pegol as prophylaxis. At study end, results for dosing (Table 1) indicated the most common treatment regimen was twice weekly (45.1%, n=23), and mean nominal dose was 50 ± 10 U/kg. Patients were highly adherent to prophylaxis with rurioctocog alfa pegol with a mean total VERITAS-Pro score of 31.4 ± 8.4; adherence improved slightly over time (32.6 ± 9.0 at baseline vs 29.2 ± 4.2 at month 12). Patients strongly preferred rurioctocog alfa pegol vs all prior factor products for controlling bleeding, convenience, finding time to take and ease of administering FVIII, and how often they were required to take factor (Table 1). Overall, 76.5% of patients were very satisfied or satisfied with rurioctocog alfa pegol. Assessment of health states indicated that patients generally had no or slight problems with mobility, activities, or self-care; and were not in pain or anxious/depressed. Patients generally missed no time from work or school. Overall health was self-rated at 89.0 ± 13.0 on a scale from 0 (worst health) to 100 (best health) and remained stable from baseline (88.0 ± 14.0) to month 12 (87.8 ± 15.3). Conclusions: Moderate and severe hemophilia A patients enrolled in ATHN 2 who received rurioctocog alfa pegol for prophylaxis enjoyed excellent health, had little to no school or work impairment and were adherent to, and satisfied with, their treatment regimen. Disclosures Recht: Spark: Research Funding; CSL Behring: Consultancy, Other: personal fees; Novo Nordisk: Consultancy, Other: personal fees, Research Funding; Genentech: Consultancy, Other: personal fees, Research Funding; Pfizer: Consultancy, Other: personal fees; BioMarin: Research Funding; Takeda: Consultancy, Other: personal fees, Research Funding; uniQure: Consultancy, Other: personal fees, Research Funding. Guelcher:Novo-Nordisk: Consultancy; Octapharma: Consultancy; Genentech, Octapharma, CSL Behring, Takeda, Pfizer, Novo Nordisk: Consultancy; Takeda: Consultancy. Neufeld:Bayer: Other: DSMB; genetech: Consultancy; Novo Nordsik: Consultancy; Octapharma: Consultancy; Takeda: Consultancy; Imara Pharma: Other: DSMB service; ApoPharma/Chiezi: Other: DSMB service; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Acceleron Pharma: Consultancy, Other: DSMB. Ragni:Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; BioMarin: Consultancy, Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; Takeda: Research Funding; Sangamo: Consultancy, Research Funding; Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Sidonio:Biomarin: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Grifols: Research Funding; Spark: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Takemoto:Novartis: Other: DMBC; Genentech: Consultancy. Tarantino:Spark: Membership on an entity's Board of Directors or advisory committees; CDC: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; HRSA: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other; Sobi: Membership on an entity's Board of Directors or advisory committees. Caicedo:Takeda: Current Employment. Denne:Takeda: Current Employment.
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Love, Neil, Steven M. Horwitz, Sagar Lonial, Antonio Palumbo, Mitchell R. Smith, Atif Mahmoud Hussein, and Kathryn Ziel. "Prioritizing Content in Continuing Hematologic Oncology Education: A Survey of 51 Clinical Investigators." Blood 120, no. 21 (November 16, 2012): 4270. http://dx.doi.org/10.1182/blood.v120.21.4270.4270.
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Abstract Abstract 4270 Background Clinical and translational research content in hematologic oncology is increasingly complex as new pathways and novel agents are investigated. Continuing oncology education (COE) for community-based oncologists (CBOs) must prioritize discussion of key new developments and clinical implications in order to optimize patient care. Clinical investigators (CIs) at tertiary academic institutions usually focus on specific areas in their research and practice, and these individuals play an important role in defining medical oncology standards of care and often participate in COE. Many CBOs and their patients turn to CIs for advice, answers and second opinions, and we hypothesized that CIs could provide a unique perspective in prioritizing COE content. This pilot project attempted to quantify and elucidate the experiences of investigators specializing in lymphoma/CLL (L) and multiple myeloma (MM), with the hope of gaining insight into current needs in COE that might directly impact patient care. Methods Between April 11 and May 16, 2012 we recruited 51 CIs (L: 26; MM: 25) to complete tandem questionnaires with about 60 items. Participants were provided a modest honorarium. As part of each survey and in order to document real-world experiences, CIs were asked to quantify how often they consult clinically with patients previously seen by another oncologist and how often they answer by phone or email case-related questions from CBOs. CIs also had the option to briefly describe up to 3 recent second opinion cases in which their recommendation differed significantly from that of a prior oncologist. Finally, CIs were also asked to define their usual nonprotocol treatment approaches to a variety of important clinical scenarios (L: 31; MM: 26) and then provide on a 4-point analog scale their perception of the need for additional COE in each of these specific areas. Results Participating CIs have considerable experience with CBOs and CBO-managed patients, providing clinical second opinions a mean of 4.0 times per week (L: 3.3; MM: 4.7; range 0–13) and responding to email or phone case queries a mean of 8.5 times per week (L: 8.4; MM: 8.6; range 0–40). CIs submitted a total of 89 case descriptions (L: 54; MM: 35) in which their treatment recommendation differed significantly from that of the prior oncologist. Specifically, in 19 of these cases (L: 13; MM: 6) the CI disagreed with the diagnosis, in 50 the choice of initial treatment differed (L: 28; MM: 22) and in 20 treatment for relapsed disease was questioned (L: 13; MM: 7). The top-rated areas of education need are presented in the table below. In many of these issues, recent research developments have resulted in controversy and heterogeneity in treatment approaches. Conclusions This pilot project demonstrates that CIs regularly evaluate patients previously managed by CBOs and also provide long-distance second opinions by email and phone that in some instances result in divergent recommendations. These informative experiences contribute to an overall perception of specific education needs that could be very useful in planning COE and in development of performance improvement programs. Additional research is needed to confirm and expand these findings and determine if this quantitative and targeted approach to COE enhances patient care and measurable clinical outcomes. Disclosures: Horwitz: Millennium: The Takeda Oncology Company: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kyowa Hakko Kirin Co Ltd: Consultancy, Research Funding; Bristol-Myers Squibb Company: Consultancy; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Lonial:Acetylon Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck and Company Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Bristol-Myers Squibb Company: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Millinnium: The Takeda Oncology Company: Consultancy, Speakers Bureau; Amgen, Inc: Speakers Bureau. Smith:Allos Therapeutics: Speakers Bureau; Cephalon Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millinnium: The Takeda Oncology Company: Speakers Bureau; Spectrum Pharmaceuticals Inc: Speakers Bureau; Genentech BioOncology: Speakers Bureau.
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Heuck, Christoph, Yogesh Jethava, Rashid Z. Khan, Scott Miller, Alan Mitchell, Donald Johann, Kelly Robbins, et al. "Targeted MEK Inhibition in Patients with Previously Treated Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 4775. http://dx.doi.org/10.1182/blood.v124.21.4775.4775.
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Abstract Background: Diagnostic and therapeutic advances have significantly improved the outcomes for multiple myeloma (MM) patients. However, pts who are refractory to or relapse after therapy with immune modulatory drugs and proteasome inhibitors remain a therapeutic challenge. Comprehensive genomic profiling via clinical next generation sequencing (NGS)-based assays studies of MM cases have revealed multiple targetable mutations that were previously unexploited in MM. Methods: Between June 2013 and May 2014 we performed genomic profiling of 351 patients who had progressed after initial therapy to assist physicians in therapy planning. Comprehensive genomic profiling was performed using the FoundationOne¨ or FoundationOne Heme¨ assays. FoundationOne assays 374 cancer-related and 24 frequently rearranged genes via DNA-seq, and FoundationOneHeme assays 405 cancer-related and 31 frequently rearranged genes via DNA-seq as well as 265 frequently rearranged genes by RNA-seq. All samples were sequenced in a CLIA-certified CAP-accredited laboratory to an average depth >500x . Patients with activating alterations of KRAS, NRAS or BRAF were considered for therapy with the targeted agent trametinib (TMTB) as were patients who had a gene expression signature suggesting activation of the MAPK pathway. Retrospective review of this case series was approved by the UAMS institutional review board. Results: We identified 63 patients who underwent treatment with Trametinib. 60 were treated based on activating mutations of KRAS, NRAS or BRAF and 3 were treated based on a GEP signature. The median age was 65 and patients had a median of 5 lines of prior therapy (range 1-20). 38 of 63 patients had prior treatment with Total Therapy. 43 underwent salvage with chemotherapy prior to initiation of TMTB, 15 had salvage transplants, 33 patients were exposed to novel agents (Pomalidomide, Carfilzomib) and 33 had Metronomic therapy before TMTB. 25% of patients were ISS stage 3 and 37% had GEP70 defined high risk. 13 had PET defined extra medullary disease (EMD). 41 patients were administered TMTB monotherapy and 22 received TMTB treatment in combination with other agents. In general the treatment was well tolerated. 10 patients discontinued therapy because of toxicities, 29 discontinued because of disease progression or death. None of the deaths were attributed to TMTB, Best treatment responses were SD in 30, PR in 8, VGPR in 2 and CR in 3 of the 63 pts. For 25 patients with evaluable PET data, treatment resulted in complete resolution of FDG avid lesions in 9 patients and a better than 50% reduction in 15 (Figure 1). We will present updated data on clinical responses as well as toxicities. Conclusions: Treatment with targeted therapy guided by prospective comprehensive genomic profiling across all classes of genomic alterations in this heavily pretreated population of MM patients resulted in an unexpectedly high objective response rate. Observation of CR with TMTB monotherapy further supports continued investigation of this individualized approach to MM management. Disclosures Van Laar: Signal Genetics: Employment, Equity Ownership. Ali:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc: Employment. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Millenium: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.
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Kleinschmit, Stephen. "Addressing procedural bias in municipal planning governance: A case for incorporating citizen participation within technical advisory committees." International Journal of Organization Theory & Behavior 18, no. 1 (March 1, 2015): 1–20. http://dx.doi.org/10.1108/ijotb-18-01-2015-b001.
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This essay presents models of multiparty negotiation as a means to compare the conventional public meetings format of planning to a preliminary process, the technical advisory committee. A metric of market concentration, the Herfindahl-Hirschman Index, is used to quantify the structural advantages in each, and presented within the context of municipal planning processes. In doing so, this work advances several propositions: First, open meetings expand power differentials between parties, which lead to outcomes that reflect the political efficacy of participants over the regulatory purpose of government. Second, such meetings create substantial transaction costs for the public, creating a barrier to the expression of community values. Finally, preliminary processes constitute a more effective forum for citizen participation than open meetings.
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Coltoff, Alexander, Joseph G. Jurcic, Peter Campbell, Daniel J. Lee, Mark L. Heaney, Nicole Lamanna, Todd L. Rosenblat, Mark G. Frattini, and George Vlad. "Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia." Blood 136, Supplement 1 (November 5, 2020): 12–14. http://dx.doi.org/10.1182/blood-2020-134237.
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Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.
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Ewins, Karl, Fionnuala Ni Ainle, Eoghan Dunlea, Sarah Kelliher, Vicky Sandys, Hannorah Rooney, Lily Macken, and Ni Cheallaigh Cliona. "Socially Excluded Persons in Ireland Have an Increased Annual Risk of Hospitalisation Due to Venous Thromboembolic Disease." Blood 134, Supplement_1 (November 13, 2019): 4702. http://dx.doi.org/10.1182/blood-2019-130371.
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Introduction Social exclusion in Ireland is strongly associated with injecting drug use, particularly injection of opiates into the groin: a strong risk factor for venous thromboembolism (VTE) (O'Reilly et al, 2015). Ní Cheallaigh et al (2017) reported a high burden of disease in socially excluded individuals in Ireland that can be effectively addressed by dedicated service planning and care provision. VTE in socially excluded persons has been identified by our group as a key knowledge gap. We have generated preliminary data demonstrating that socially excluded people account for a significant proportion of patients presenting with VTE in Dublin. Methods We extracted national Hospital InPatient Enquiry (HIPE) data from Health Atlas Ireland using the methods outlined in Kevane et al (2019). We identified individuals as "socially excluded persons" if their records contained one or more of the variables identified by Aldridge et al (2018): homeless individuals, prisoners, sex workers and individuals with substance use disorders. We identified all emergency inpatient hospital admissions for those with any diagnosis of VTE during 2017 using VTE-associated ICD-10 codes. Results There were 494,972 emergency inpatient admissions in patients >16 years during this 12 month period, of which 5,717 (1.2%) had a VTE diagnosis (55% of which were DVTs). 306 (5.3%) of hospital episodes with VTE occurred in socially excluded individuals. Applying maximum and minimum assumptions on the estimated population denominator we estimated that overall the annual incidence rate of VTE-related hospitalisation per person was approximately 10-fold higher in socially excluded individuals when compared to the general population (in which it was 0.12%). Conclusions This is the first time that an approximately ten-fold increase in the risk of hospitalisation due to VTE has been shown to be associated with social exclusion. This information was generated from national data, using surrogate identifiers for socially excluded persons. We hypothesise that detailed characterisation of VTE events in socially excluded clients will permit improved service planning and care provision for these vulnerable patients, enabling better VTE prevention and management. This may save lives and prevent the disabling and common long-term consequence of post-thrombotic syndrome with debilitating leg ulcers, which in this population results in numerous admissions and severe mobility issues. Planning such initiatives has the potential to reduce morbidity and mortality, improve quality of life but also to reduce hospital admissions (which are hugely over-represented in this patient group), save costs and resources and most importantly results in more equitable health care for socially excluded patients. Disclosures Ewins: Amgen: Other: Conference Fees & Travel Expenses; Bayer: Other: Conference Fees & Travel Expenses. Ni Ainle:BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding; Actelion: Research Funding. Cliona:Pfizer: Research Funding; MSD: Other: Travel Expenses.
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Abboud, Miguel R., Jo Howard, Rodolfo Cançado, Wally R. Smith, Birol Güvenç, Noemi Espurz, Marine Weill, and Mariane de Montalembert. "Crizanlizumab Versus Placebo, with or without Hydroxyurea/Hydroxycarbamide, in Adolescent and Adult Patients with Sickle Cell Disease and Vaso-Occlusive Crises: A Randomized, Double-Blind, Phase III Study (STAND)." Blood 134, Supplement_1 (November 13, 2019): 998. http://dx.doi.org/10.1182/blood-2019-125775.
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Background: Sickle cell disease (SCD) comprises a group of genetic blood disorders caused by a single missense mutation (Glu6Val) in the β-globin gene. In early childhood, SCD progresses into a systemic disease resulting in complications that include vaso-occlusion, multi-organ damage, and early death. P-selectin, an adhesion molecule expressed on activated vascular endothelial cells and platelets, contributes to the cell-to-cell and cell-to-endothelium interactions that are involved in the pathogenesis of vaso-occlusive crisis (VOC) in SCD. Crizanlizumab is an investigational, humanized, anti-P-selectin monoclonal antibody under evaluation for the prevention of VOCs in patients with SCD. In the Phase II SUSTAIN study, crizanlizumab 5.0 mg/kg significantly reduced the median annual rate of VOCs compared with placebo (P=0.010). The purpose of the randomized, double-blind, Phase III placebo-controlled STAND study is to compare the efficacy and safety of two doses of crizanlizumab (5.0 and 7.5 mg/kg) versus placebo in adolescent and adult patients with SCD and a history of VOCs leading to a healthcare visit. Methods: The STAND study aims to randomize 240 patients with SCD (all SCD genotypes eligible) aged ≥12 years (including at least 48 adolescents), who experienced ≥2 VOCs leading to a healthcare visit in the 12 months prior to screening, and who are not planning to initiate hydroxyurea (HU)/hydroxycarbamide (HC) or erythropoietin-stimulating agents (ESAs) or L-glutamine during the trial. Patients who have been taking HU/HC, ESAs or L-glutamine for ≥6 months and plan to continue the same dose at least until they reach 1 year of investigational treatment will be permitted. Exclusion criteria include: history of stem cell transplant; receipt of blood products within 30 days of the first dose; participation in a chronic exchange or transfusion program; and receipt of therapeutic anticoagulation or antiplatelet therapy within the 10 days prior to the first dose. Patients in the study will be randomized into 1 of 3 treatment arms: crizanlizumab 5.0 mg/kg, 7.5 mg/kg, or placebo administered intravenously over a period of 30 minutes on week 1 day 1, week 3 day 1, and day 1 of every 4-week cycle thereafter. Primary analysis cut-off date will occur once all patients have reached 1 year of treatment or discontinued within year 1. An open-label extension will offer the possibility to switch treatment (Figure). The primary endpoint is the annualized rate of VOCs leading to a healthcare visit in each treatment group over the first year of treatment. The key secondary endpoint is the annualized rate of all VOCs (leading to a healthcare visit or treated at home) over the first year post randomization. Other objectives include the rate of patients free from VOCs leading to a healthcare visit, time to first and second VOC leading to a healthcare visit, number of days with VOCs leading to a healthcare visit, healthcare resource utilization, SCD-related renal damage, pharmacokinetics and pharmacodynamics (P-selectin inhibition), immunogenicity, biomarkers and quality of life. The primary efficacy endpoint will be analyzed based on the data from the full analysis set comprising all randomized patients. A negative binomial regression model with treatment and randomization stratification factors as covariates will be used for analysis, with the logarithm of observation time as offset. The estimates of annualized VOC rates between treatment groups and their 95% confidence intervals will be provided [NCT03814746, EudraCT 2017-001746-10]. Conclusion: This study is designed to confirm the efficacy and safety of crizanlizumab 5 mg/kg and assess the safety and efficacy of a higher dose (7.5 mg/kg) in patients with SCD and history of VOCs. Figure. Disclosures Abboud: GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other: Travel support; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Modus: Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Howard:Resonance Health: Other: Travel grant; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Imara: Consultancy, Other: Travel grant. Cançado:Novartis: Membership on an entity's Board of Directors or advisory committees. Smith:Novartis: Consultancy, Honoraria. Espurz:Novartis Pharma AG: Employment. Weill:Novartis Pharma AG: Employment. de Montalembert:bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Vladimer, Gregory Ian, Christian Schmidl, Andre Renderio, Susanne Schnabl, Tea Pemovska, Berend Snijder, Thomas Krausgruber, et al. "Integrated ATAC-Seq and Chemosensitivity Profiling Identifies Rational Drug Combinations in Ibrutinib-Treated CLL Patients." Blood 130, Suppl_1 (December 7, 2017): 800. http://dx.doi.org/10.1182/blood.v130.suppl_1.800.800.
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Abstract Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of malignant B lymphocytes in the blood, bone marrow, spleen, and lymph nodes. This process is associated with constitutively activated B cell receptor (BCR) signaling, and interference with BCR signaling provides therapeutic benefit. Specifically, the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib prevents BTK tyrosine phosphorylation and thereby interferes with pathways downstream of BCR. It has shown high clinical response rates in patients with relapsed and refractory CLL, including patients with adverse cytogenetic profiles. Despite the high response rates achieved by ibrutinib, the drug has important limitations. Ibrutinib treatment induces a redistribution of CLL cells from protected niches to the peripheral blood, and the cellular response to ibrutinib is slow and often incomplete. Further, there is no evidence that a cure can be achieved, and drug discontinuation (e.g., due to toxicity) is associated with rapid progression. Even among patients that tolerate long-term treatment with ibrutinib, a considerable percentage develops drug resistance (e.g., due to mutations in the BTK gene), BTK independent disease progression, or Richter's transformation, indicating drug synergies with ibrutinib may increase prognosis. Recent studies have explored the combined use of ibrutinib with the proteasome inhibitor carfilzomib, the BCL2 inhibitor venetoclax, and the HDAC inhibitor abexinostat in preclinical models, which has shown promising initial results. However, these approaches were largely empirical, and little is known about the gene-regulatory effects of ibrutinib treatment in CLL cells. Here, we charted the ibrutinib-induced chromatin regulatory landscape of CLL, and in parallel mapped targetable pathways for synergistic combination therapies that could potentially improve disease control. Therefore, peripheral blood from 24 fully characterized CLL cases, including the clinical and hematological parameters, disease stage, cytogenetics (13q del, 11q del, 17p del, trisomy 12), p53 and IGHV mutation status were collected before and during therapy with ibrutinib. Chromatin accessibility was measured by ATAC-seq, a powerful assay for mapping the genome-wide regulatory landscape of cell. In addition, the ex vivo chemosensitivity to >140 drugs on paired CLL samples collected before and during ibrutinib treatment was measured using a novel method for ex vivo single-cell drug cytotoxicity profiling in primary samples (Snijder et al. submitted; NCT03096821). We bioinformatically analyzed the changes in chromatin accessibility and differential drug responses before and during ibrutinib treatment, thereby establishing a comprehensive picture of the cellular responses to the drug. As a proof of principle for this approach, ex vivo results confirmed strong clinical activity of BCL2 inhibitors with and without ibrutinib. We identified increases in chromatin accessibility and chemosensitivity in proteasome, inflammatory NF-κB/TNF signaling, CoA biosynthesis, PI3K/Akt, caffeine metabolism pathways, along with changes affecting genes such as FOXO3 and IκBa. Integration of chromatin accessibility and differential chemosensitivity data revealed robust ibrutinib-induced signatures, which we exploited to prioritize approved drugs and drug candidates for synergistic treatment of CLL cells in co-culture models using primary bone marrow stromal cells. Cell viability assays revealed that ibrutinib treatment in vivo and in vitro sensitizes CLL cells to compounds such as the proteasome inhibitor bortezomib, the JAK inhibitor ruxolitinib, the PLK1 inhibitor volasertib, and the bisphosphate zoledronate. In summary, our results show that the synergistic combination and bioinformatic integration of chromatin profiling with functional drug screening is a powerful tool to identify targetable pathways in CLL. This approach may be useful for designing personalized therapies as well as the rational planning of clinical studies. Our approach is directly transferable to other leukemic diseases in which malignant cells can be obtained for chromatin profiling and drug sensitivity analysis, thus providing a widely applicable tool for the rational development of combination therapies. Figure Figure. Disclosures Vladimer: Allcyte Gmbh: Equity Ownership. Snijder: Allcyte: Equity Ownership. Krall: Allcyte Gmbh: Equity Ownership. Hoermann: Gilead: Honoraria, Research Funding; Amgen: Honoraria; Novartis: Honoraria; Ariad: Honoraria. Staber: Morphosys: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Gilad: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria. Superti-Furga: Allcyte GmbH: Equity Ownership. Jaeger: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: 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; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Di Maio, Nicoletta, Giovanna Russo, Susanna Barella, Gian Luca Forni, Raffaella Colombatti, Lucia Notarangelo, Giovanna Graziadei, et al. "Influenza Vaccination in Asplenia: Improving Quality of Care in Time of Coronavirus." Blood 136, Supplement 1 (November 5, 2020): 39–40. http://dx.doi.org/10.1182/blood-2020-142335.
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Introduction Asplenic patients are at high risk of potentially fatal invasive infections, such as sepsis, meningitis, and pneumonia. It has been shown that infection from influenza viruses can precede or increase the risk of bacterial infection and of serious complications of the underlying disease. International and national guidelines recommend annual influenza vaccination in asplenic subjects. Following the Covid-19 pandemic, the major government and medical-scientific institutions in the US and in Europe have been planning how to contain infection during the 2020-2021 influenza season. Extending influenza vaccination is the safest and most effective way to reduce the circulation of influenza virus and to promote the correct diagnosis and management of suspected cases of SARS-CoV-2. Influenza vaccination also reduces complications associated with the underlying disease and visits to Emergency Units. Our study aims to evaluate influenza vaccination in a large population of asplenic patients and explore the main causes for non-vaccination to identify critical areas for improvement in the vaccination programme in these at-risk patients for the 2020-2021 influenza season. Methods The Italian Network of Asplenia (INA) is made up of 88 doctors working in 50 clinical centers in 27 cities and 16 of the 20 regions of Italy. It aims to build a large, prospective cohort of asplenic patients throughout Italy through which to study the interaction between asplenia and its associated underlying conditions, collecting precise, accurate data also in cases of rarer diseases. The study also aims to improve the quality of healthcare for this at-risk population. The number of patients enrolled in the Network who had had at least one dose of influenza vaccine at the time of diagnosis of asplenia was retrieved from the INA database. All participating centers were asked to answer a questionnaire to report the main obstacles for influenza vaccination. Results At 1st August 2020, 1,670 patients had been enrolled in the INA (783 females; 887 males). All underlying causes of asplenia are shown in Table 1. Only 466 (28%) patients had had at least one influenza vaccination, while 1,204 (72%) had never been vaccinated since diagnosis of asplenia. Thirty-five (70%) of the 50 centers answered the questionnaire. Main causes of non-vaccination were physicians' ambivalence concerning vaccination and patients' inadequate awareness or logistical problems. Conclusions These data show very low seasonal influenza vaccination cover even though asplenic patients are considered at-risk of complications associated with infection from influenza viruses. Since the 2020-2021 influenza season could see influenza viruses in circulation with SARS-CoV-2, influenza vaccination must be expanded as widely as possible, in particular to subjects of all ages at high risk. These results reveal important areas of concern in the management of asplenic patients and the need to improve the quality of information to physicians and patients alike. The INA co-ordinating center will launch a campaign to provide information and organize ad hoc meetings to widen influenza vaccination coverage in asplenic patients and reduce the pressure on the national health service during the next influenza season. Disclosures Forni: Novartis: Membership on an entity's Board of Directors or advisory committees. Colombatti:Addmedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giona:Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Research Funding. Ferrero:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Servier: Speakers Bureau. Perrotta:Novartis: Consultancy, Research Funding, Speakers Bureau. Casale:Novartis: Membership on an entity's Board of Directors or advisory committees.
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Berry, Donald, Kristine Broglio, Carol Ward, Federico Mattiello, Deniz Sahin, Tina G. Nielsen, Anna McGlothlin, et al. "Patient-Level Meta-Analysis of End-of-Therapy PET-CR as a Surrogate Endpoint for PFS and OS in Patients with Previously Untreated DLBCL: Implications for Clinical Trial Design." Blood 134, Supplement_1 (November 13, 2019): 4101. http://dx.doi.org/10.1182/blood-2019-124067.
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Introduction: The use of PET-CR as a surrogate endpoint would expedite the development of novel therapies and enable better estimates of sample size based on early outcomes of a trial. Previous studies have reported an association between end-of-therapy (EOT) PET results and long-term progression-free (PFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) patients receiving standard first-line chemoimmunotherapy. We have also previously shown that the overall predictability of PET-CR for PFS and OS in these trials is similar to that in 18 literature-based studies. (15-ICML 2019, P195). To assess the potential for PET-CR as a surrogate endpoint in registration trials, we conducted a prospectively designed individual patient-level-data meta-analysis of available clinical trials. Methods: We synthesized patient-level data from three prospective phase II and III trials (GOYA [NCT01287741], GATHER [NCT01414855], MAYO [NCT00670358]) conducted in previously untreated DLBCL patients, using a Bayesian hierarchical model. We considered the two treatment arms in GOYA (GOYA-R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] and GOYA-G-CHOP [obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone]) separate; hence a total of four arms, excluding patients without baseline PET scans. We investigated the relationship between PET-CR and long-term survival outcomes overall and within patient subgroups. We used Kaplan-Meier plots to compare survival endpoints by PET-CR status. We considered hypothetical RCTs that have PET-CR and PFS as endpoints to show how our model of the relationship between PET-CR and PFS can be used to predict the trial outcome. Results: We included 1496 patients (GOYA-R, GOYA-G, GATHER, MAYO, respectively: 665, 669, 100, 62). EOT PET-CR status was determined by the Lugano criteria in GOYA and by IHP in the other two studies. The overall rate of PET-CR was 72%; respectively 72%, 73%, 62% and 74% per arm. Panel A of the Figure shows Kaplan-Meier plots of PFS by PET-CR status. The Bayesian modeled hazard ratio (HR) comparing PET-CR versus nonCR was 0.13 (95% CI: 0.10, 0.15). The model can be used in planning a clinical trial as follows. Suppose a new therapy improves the PET-CR rate from 70% to 85%. Based on our model the expected HR for PFS treatment effect would be 0.71 (95% CI: 0.58, 0.84). The trial sample size required to demonstrate such an improvement with 90% power is about 650 patients, assuming an accrual rate of 50 patients per month and a minimum follow-up time of 12 months. Panel B of the Figure shows the model-based PFS HR and its CI (shaded) as it depends on the PET-CR rate of the new therapy. This plot also shows the estimated total trial sample size (in red), again assuming the relationship between PET-CR and PFS in our model. However, our model may not apply for the new therapy; and the trial could have an adaptive design with final sample size tailored to the accruing information about PET-CR and PFS and their relationship for the therapies in the trial. Conclusions: Achieving an EOT PET-CR in newly diagnosed DLBCL is highly predictive of favorable outcome in the populations we considered. The estimated HR is 0.13 for PFS, PET-CR versus nonCR, and it is 0.10 for OS. Based on our model, a treatment that improves PET-CR rate could be reasonably expected to have a benefit on PFS and OS, for the populations we considered. Whether a new therapy, with a different mechanism of action, that improves PET-CR rate will extend PFS in a clinical trial is less clear. An adaptive trial could be initiated based on our model as a hypothesis. This hypothesis can be verified or updated using accruing information in the trial itself. Our model can also help in planning clinical trials for re-estimating sample size during the trial and considering early stopping for futility. Further work should investigate the applicability of PET-CR in predicting PFS and/or OS for treatments that have different mechanisms of action and for other populations of patients. Acknowledgements: This work was funded by Genentech/Roche. Disclosures Berry: Berry Consultants, LLC: Consultancy, Employment, Equity Ownership, Other: Berry Consultants, LLC is a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia. Broglio:Berry Consultants LLC: Employment. Ward:Hoffmann La Roche: Employment, Equity Ownership. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. McGlothlin:Berry Consultants, LLC: Consultancy, Employment. Elliott:Berry Consultants, LLC: Employment. Sehn:Lundbeck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Trněný:Abbvie: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Vitolo:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: 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; Janssen: 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, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding.
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Ibidunni, Laura, Kristin Paulyson Nunez, Jude C. Jonassaint, and Laura De Castro. "Beliefs and Practices Among Adults with Sickle Cell Disease Regarding Reproductive Health Decisions and Family Planning." Blood 134, Supplement_1 (November 13, 2019): 2101. http://dx.doi.org/10.1182/blood-2019-122255.
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Background. With improvements in early diagnosis and health care for those with sickle cell disease (SCD), many affected are living longer and having families of their own. Despite medical advancements in this field, pregnancy in this population is still associated with an increased risk for maternal and infant morbidity and mortality compared to the general population. Due to increased maternal risks associated with childbirth and the risk of having children who inherit the disease, communication between providers and patients regarding reproductive health is imperative. However, providers' understanding of reproductive health knowledge and perceptions within this population and methods to improve family planning education which can result in autonomous and informed decisions amongst adults with SCD is still limited. Our study aims to quantify current knowledge and perceptions in adults with SCD regarding reproductive health choices and genetic counseling. Methodology. Study participants had to be at least 18 years old and have a diagnosis of SCD. Participants were asked to complete an anonymous survey instrument consisting of 43 questions that was administered using Qualtrics Survey Software. The survey was comprised of questions about participants' demographics, knowledge base and perceptions about reproductive health and genetic counseling. Participants were recruited using convenience sampling in two ways: 1) through online social media via Facebook and Twitter sickle cell patient groups; 2) patients at an adult sickle cell clinic were invited to complete the survey in clinic or afterwards. A total of 152 participants accessed the survey, and of those, 105 that completed more than 90% of the survey, were used in the analysis. Results. Demographics: Participants were between 18-57 years of age, 85 females (81.0%), 19 males (18.1%), and 1 transgender (1.0%). Among 99 people who disclosed their place of birth, 49 (49.5%) were from North America (U.S. and Canada), 38 (38.4%) were from African countries, and 12 (12.1%) were from other parts of the world. Fifty-six (53.5%) reported having no children and 49 (46.7%) had a minimum of one child. Knowledge: Ninety-three (88.6%) agreed that women with SCD are at a higher risk of pregnancy complications and 82 (78.1%) understood the chance of having a child with SCD if both parents have the trait. However, one-third (33.3%) did not know that women with hemoglobin SS will always pass down the trait to their children, and 90 (85.7%) were unaware of contraceptive methods available that have been shown to reduce the risk of sickle cell crisis. Perception: Sixty-four (61.5%) participants agreed that having children in the future was very important to them. Majority, 96 (91.4%), also agree that they want to avoid having a child with SCD. Fifty-eight (55.2%) indicated they received a majority of their information about partner screening, and reproductive health from a healthcare provider while 47 (44.8%) reported receiving most of their information from other sources (school, family members, friends, and independent research). Fifty-nine (59.6%) out of the 89 participants who responded agreed that they wished they had more conversations about partner screening and reproductive health with their hematologist. Seventy-five (72.1%) respondents reported that they know what a genetic counselor is and 40 (39.2%) reported having formal genetic counseling in the past. Among those who know what a genetic counselor was, only 30 (40.0%) actually knew how to get in contact with a genetic counselor in their community. Of those that have had formal genetic counseling in the past 15 (37.5%) reported having formal genetic counseling by a genetic counselor, while 25 (62.5%) had some form of counseling by another healthcare provider (i.e. hematologist, gynecologist, PCP, other); and 24 (60%) had one child or more. Conclusion. Our study suggests that many individuals with SCD may still lack important reproductive health and genetic counseling knowledge and resources. We believe that improved communication between healthcare providers and SCD patients is wanted and needed by this population to prevent pregnancy-related complications and improve outcomes. Future studies should focus on genetic counseling access, and reproductive health and family planning education to promote ongoing discussions and increase knowledge of both providers and individuals with SCD. Disclosures Nunez: American Board of Genetic Counseling: Membership on an entity's Board of Directors or advisory committees; Foundation for Women and Girls with Blood Disorders: Membership on an entity's Board of Directors or advisory committees. De Castro:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy.
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Ibidunni, Laura, Kristin Paulyson Nunez, Jude C. Jonassaint, and Laura De Castro. "Regional Differences in the Beliefs and Practices Among Adults with Sickle Cell Disease Regarding Reproductive Health and Family Planning: A Sub-Analysis." Blood 134, Supplement_1 (November 13, 2019): 2114. http://dx.doi.org/10.1182/blood-2019-129554.
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Background. Sickle cell disease (SCD) remains the most common genetic hematologic disorder, with a disproportionally high incidence and prevalence in African countries. It is associated with an increased risk of maternal and infant morbidity and mortality compared to the general population. As more young adults living with SCD reach healthier reproductive ages, it is imperative that there is open communication between providers and patients regarding reproductive health, maternal risks associated with childbirth, and the risk of having children who inherit SCD. It is also important that providers understand reproductive health knowledge and perceptions within this population and methods to improve family planning education. We performed a survey-based study aimed to quantify current knowledge and perceptions regarding reproductive health choices, family planning and genetic counseling-presented in another abstract-. Here we present a sub-analysis, aiming to quantify differences, based on the participants region, concerning reproductive health knowledge and perceptions amongst adults with SCD. Methodology. All study participants were at least 18 years old and have a SCD diagnosis. They were asked to complete an anonymous survey instrument consisting of 43 questions, administered using Qualtrics Survey Software. The survey was comprised of questions about participants' demographics, knowledge base and perceptions about reproductive health and genetic counseling. Participants were recruited using convenience sampling in two ways. The first was through reaching sickle cell patient groups online via social media through Facebook and Twitter. The second was at an adult SCD clinic where participants were invited to complete the survey in clinic or afterwards. 152 participants accessed the survey, and 105 that completed more than 90% of the survey were included in the primary analysis. Further analysis was done to compare data from 70 participants who did not migrate from their reported birth country. Comparison groups were generated using reported birth country and current location. Forty-seven participants from North American (U.S. and Canada) and 23 from African Countries (Nigeria, Zambia, Kenya, and South Africa) were included in this analysis. Results. Demographics: Among the 70 analyzed, 47 (67.1%) respondents were from North America (N.A.) and 23 (32.9%) were from African Countries (A.C). Knowledge: People from both N.A. and A.C. agreed that women with SCD were at higher risk of pregnancy complications (91.5% and 87%, respectively), and understood the chance of having a child with SCD if both parents have the trait (78.7% and 78.3%). Perception: Participants from N.A. reported receiving most of their information about family planning, partner screening, and reproductive health from healthcare providers more frequently than participants from A.C. (67% vs 39%). More participants from A.C, 21 (91.3%), agreed that having children in the future was important to them, while 21 (45%) of the participants from N.A agreed to this. Participants from A.C. and N.A. equally agreed that is it important to know if their partner has the sickle cell trait (SCT) (95.7% and 93.6%). However, more participants from A.C., 21 (91.3%), reported having any discussion with their partner about being screened for the SCT, versus 29 (61.8%) from N.A. Participants from N.A. and A.C. were equally knowledgeable about what a genetic counselor is (72% v. 70%, respectively), and utilized genetic counseling at low rates (37% v. 39.1%, respectively). Most participants reported that they do not know how to get in contact with a genetic counselor in their community, 31 (66%) from N.A. and 18 (78.3%) from A.C. Many have not been referred to a genetic counselor in the past by a healthcare provider, 39 (83%) from N.A. and 20 (87%) from A.C. Conclusion. Our study suggests that there are differences in reproductive health and genetic counseling knowledge and perceptions when comparing SCD participants living in two world regions. Independently of regional differences, many people with SCD appear to lack key reproductive health and genetic counseling knowledge and resources. We believe there is a need for improved communication between providers and patients in family planning education, as well as further studies to address access to reproductive health and genetic counseling resources. Disclosures Nunez: American Board of Genetic Counseling: Membership on an entity's Board of Directors or advisory committees; Foundation for Women and Girls with Blood Disorders: Membership on an entity's Board of Directors or advisory committees. De Castro:Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy.
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Issaragrilsil, Surapol, Yeow-Tee YT Goh, Anskar Y. H. Leung, S. Fadilah S. Abdul Wahid, and Hwai Tzeng Cheng. "A Retrospective Study on Safety, Efficacy and Cost of the Chemo-Mobilization for Patients Planned to Undergo Autologous Hematopoietic Stem Cell Transplant: The Secom Study." Blood 124, no. 21 (December 6, 2014): 5903. http://dx.doi.org/10.1182/blood.v124.21.5903.5903.
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Abstract Introduction: Failure of hematopoietic stem cell (HSC) mobilization occurs in 5 to 30% patients planning for high dose chemotherapy and autologous HSC transplantation worldwide. It has adverse impact on patient outcomes and significantly increases health care burden. Data regarding HSC mobilization based on chemotherapy + granulocyte colony stimulating factor (G-CSF) in Asia are currently limited. Objective: The primary objective was to determine the safety and efficacy of HSC chemo-mobilization protocols in Asia for patients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) planning for autologous HSCT. The secondary objective was to provide an estimate of the cost of chemo-mobilization in Asian countries Study Design: This was a multicenter, multinational retrospective observational study. Patients with NHL or MM undergoing chemo-mobilization for planned autologous HSCT between 1 Jan 2009 to 31 Dec 2012 in five Asian countries including Thailand, Singapore, Malaysia, Hong Kong and Taiwan, were retrospectively included in the study. Patient demographics, disease diagnoses, previous treatment history as well as complete blood counts prior to chemo-mobilization and apheresis, were collected. Results: A total of 526 patients (male/female = 207/219) were analyzed (diagnoses: NHL=257; MM=269). 160 patients were recruited from Thailand, 98 from Malaysia, 161 from Taiwan, 59 from Singapore and 48 from HK. Median age for the overall group was 53 years (range: 15-82). The most common mobilization regimen was cyclophosphamide + G-CSF; 235 (87.4%) in MM and 72 (28%) in NHL patients. 448 (85.2%) patients had reached at least HSC yield of 2 x 106CD 34+ cells/kg in 1 or 2 apheresis days. During chemo-mobilization, 108 (20.5%) patients were without negative clinical events (grade 3/4 neutropenia, febrile neutropenia, prolonged hospitalization, bone pain, fever, gastrointestinal, line infections or others). Grade 3/4 neutropenia and febrile neutropenia occurred in 401 (76.2%) and 72 (13.7%) patients, respectively. Median number of apheresis sessions was 2 (range: 1-5). Median cost of mobilization was 6,200USD (9,000-48,000). The respective median costs in USD (range) was; 3,500 (1,500-28,500) in Thailand, 6,900 (2,300-29,600) in Malaysia, 7,700 (3,400-48,000) in Taiwan and 9,200 (900-45,400) in Singapore. 436 (82.9%) patients proceeded to receive high dose chemotherapy and HSCT but 94 (17.87%) patients did not, due to insufficient HSC yield (n=26, 4.94 %), progression of disease (n=18, 3.42 %), patient not fit/ withdrawal from study (n=19, 3.61 %), patient expiry (n=11, 2.09 %) and other reasons (n=20, 3.80 %). Conclusion: Cyclophosphamide and G-CSF is the most common mobilization regimen used in Asian countries. Current chemo mobilization regimens are associated with a satisfactory rate of successful stem cell collection but with a high rate of significant toxicity. More than three-quarter of patients suffered from grade 3/4 toxicity during chemo-mobilization, however, only 20% of them had febrile neutropenia. Variations exist in the cost of chemo-mobilization in Asia, both among and within countries. Disclosures Goh: Novartis Pte Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceuticals Inc: Research Funding; Bristol-Myres Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hospira Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Merli, Francesco, Stefano Luminari, Alessandra Tucci, Federica Cavallo, Caterina Mammi, Luigi Rigacci, Erica Finolezzi, et al. "The Elderly Project By the Fondazione Italiana Linfomi (FIL): A Prospective Multidimensional Assessment of Elderly Patients with Diffuse Large B-Cell Lymphoma." Blood 128, no. 22 (December 2, 2016): 3049. http://dx.doi.org/10.1182/blood.v128.22.3049.3049.
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Abstract Introduction: The initial approach to elderly patients with Diffuse Large B-cell lymphoma (DLBCL) is usually based on the subjective judgment of the physician on the individual patient's ability to tolerate treatment with curative intent. "Comprehensive Geriatric Assessment" (CGA) is based on the use of the ADL (Activity of Daily Living), IADL (Instrumental ADL) and CIRS-G (Comorbidity Index Rating Scale for Geriatrics) scales and represents a tool to standardize initial patients fitness assessment and for planning systemic therapy. So far CGA has been rarely used in prospective studies and lacks a formal validation in patients with lymphoma. Objectives: FIL is conducting a prospective study with the aim of validating the use of CGA on a large series of elderly patients with DLBCL and to test a CGA based approach to the patient. CGA results will be used to define treatment goals that are the cure for the FIT subjects, and palliation for the FRAILs. Treatment goal for the UNFIT is cure with less toxic regimens. Methods: This study is conducted using a web based platform, accessible from the reserved area of the FIL website, to perform a quick and objective CGA evaluation of consecutive patients ≥ 65 years with untreated DLBCL. Patients younger than 80 years, without impairment of ADL and IADL and without severe comorbidities were considered FIT; those with intermediate fragility or those older than 80 years with FIT profile were classified as UNFIT (UN); those with severe impairment of ADL, IADL and CIRS and those older than 80 years with an UN profile were classified as FRAIL (FR). Informed consent was required to enrol patients in this study; the planned sample size was 1000 patients. Results: The study started in December 2013. At time of current analysis 792 patients have been registered by 45 centres: 328 (41%), 207 (26%), and 257 (33%) were classified as FIT, UN and FR, respectively. Median age was 77 years (yrs) (65-95); 73 (65-79), 80 (65-95) and 81 (65-95) yrs for FIT, UN and FR patients respectively; overall 65% were in stage III-IV. By univariate analysis, the three categories differed in terms of median age (p<0.001), B-symptoms (p=0.035), ECOG PS>1 (p<0.001), elevated LDH (p=0.035) and IPI score (p=0.004). Fourty-nine percent of cases were defined as UN only because of age (≥80 yrs); other reasons for UN were impairment of IADL, ADL in 30% and 18%, respectively. Only 3% of cases were UN due to CIRS (5-8 comorbidities of grade 2). Regarding FRAIL patients 27% of patients were classified in this group due to CIRS impairment, 24% and 18% due to IADL and ADL impairment, respectively. In remaining 31%, patients were FRAIL due to age ≥80 yrs (Figure 1). The most frequent altered ADL items among UN and FR patients were continence (15%) and bathing (30%), respectively; regarding IADL the most frequent altered items were buying and food preparation for either UN (19% and 12%) and FR (53% and 41%). Most frequent grade 3 comorbidities among the 257 FR patients were those referred to heart (16%), vascular system (9%), muscoloskelatal (7%), and genitourinary (5%). Data on planned treatment were available in 643 patients. Rituximab was used in all but 6 (2%), 18 (12%), and 35 (17%) FIT, UN, and FR cases. Treatment with curative intent (full doses R-CHOP-like regimens) was used in 94% and 65% of FIT and UNFIT cases; surprisingly curative intent was declared also in 38% of FRAIL cases. Six percent, 25% and 26% of FIT, UN and FR patients were treated with an attenuated R-CHOP-like immuno-chemotherapy regimens. Palliative regimens were used in 36% and 10% of FR and UN patients respectively. Conclusion: The preliminary data of Elderly Project showed that, with the CGA criteria as adopted in this study, the 59% of elderly patients with DLBCL at diagnosis were not FIT. Rituximab and doxorubicin containing regimen seems to be the reference treatment for FIT, UN and also for a significant proportion of FR patients but the actual value of using this approach for non-FIT patients is not clear and will be assessed with this project. Figure 1 Contribution of Activity of Daily Living (ADL), Instrumental ADL (IADL), Comorbidity Index Rating Scale for Geriatrics (CIRS-G) scales and Age to Fitness Status Figure 1. Contribution of Activity of Daily Living (ADL), Instrumental ADL (IADL), Comorbidity Index Rating Scale for Geriatrics (CIRS-G) scales and Age to Fitness Status Disclosures Merli: Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Luminari:Roche: 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, Accomodations, Expenses; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Cavallo:JANSSEN: Honoraria; CELGENE: Honoraria; ONYX: Honoraria. Chiappella:Roche: Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Speakers Bureau; Teva: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Celgene: Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee.
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Giroux, Dominique, Mélanie Tremblay, Karine Latulippe, Véronique Provencher, Valérie Poulin, Anik Giguere, Véronique Dubé, et al. "Promoting Identification and Use of Aid Resources by Caregivers of Seniors: Co-Design of an Electronic Health Tool." JMIR Aging 2, no. 2 (August 22, 2019): e12314. http://dx.doi.org/10.2196/12314.
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Background The importance of supporting caregivers is recognized in home care for older persons, and facilitating their help-seeking process is a way to meet that need. The use of electronic health (eHealth) is a potentially promising solution to facilitate caregivers’ help-seeking process. Objective The aim of this research was to develop, in partnership with community organizations, health and social service professionals and caregivers, an eHealth tool promoting the earlier identification of needs of older persons and an optimal use of available resources. Methods To design the tool, 8 co-design sessions (CoDs) were conducted and 3 advisory committees were created (in 11 regions) in Quebec between May 2017 and May 2018. A variety of methods were used, including the sorting method, the use of personas, eHealth tool analysis, brainstorming, sketching, prototyping, and pretesting. Results A total of 74 co-designers (women n=64 and men n=10) were recruited to participate in the CoDs or the advisory committees. This number allowed for the identification of needs to which the tool must respond and for the identification of its requirements (functionalities and content), as well as for the development of the information architecture. Throughout the study, adjustments were made to the planning of CoD, notably because certain steps required more sessions than expected. Among others, this was true for the identification of functionalities. Conclusions This study led to the development of an eHealth tool for caregivers of functionally dependent older persons to help them identify their needs and the resources available to meet them. International Registered Report Identifier (IRRID) RR2-10.2196/11634
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Kluch, Yannick, and Amy S. Wilson. "#NCAAInclusion: Using Social Media to Engage NCAA Student-Athletes in Strategic Efforts to Promote Diversity and Inclusion." Case Studies in Sport Management 9, S1 (January 1, 2020): S35—S43. http://dx.doi.org/10.1123/cssm.2019-0027.
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In an increasingly diverse sports industry, inclusive excellence becomes an important axiom to engage a variety of stakeholders. This case study outlines the development of the National Collegiate Athletic Association’s (NCAA) inaugural Diversity and Inclusion Social Media Campaign launched by the NCAA’s Minority Opportunities and Interest Committee in partnership with the national Student-Athlete Advisory Committees. The goals of this campaign were to provide the more than 500,000 student-athletes in the NCAA with a platform to create a dialogue on diversity and inclusion on their campuses as well as to communicate the benefit of inclusive environments to the student-athlete experience. By outlining the steps from the campaign idea to its implementation, this case study provides students with the ability to (a) understand a major sport organization’s planning process for a national social media campaign focused on diversity and inclusion, (b) analyze current diversity trends in the sports industry using the NCAA as an example, (c) trace the NCAA membership’s engagement with the campaign, and (d) determine to which extent a campaign such as this one can serve as a starting point for anchoring inclusive excellence in the fabric of intercollegiate athletics departments.
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Knight, Thomas G., Myra Robinson, Jing Ai, Brittany K. Ragon, Rhonda Davis, Cindy Shiflett, Erica Ruston, et al. "Patient Reported Financial Toxicity in Myeloproliferative Neoplasms." Blood 134, Supplement_1 (November 13, 2019): 2099. http://dx.doi.org/10.1182/blood-2019-128858.
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Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Previous research has demonstrated patients with myeloproliferative neoplasms (MPNs) exhibit a substantial comorbidity burden and have an increased risk of mortality. The purpose of this study was to define rates of FT and the implications on morbidity and mortality in this population using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based specialty practice, were surveyed prior to their visit over a six-month period. All patients were aged ≥18 years and diagnosed with Philadelphia chromosome−negative classical MPNs including myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 4 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Patient disease and treatment characteristics were summarized with frequencies and proportions for categorical variables and medians and ranges for continuous variables. Correlation of numerical FT scores with PROMIS scores was assessed with Pearson correlation coefficients and ANOVA regression. Additionally, model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity (where FT score <=4). Kaplan Meier methods were used to estimate overall survival distributions and log rank tests were used to compare between groups. Results: A total of 51 patients were surveyed. Disease type consisted of 45.1% MF, 31.4% PV, and 23.5% ET. Median age was 62 years. Most patients were high risk by disease specific scoring systems (58.8%), Caucasian (82.4%), and had commercial insurance (56.9%). Median distance from the clinic was 21 miles and median time from diagnosis was 2.2 years. Of the 51 patients surveyed, 20 (39.2%) met the predefined definition of exhibiting severe FT. Lower FT scores (indicating a higher degree of FT) were associated with lower global physical (p < .001) and mental (p < .002) scores by the PROMIS measures (Figure 1). There was no statistically significant difference in survival between patients with FT scores >4 compared to patients with FT scores <=4; however, there was a trend toward decreased survival in those with lower FT scores. The rate of mortality in those with FT score ≤4 was 15.0% compared to 3.2% in those with FT score >4 (p =.287). There also appeared to be a separation of the survival curves when looking at both time from diagnosis and time from survey administration (Figures 2 and 3). Age, race, gender, insurance type, distance from the hospital, disease type, disease specific risk classification, medications utilized, and history of blood/marrow transplant were not found to be significantly different in the two groups. Conclusions: Patients with myeloproliferative neoplasms represent an extremely vulnerable population for financial toxicity with quantifiably increased distress related to this toxicity increasing morbidity and potentially mortality. These findings should be validated in a larger patient cohort and interventions devised to reduce financial distress. Disclosures Knight: Foundation for Financial Planning: Research Funding. Ai:InCyte: Speakers Bureau; Amgen: Speakers Bureau. Trivedi:Incyte: Speakers Bureau. Avalos:Best Practice-Br Med J: Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia; Juno: Membership on an entity's Board of Directors or advisory committees. Symanowski:Boston Biomedical: Membership on an entity's Board of Directors or advisory committees; Carsgen Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Immatics: Membership on an entity's Board of Directors or advisory committees. Grunwald:Amgen: Consultancy; Novartis: Research Funding; Genentech/Roche: Research Funding; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Trovagene: Consultancy; Agios: Consultancy; Incyte: Consultancy, Research Funding; Cardinal Health: Consultancy; Forma Therapeutics: Research Funding; Abbvie: Consultancy; Celgene: Consultancy; Merck: Consultancy; Medtronic: Equity Ownership; Janssen: Research Funding.
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Leissinger, Cindy A., Eric Berntorp, Chiara Biasioli, Shannon Carpenter, Hyejin Jo, Kaan Kavakli, Claude Negrier, et al. "Prophylactic Dosing of Anti-Inhibitor Coagulant Complex (FEIBA) Reduces Bleeding Frequency In Hemophilia A Patients with Inhibitors: Results of the Pro-FEIBA Study." Blood 116, no. 21 (November 19, 2010): 720. http://dx.doi.org/10.1182/blood.v116.21.720.720.
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Abstract Abstract 720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Anecdotal reports and small case series suggest that regular doses of anti-inhibitor coagulant complex (AICC; FEIBA VH) may be effective in preventing bleeding episodes in patients with hemophilia A and inhibitors. The Pro-FEIBA study is the first prospective controlled clinical trial to study the efficacy of AICC in bleed prevention. Study Population and Design: The study was conducted in hemophilia A patients >2 years with a history of high-titer inhibitors who were using bypassing therapy for the treatment of bleeding episodes. Subjects on or planning immune tolerance therapy were excluded as were patients with thrombocytopenia or other bleeding disorders. This randomized, crossover study compared 6 months of AICC prophylactically dosed at 85 U/kg ± 15% on 3 nonconsecutive days per week (Prophy period) to 6 months of on-demand therapy (OD period) (target dose for the treatment of bleeds: 85 U/kg ± 15%). The 2 study periods were separated by a 3-month washout, during which time patients used on-demand therapy for bleeding. Patients were randomized to initially enter either the 6-month Prophy period or the 6-month OD period. Each patient then crossed-over to the alternate study period after a 3-month wash-out. Results: Thirty-four subjects were randomized; 26 subjects completed both study periods and were deemed evaluable per protocol (PP) for efficacy analysis of the primary outcome to compare bleeds in each 6-month treatment period. Eight subjects did not complete the study (1 patient in the Prophy treatment arm and 1 patient in the post-prophylaxis washout period died of complications associated with underlying illness and bleeding, 1 patient experienced an allergic reaction to study drug, 1 patient was lost to follow-up, and 4 patients withdrew from study). All randomized subjects were evaluated for safety. In the PP group, mean patient age was 26.9 years (median: 24.7; range: 2.8–67.9). In the total randomized group, mean patient age was 27.1 years (median: 28.7; range: 2.8–67.9). Of the 26 subjects who completed the study PP, 14 were randomized to enter the Prophy period first and then crossed-over to the OD period, while 12 subjects were initially randomized to enter the OD period and then crossed-over to the Prophy period. For the PP analysis, total bleeds and joint bleeds requiring treatment during the 2 study periods were compared (p-value is for the Wilcoxon signed-rank test of difference between OD and Prophy periods). In addition, bleeds for the 6-month period prior to enrollment were recorded retrospectively on study entry. Efficacy: Both total bleeds and joint bleeds were significantly reduced during the Prophy period as compared with the OD period (p < .0001) Table 1. There was no difference in bleed event rates based on randomization sequence (ie, no carry-over effect was detected when the Prophy period preceded the OD period). Safety: A total of 38 serious adverse events (SAEs) occurred, none of which was thrombotic in nature. One SAE was deemed by the study safety monitor to be related to the study drug (an allergic reaction). Otherwise, treatment was safe and well tolerated. Conclusion: These results in patients with hemophilia A and inhibitors show that AICC, dosed at 85 IU/kg +/− 15% given on 3 non-consecutive days each week was associated with a 62% reduction in all bleeds and a 61% reduction in joint bleeds as compared with on-demand therapy. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: This is a report of a clinical trial using the Anti-Inhibitor Coagulant Complex, FEIBA, as prophylactic therapy to prevent bleeding in hemophilia patients with inhibitors. FEIBA is not currently licensed for use in prophylaxis in the US. Berntorp:Baxter: Consultancy, Honoraria, Research Funding. Negrier:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rocino:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Windyga:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gringeri:Baxter: Consultancy, Honoraria, Research Funding; NovoNordisk: Honoraria.
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Walker, Irwin, Aicha N. Traore, Alfonso Iorio, Bruce Ritchie, Nancy Heddle, Kathryn E. Webert, Jean St. Louis, David Lillicrap, Jerome M. Teitel, and Anthony K. C. Chan. "Ten-Year Canadian National Prospective Data On Utilization of Anti-Hemophilic Concentrates: Indications and Trends." Blood 120, no. 21 (November 16, 2012): 1186. http://dx.doi.org/10.1182/blood.v120.21.1186.1186.
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Abstract Abstract 1186 Background: In response to the transfusion-transmitted AIDS epidemic the Commission of Inquiry on the Blood System in Canada recommended the development of a monitoring and tracking system of product usage. The Association of Hemophilia Clinic Directors of Canada (AHCDC) implemented the Canadian Hemophilia Assessment and Resource Management System (CHARMS) to track factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema-Quebec (HQ), to hospitals and to patients' homes. Objective: To identify the indications and locations for infusions of factor VIII (FVIII), factor IX (FIX), recombinant factor VIIa (rFVIIa) and FVIII inhibitor bypass activity (FEIBA) and review utilization during 2000–2009. Methods: All Canadian patients with hemophilia attend the 26 Canadian Hemophilia Treatment Centres (HTCs) and are registered with the Canadian Hemophilia Registry (CHR; ahcdc.ca) from which they receive a unique number suitable for anonymizing data. HTCs receive product and infusion data from the blood suppliers (CBS, HQ), regional hospitals and patients. HTCs enter these data into their clinic-based CHARMS software program and then export the data to the national database (CentrePoint) where data are validated. Results: From 2000 to 2009, 2,904 patients received, predominantly, FVIII (902 million Units) and FIX (240 million Units). A total of 2,386(82%) had congenital bleeding disorders listed in the Canadian Hemophilia Registry. The remaining 518 were not registered because they either did not have inherited factor deficiency or had registrations pending. Most of FVIII and FIX was infused by patients at home: 90% to 95% for FVIII and 85% to 94% for FIX. The yearly amount of FVIII infused increased over time; this was accounted for by an increase in the number of patients who were treated shown by positive and significant correlation(r=0.89; p=0.04), not so by amount infused per patient which remained constant (p=0.57). Furthermore, there was a linear relationship between an increase in patients and increased utilization, each additional patient predicting for an increased utilization of 96,217 units (P=.04). The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion increased over time, while the proportion used for bleeding remained steady. In 2009, the proportions used for prophylaxis were 73% and 60% for factor VIII and factor IX respectively; for bleeding the proportions were 16% and 30%, for surgery 1% and 4%, for immune tolerance induction 3% and 1%, and unclassified use was 6% and 5% respectively. Among inhibitor by-passing products, rFVIIa was the product most used by patients without bleeding disorders, 20% of VIIa being used by these patients but only 6% of FIEBA. FIEBA was predominant over rFVIIa for prophylaxis in children. Improvements in data collection included a notable decrease in the proportion of Unclassified usage; for FVIII from 12–36% each year from 2000–2004 to 6–16% from 2005–2009; for FIX from 14–41% each year before 2005 to 4–14% after 2004. Specifically, the decrease in Unclassified infusions of FVIII from 16% in 2005 to 6% in 2009 showed a statistically significant trend (p=.02). Conclusions: 1) Data collection became reliable after 2004 when the proportion of Unclassified indications and the annual increase in patient numbers fell to low levels; hence subsequent trends should be compared with the period 2005–2009. 2) The increase in total annual FVIII concentrate use is accounted for by the annual increase in patient numbers, not by the annual use per patient, 3) FC are increasingly being infused for prophylaxis. 4) The major site of infusion is at home, which is outside the scope of the existing tracking system and which comprises only blood suppliers and hospitals; hence, HTCs and a comprehensive data collection system, CHARMS in this case, are both required components of an effective national tracking system and 5) a tracking system involving the entire supply and treatment chain is essential for predicting utilization and planning for future needs. Disclosures: Walker: Baxter Corporation: Research Funding. Iorio:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxter: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BioGen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Heddle:Baxter: Research Funding; Association of Hemophilia Clinic Directors of Canada: Research Funding. Chan:Bayer: Consultancy; Boehringer ingelheim: Member of DMSB for Clinical Trial, Member of DMSB for Clinical Trial Other; Aventis: Chair of Steering Committee, Chair of Steering Committee Other; BMS: Chair of Adjudication Committee Other.
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L. Basser, Margaret. "Evaluation of Outreach Community Health Care to Insecurely Housed Sydney Men." Australian Journal of Primary Health 5, no. 3 (1999): 82. http://dx.doi.org/10.1071/py99038.
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A community health outreach service was piloted among older homeless Sydney men in 1997/98 from Darlinghurst Community Health Centre, responding to an observed disparity between their high health needs and low use of community health care. The project tried to improve their access to community health services, their health and quality of life by allocating a project worker who built referral networks, assisted the men and advocated for them with other agencies. From the impact evaluation, the conclusion could be drawn that the men's access to community services improved, but whether lasting benefits were delivered by the interventions remained ambiguous. Referrals of homeless men from GPs and hospitals to the health centre increased in the year following the pilot, despite the absence of a project worker for most of that time. The project was guided by an inter-sectoral advisory committee, whose deliberations altered the evaluation questions, the interpretation of findings and recommendations. Reflection on this process led to some lessons about working with committees. The pilot project has contributed to the current planning in South Eastern Sydney Area Health Service to address homeless people's health care issues by highlighting some of the issues and viable responses to them.
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Shouval, Roni, Joshua A. Fein, Myriam Labopin, Ali Bazarbachi, Frédéric Baron, Gesine Bug, Fabio Ciceri, et al. "The Disease-Risk Stratification Scheme (DRSS), a Contemporary Risk-Stratification System for Allogeneic Stem Cell Transplantation." Blood 134, Supplement_1 (November 13, 2019): 43. http://dx.doi.org/10.1182/blood-2019-123310.
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The first two and last authors had an equal contribution. Background: The Disease-Risk Index (Armand et al., Blood 2014) is an established system for risk stratification of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). However, it was developed in patients transplanted approximately a decade ago, does not incorporate prognostic molecular data in acute myeloid leukemia (AML), and is not inclusive of several hematological malignancies. We sought to develop a contemporary risk-stratification scheme accounting for these limitations. Methods: This retrospective study included adult patients treated for hematologic malignancies who underwent first allogeneic-HSCT between 2012 and 2016 in EBMT (European Society for Blood and Marrow Transplantation) centers. All donor types were included. Patients missing information on disease type, remission status, or survival data were excluded. Combinations of disease type and remission status were studied in a multivariable Cox-regression model for overall survival, adjusted for age, donor-type, cell source, donor/recipient sex disparity, and conditioning intensity. In de-novo AML and the myelodysplastic syndrome, cytogenetics were also integrated into the disease/remission status combinations. FLT3 and NPM1 mutational status were considered in de-novo AML patients in complete remission (CR). The risk model was developed on patients transplanted between 2012 to 2015 (training cohort). Temporal validation was performed on patients transplanted in 2016 (testing cohort). The DRSS was validated again on a cohort of patients transplanted between 2012 and 2016, in Italian centers reporting to the EBMT (validation cohort), who were excluded from the derivation or testing set. Results: A total of 47,880 patients was studied. In the derivation cohort (n=33,943), the median age was 52 years. Indications for HSCT included acute leukemia (59%) followed by chronic myeloid malignancies (21%), lymphoma (16%), and plasma cell dyscrasia (4%). Unrelated donors were utilized in 57% of cases and HLA-matched related donors in 35%. Half of all patients received myeloablative conditioning. There were no clinically significant differences between the derivation and testing cohort (n=8,392), except an increase in Haplo-HSCT (5% to 9%, p<0.001). The validation cohort (n=5,545) was also similar to the derivation cohort with a high proportion of Haplo-HSCT (25%, [p<0.001]). Combinations of disease and remission status were studied in a multivariable Cox-regression model developed on the training test (Figure 1A). We defined five risk groups based on a 33% increase in the hazard of mortality in each stratum. There was a monotonic increase in risk of mortality with each risk group in the derivation, test, and validation sets; the test set is presented here: low (HR=1), INT 1 (HR 1.20 [95% CI: 1.10-1.30]), INT 2 (HR 1.60 [1.43-1.79]), high (2.22 [1.99-2.47]), very high (2.81 [2.39-3.30]). On the test set, the low, intermediate 1, intermediate 2, high, and very high risk-groups had a 2-year overall-survival probability of 68%, 61%, 51%, 44%, and 31%, respectively (p<0.001) (Figure 1B); in the validation cohort, 2-year overall survival probabilities were similar: 70%, 62%, 54%, 36%, 20% (p<0.001). The decreasing survival was driven by a corresponding increase in 2-years relapse incidence (test: 22%, 28%, 34%, 40%, 48%, p<0.001; validation: 20%, 24%, 32%, 43%, 60%) (Figure 1C-D). Conclusion: The DRSS is a contemporary risk stratification system for patients with hematological malignancies undergoing allogeneic-HSCT. The large cohort used to develop the system, along with temporal and geographical validation, suggest that the system is generalizable. Another advantage of the scheme is the incorporation of FLT3 and NPM1 in AML, the leading HSCT indication. DRSS should be used for risk stratification in statistical analyses, informed decision making, and planning of potential interventions across groups, including mixed indications for allogeneic-HSCT. Figure Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Bug:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Sanofi: Other: travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Neovii: Other: travel grant. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.
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Ewins, Karl, Fionnuala Ni Ainle, Cliona Ni Cheallaigh, Eoghan Dunlea, Sarah Kelliher, Egidio Imbalzano, Cristiano Bortoluzzi, et al. "Higher Rates of Death and Major Bleeding Highlight the Inequities That Exist in the Care of People with Venous Thromboembolism Who Experience Social Exclusion: Findings from a Prospective Registry of 79735 Patients (RIETE)." Blood 134, Supplement_1 (November 13, 2019): 4677. http://dx.doi.org/10.1182/blood-2019-130745.
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Background Social exclusion, experienced by vulnerable people at the margins of society, causes severe health inequity with dramatically increased risks of chronic disease and reductions in life-expectancy. Health services are not designed to meet the complex needs of socially excluded people (SEP). SEP are frequently unintentionally excluded from large observational studies such as household surveys and surveys requiring active participation (Levitas et al, 2007). This lack of data deepens inequity. Social exclusion in Ireland is strongly associated with injecting drug use, a strong risk factor for venous thromboembolism (VTE) (O'Reilly et al, 2015). Although an increased prevalence of VTE in lower socioeconomic groups has been described (Zoller et al, 2012), the impact of social exclusion and marginalisation on VTE has never been characterised in detail. The Registro Informatizado de Enfermedad TromboEmbólica (RIETE Registry) is the world's largest database on patients with VTE. It was commenced in 2001 and continues to collect prospective data on consecutive patients presenting to hospital with acute VTE events. Patients are followed longitudinally, for a minimum of three months (Bikdeli et al, 2018). One objective of the registry is to provide information on the natural history of VTE - particularly in subgroups of patients who would not usually be recruited to randomised clinical trials. Methods Our group has generated preliminary data (submitted separately to ASH 2019) which demonstrate that people with social exclusion can be identified from large national and international datasets using surrogate identifiers. The RIETE registry already collects several of these data elements that can be used to identify people who are socially excluded: HIV infection (which is strongly associated with injecting drug use), liver disease, chronic alcoholism and chronic psychiatric illness. We adapted the methodology developed in the Irish dataset and interrogated the RIETE registry utilising the available surrogate identifiers. We aimed to estimate the prevalence of social exclusion amongst patients with VTE, and to determine their clinical characteristics, treatment details and outcomes, with the ultimate goal of informing future service-planning and care-provision to this vulnerable group. Results At the time of interrogation of the RIETE registry, 79735 patients with VTE had been enrolled in 24 countries worldwide. Of these, 9211 (12%) met our criteria for SEP due to the presence of one or more of our surrogate identifiers. Of these, 60% presented with pulmonary embolism vs 52% in the non-SEP group (P<0.001), and SEP were more likely to have other medical co-morbidities. Major bleeding was more frequent in the SEP group (5.36 vs 3.55 events per 100 patient-years; HR 1.51 (1.35-1.69)), particularly in those with liver disease (8.70 events per 100 patient years) or psychiatric disorders (5.31 per 100 patient years). Death occurred more frequently in the SEP group (17.9 vs 12.0 events per 100 patient years; HR 1.49 (1.40-1.58)), and recurrent VTE occurred most frequently in those with HIV infection (4.31 events per 100 patient-years) and liver disease (4.46 events per 100 patient years, compared with 3.46 in the non-SEP group). Although Vitamin K Antagonists were used for longer term therapy in the majority of both patient groups (50% SEP, 63% non-SEP), the proportion who received low molecular weight heparin was higher in the SEP group (36% vs 26%). This was highest in the HIV infected subgroup, our identifier that best correlates with injecting drug use. Conclusions Social exclusion, as determined by the use of surrogate markers from a large prospective VTE registry, was associated with a higher overall incidence of death and major bleeding in patients treated for VTE. These data highlight the inequities experienced by this vulnerable patient group, demonstrating the need for increased funding for service planning and care provision to better prevent and manage VTE. This can lead to reductions in hospital admissions and costs, but ultimately to the provision of equitable healthcare for SEP. Disclosures Ewins: Bayer: Other: Conference Fees & Travel Expenses; Amgen: Other: Conference Fees & Travel Expenses. Ni Ainle:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Leo Pharma: Research Funding; Boehringer: Membership on an entity's Board of Directors or advisory committees; Actelion: Research Funding. Ni Cheallaigh:MSD: Other: Travel Expenses; Pfizer: Research Funding.
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Mehrotra, Devan V. "A note on the draft International Council for Harmonisation guidance on estimands and sensitivity analysis." Clinical Trials 16, no. 4 (April 12, 2019): 339–44. http://dx.doi.org/10.1177/1740774519844259.
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In the second half of 2014, the Steering Committee of the International Council for Harmonisation endorsed the formation of an expert working group to develop an addendum to the International Council for Harmonisation E9 guideline ( Statistical Principles for Clinical Trials). The addendum was to focus on two clinical trial topics: estimands and sensitivity analysis. A draft of the addendum, referred to as E9/R1, was developed by the expert working group and made available for public comments across the International Council for Harmonisation regions in the second half of 2017. A structured framework for clinical trial design and analysis proposed in the draft addendum are briefly described, including four key inputs for developing objective-driven estimands and strategies for tackling one of the inputs (‘intercurrent events’). The proposed framework aligns each clinical trial objective with the corresponding statistical target of estimation (estimand), trial design and data to be collected, main method of estimation/inference, and sensitivity analysis to pressure test key analytic assumption(s) in the main analysis. A case study from the diabetes therapeutic area illustrates how the framework can be implemented in practice. International Council for Harmonisation E9/R1 is expected to enable better planning, conduct, analysis, and interpretation of randomised clinical trials. This will facilitate improvements in new drug applications and strengthen understanding of decision making by regulatory authorities and advisory committees.
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Ball, Marion, and Judith Douglas. "Informatics in Professional Education." Methods of Information in Medicine 28, no. 04 (October 1989): 250–54. http://dx.doi.org/10.1055/s-0038-1636794.
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Abstract:The University of Maryland at Baltimore (UMAB) is a professional school campus, including schools of Dentistry, Law, Medicine, Nursing, Pharmacy, Graduate Studies, and Social Work and Community Planning. In late 1987, UMAB convened a Task Force on Informatics, intended to support the campus as it worked to become a Centre of Excellence for Informatics. The Task Force reviewed the current computing environment at UMAB and the individual schools. In assessing the state ofthe art in informatics, its work was supplemented by the formation of external advisory committees of national and international informaticians. Deliberations proceeded according to a methodology designed to develop factual databases and to generate consensus. The Task Force report, which is excerpted in the following paper, established a tiered taxonomy of competencies; defined the three levels; and set forth program models for the two higher levels. Special note was made of the programs in ´nursing and dental informatics newly established at UMAB. The report concluded with three recommendations, each with detailed action points identified.
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Lynch, Ryan C., Victor A. Chow, David G. Maloney, Cameron J. Turtle, Mazyar Shadman, Chaitra S. Ujjani, Ryan D. Cassaday, et al. "Low Achievement of End of Life Quality Measures in Large B-Cell Lymphoma Patients Who Progressed after CD19-Specific CAR-T Cell Therapy." Blood 134, Supplement_1 (November 13, 2019): 413. http://dx.doi.org/10.1182/blood-2019-124857.
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Introduction: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is FDA-approved in patients with relapsed or refractory large B-cell lymphomas and can lead to long-term remissions in 35-40% of patients. Outcomes in patients who progress after CAR T-cell therapy is poor, with a median overall survival (OS) of 5.3 months with few long-term survivors (Chow et al. AJH 2019). Achieving quality end of life (EOL) care for patients with hematologic malignancies has been a challenge, and widespread consensus on what are acceptable metrics is lacking (Odejide et al JCO 2016). EOL care among large B-cell lymphoma patients who progressed after CAR-T cell therapy has not been previously examined. Methods: Adults with large B-cell lymphomas who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance since 2011 who subsequently progressed and ultimately died were included. Patients who received CAR T-cell therapy with additional concurrent protocol-specified therapy were excluded. We also examined a similar cohort of chemorefractory large B-cell lymphoma patients who did not receive CAR T-cell therapy and later died of their disease (Smith et al. AJH 2019). EOL metrics including death in an acute care facility, transfusion or hospice admission within 7 days of death, lymphoma treatment (excluding steroids) within 14 days of death, ED visit, and hospitalization, or ICU admission within 30 days of death were abstracted from medical records under IRB approval. We also analyzed data based on death ≤90 days or > 90 days after CAR T-cell therapy or date determined chemorefractory in the cohort receiving non-CAR T-cell treatments. Statistical analyses were descriptive, with univariate analyses performed between the subsets mentioned above. P-values were calculated using Fisher's Exact test for categorical variables, and Wilcoxon Rank Sum test for continuous variables. Results: We identified 49 patients who progressed after CD19-specific CAR T-cell treatment and subsequently died, and 31 patients with chemorefractory DLBCL who did not receive CAR T-cells. 37 of 49 post-CAR patients, and 17 of 31 chemorefractory patients had adequate data for analysis. Baseline characteristics were balanced between the two groups except that post-CAR patients had more median prior therapies (4 (range 1-9) vs. 3 (range 2-3), p = 0.005). There was no significant difference in EOL measures between the post-CAR and chemorefractory subsets. While few patients received chemotherapy (8.1% vs. 11.8%) or oral therapy (10.8% vs. 17.6%) within 14 days of death, there were high rates of ED visits and hospitalizations (73.0% vs. 82.4%), as well as hospice enrollment within 7 days of death (43.8% vs. 50.0%). When we stratified post-CAR patients by death ≤ 90 days vs > 90 days after progression, we found that late death was associated with increased rates of ICU stays within 30 days of death (55.0% vs. 11.8%, p = 0.014), hospice enrollment within 7 days of death (73.3% vs. 17.6%, p = 0.004), death in an acute care facility (45.0% vs. 11.8%, p = 0.036), and inability to meet all EOL measures (95.0% vs. 64.7%, p = 0.033). No significant differences were seen in chemorefractory patients when stratified by time of death. Conclusions: Patients who succumb to refractory DLBCL received aggressive care at the EOL, including high rates of ED/hospital visits and ICU stays near death, whether treated with CAR T-cell therapy or alternative treatments at our center. In particular, patients with death more than 90 days after relapse from CAR T-cell therapy rarely achieved standard EOL measures. While these data require validation in other cohorts, improvements in EOL care and planning appear critical in the setting of refractory DLBCL. Disclosures Lynch: Juno Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Takeda Pharmaceuticals: Research Funding. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options . Turtle:Humanigen: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member; T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member. Shadman:Sunesis: Research Funding; Atara Biotherapeutics: Consultancy; TG Therapeutic: Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Research Funding; Acerta Pharma: Research Funding; Sound Biologics: Consultancy; AbbVie: Consultancy, Research Funding; Mustang Bio: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Astra Zeneca: Consultancy; Celgene: Research Funding; ADC Therapeutics: Consultancy. Ujjani:AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria; PCYC: Research Funding; Genentech: Honoraria; Gilead: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy. Cassaday:Merck: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy. Smith:Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Bristol-Myers Squibb (spouse): Research Funding.
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Mitchell, Bruce, Kathryn Bellette, and Stacey Richardson. "Natural resources management in South Australia – regional and collaborative approaches." Water Policy 17, no. 4 (October 28, 2014): 630–48. http://dx.doi.org/10.2166/wp.2014.153.
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Experiences with three approaches intended to achieve increasing levels of regional and collaborative engagement – Ministerial water advisory committees, Catchment Water Management Boards and Natural Resources Management Boards – are examined over the period from the 1970s to early 2014. Attention focuses on two tensions: (1) whether to have a system-wide or regional focus and (2) whether to pursue extensive consultation and seek consensus, or have government agencies limit consultation and take decisions in a timely manner, knowing that winners and losers will emerge. Supporting legislation, policies, plans and programmes were reviewed, and interviews were completed with 88 individuals. Support generally exists for regional and collaborative approaches, but with recognition of a need to balance strengths and limitations for whatever choice is made.
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Abruzzese, Elisabetta, Anna G. Turkina, Jane F. Apperley, Francesco Bondanini, Paolo de Fabritiis, Dong-Wook Kim, Iryna Dyagil, et al. "Pregnancy Management in CML Patients: To Treat or Not to Treat? Report of 224 Outcomes of the European Leukemia Net (ELN) Database." Blood 134, Supplement_1 (November 13, 2019): 498. http://dx.doi.org/10.1182/blood-2019-124430.
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Pregnancy in CML patients (pts) is becoming a reality due to the increase in information from published cases or larger multicentric database (GIMEMA and ELN). Interferon (IFN) has been used during pregnancy, but little is known about the use of tyrosine kinase inhibitors (TKIs), which should be stopped early due to their teratogenic effects. Female pts can ideally plan a pregnancy if they are in a deep, stable, molecular response (DMR=MR≥ 4, ≤0.01%IS) and treatment free remission (TFR) parameters are satisfied. Molecular remission can be maintained throughout the pregnancy, but how to proceed if the remission is rapidly lost, or if the patient is not in DMR, or when CML is discovered during pregnancy? To address these questions, we analyzed more than 300 pregnancies registered through the ELN database. Pts completing pregnancy were grouped as follow: 1) pts diagnosed with CML while pregnant 2) pts in DMR 3) pts with ≤MR3 (≥ 0.1%IS) In 47 patients CML was diagnosed during pregnancy, 21 during the 1st trimester, 15 in the 2nd , and 11 in the 3rd (range 3-38 wk). Sixteen patients were not treated until delivery, 15 were treated with IFN; 19 with Imatinib (IM), 12 in the 2nd trimester (>16 wk), and 7 in the 3rd. Forty-eight children were born (one set of twins). Three were preterm (35-37 wk), and one pregnancy is ongoing. No births defects were observed. Seven newborns had a low birth weight (< 2.5 Kg) 6 of them were exposed to IM at late pregnancy and 3 were preterm. Follow-up was uneventful. The majority of pts achieved ≥ MR3 after starting TKI. Two pts died: 1 in blast crisis (BC) after 9 years, but she was not adherent to treatment; 1 of transplant complication (resistant to>2TKI). Seventy five pts had 80 pregnancies in DMR. Six were in TFR (no therapy) for more than 12 mo, while 8 stopped TKI in order to conceive (2-8 mo before conception). Twenty two pts were treated during pregnancy: 12 with TKI (8 IM, 4 nilotinib, NIL) 1 in the 1st trimester (never stopped IM), 7 in the 2nd and 4 in the 3rd; 10 pts received IFN. Eighty one children were born (6 patients had 2 pregnancies, 1 had twins) with one baby born preterm (wk 35). No births defects were observed and two pregnancies are ongoing. Fifty eight pregnancies were carried without any CML treatment. Twenty six maintained DMR, 28 ≤ MR3 and considered in "treatment free pregnancy" (TFP), and 5 had >10% transcript levels at delivery, considered as high tumor burden (HTB). None of the patients progressed after pregnancy, 4 patients maintained TFR. Four patients did not return to MR3 <12 months after restarting TKI; 3 were switched to a more potent TKI rapidly achieving ≥ MR3, while 1 pt, who did not, is in hematologic remission after 3 years. Pts belonging to ≤MR3 do not satisfy TFR criteria, and were discouraged from starting a pregnancy. However 95 pregnancies (90 pts) were reported; 29 had stopped TKI prior to conception (5 of them had HTB at pregnancy onset). Fifty eight (61%) were treated with IFN (20), TKIs (35), or HU (3). Thirteen patients were treated with IM during 1st trimester (10 throughout the pregnancy). Among the untreated pts, 6 were surprisingly in DMR at delivery, 20 were in TFP, and 11 had HTB. Two babies were born with polydactyly and hypospadias (IFN treatment since 1st trimester), and 2 exhibited a non-closed foramen ovale (IM during 2-3rd trimester) which was considered unlikely to be related to treatment. Four pts progressed in BC and died after pregnancy but all were not compliant to therapy. This is the first, large, multicenter report focusing on treatment during pregnancy. Results suggest that CML patients can pursue a normal life including planning a family, with several caveats. Based on the different situations examined, treatment with IFN is confirmed safe. In contrast TKIs should not be used during pregnancy. Selected TKIs, specifically IM and NIL which have little placental transfer, can be started after organogenesis. Pts at onset can delay therapy without jeopardizing the future CML outcome. If therapy during pregnancy is deemed necessary, IFN can induce and maintain hematologic remission, or, if introduced earlier, preserve molecular remission after TKI interruption, while TKIs can reduce HTB. Caution should be taken when considering stopping TKI prior to conception due to the possibility of losing response, while an early stop (at first positive pregnancy test, 4-5 wk) could be considered. Detailed results, mother and child follow up and practical management will be presented. Disclosures Abruzzese: BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Turkina:Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy. Apperley:Bristol Myers Squibb: 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, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding; Takeda: Research Funding. Garcia-Gutiérrez:Novartis: Honoraria, Other: Advisory Committees. Mauro:Novartis Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Takeda: Consultancy. Milojkovic:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Moriaghi:novartis: Speakers Bureau; BMB: Speakers Bureau; Takeda: Speakers Bureau. Nicolini:Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Rea:Pfizer: 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; BMS: Honoraria; Incyte Biosciences: Honoraria. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Shacham:novartis: Consultancy. Trawinska:Novartis: Consultancy, Honoraria. Chelysheva:Fusion Pharma: Consultancy; Novartis: Consultancy, Honoraria. OffLabel Disclosure: informations on the use of interferon and/or TKIs (imatinib, nilotinib) during pregnancy.
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Castro, Michael, Drew Watson, Ansu Kumar, Prashant Ramachandran Nair, Himanshu Grover, Diwyanshu Sahu, Subrat Mohapatra, et al. "Monosomy 7 and Co-Occurrent Genomic Aberrations Determine Chemotherapy Response in Acute Myeloid Leukemia (AML) Patients Using the Cellworks Omics Biology Model (CBM): Mycare-021-04." Blood 136, Supplement 1 (November 5, 2020): 9. http://dx.doi.org/10.1182/blood-2020-140087.
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Background: Monosomy 7/Del 7 (-7) or its long arm (del(7q)) is one of the most common cytogenetic abnormalities in pediatric and adult myeloid malignancies, particularly in adverse-risk acute myeloid leukemias (AMLs). In general, (-7) is associated with poor response to induction chemotherapy (PMID 12393746). At the same time, not all patients fare poorly so the ability to identify responders and non-responders remains a high priority. Aim: To predict the response for induction chemotherapy in AML patients with (-7) and identify novel genomic signatures of response and resistance. Methods: Genomic data from 13 consecutive patients with (-7) were analyzed using the Cellworks Omics Biology Model (CBM) to generate patient-specific protein network models. All data was anonymized, de-identified and exempt from IRB review. For each model, disease simulations were performed and patients were segregated into HOXA-upregulated and HOXA-downregulated cohorts based on the simulation levels of HOXA5 and HOXA9. Digital drug simulations for induction chemotherapy were accomplished by measuring the impact of drug effect on a cell growth score, a composite of cell proliferation, viability and apoptosis indices. Each patient-specific model was analyzed to identify mechanisms underlying treatment outcomes. Results: 7/13 (54%) of (-7) patients failed to achieve remission after induction chemotherapy (Table 1) which highlighted that (-7) alone does not confer resistance to chemotherapy. CBM identified other genomic alterations that determine chemotherapy response, including DNA repair deficiency genes, mismatch repair (MMR), and homologous recombination repair (HRR) genes. DNA methylation and histone methylation (H3K27me) impacting HOXA gene expression, mainly HOXA5 and HOXA9, were identified as upstream regulators of DNA repair genes. Loss or reduced levels of EZH2 is associated with lower H3K27 methylation and thereby higher expression of HOXA5 and HOXA9 gene targets. High active levels of HOXA correlated with low rates of successful remission induction (22%, n=7) and lower activity levels of HOXA correlated with successful induction chemotherapy (100%, n=4) (Table 1). CBM identified that (-7) results in a decreased expression of EZH2, CARD11, EIF3, PMS2, HUS1, KMT2C (MLL3), CDK5 and IKZF1 genes. Since EZH2 abnormalities alone are not implicated in poor prognosis for AML patients, we sought other aberrations that prevent HOXA upregulation. Using CBM, we identified multiple accompanying aberrations which regulate HOXA genes. Deletions of KAT6A, ASXL1, DNMT3B, DNMT3L genes and high KMT2A-partial tandem duplication correspond to HOXA-upregulation whereas EED amplification, gain of function mutations in DNMT3A, mutations in IDH1/2, MYC and KAT6A amplification and KDM4A deletion result in HOXA-downregulation. Conclusion: Alterations of chromatin regulation have consequences for transcription factors that regulate expression of DNA repair genes. Under conditions where DNA repair is enhanced, induction chemotherapy was 78% less likely to effect remission in (-7) AML patients undergoing induction chemotherapy. Loss of H3K27 methylation associated with loss of PRC2 function by any means resulted in HOXA-upregulation and upregulation of DNA repair genes induced resistance to induction therapy. On the other hand, CBM analysis identified genetic signatures associated with a 100% remission rate from AML induction therapy despite the presence of (-7). Generation of H3K27me caused by PRC2 activation resulting from numerous mechanisms led to HOXA-downregulation and 100% response to induction therapy. Stratification of patients harboring (-7) by HOXA biomarker analysis could inform treatment planning, avoid drug-related adverse events and reduce treatment costs after validation with a larger prospective dataset. Disclosures Castro: Cellworks Group Inc: Consultancy. Watson:Cellworks Group Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellmax Life Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mercy Bioanalytics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; SEER Biosciences, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioAI Health Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar:Cellworks Research India Private Limited: Current Employment. Nair:Cellworks Research India Private Limited: Current Employment. Grover:Cellworks Research India Private Limited: Current Employment. Sahu:Cellworks Research India Private Limited: Current Employment. Mohapatra:Cellworks Research India Private Limited: Current Employment. G:Cellworks Research India Private Limited: Current Employment. Agarwal:Cellworks Research India Private Limited: Current Employment. Suseela:Cellworks Research India Private Limited: Current Employment. Ganesh:Cellworks Research India Private Limited: Current Employment. Sauban:Cellworks Research India Private Limited: Current Employment. Kumar:Cellworks Research India Private Limited: Current Employment. Raman:Cellworks Research India Private Limited: Current Employment. Singh:Cellworks Research India Private Limited: Current Employment. Basu:Cellworks Research India Private Limited: Current Employment. Lunkad:Cellworks Research India Private Limited: Current Employment. Mundkur:Cellworks Group Inc.: Current Employment. Macpherson:Cellworks Group Inc.: Current Employment. Kapoor:Cellworks Research India Private Limited: Current Employment. Howard:Servier: Consultancy, Other: Speaker; Boston Scientific: Consultancy; Sanofi: Consultancy, Other: Speaker; EUSA Pharma: Consultancy; Cellworks: Consultancy.
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Cottereau, Anne Ségolène, Annibale Versari, Loïc Chartier, Jehan Dupuis, Vittoria Tarantino, Rene-Olivier Casasnovas, Antonella Franceschetto, et al. "Low Suvmax Measured on Baseline FDG-PET/CT and Elevated β2 Microglobulin Are Negative Predictors of Outcome in High Tumor Burden Follicular Lymphoma Treated By Immunochemotherapy: A Pooled Analysis of Three Prospective Studies." Blood 128, no. 22 (December 2, 2016): 1101. http://dx.doi.org/10.1182/blood.v128.22.1101.1101.
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Abstract Early identification of high risk patients is warranted in high tumor burden or advanced follicular lymphoma. In this regard post induction FDG-PET/CT and parameters obtained from quantitative baseline FDG-PET such as total metabolic tumor volume (TMTV) have been proposed as prognostic tools (J Clin Oncol, 2016, in press). It has been shown recently that the presence of large TMTV>510cm3 can help to early detect patients who relapse within two years of therapy but TMTV is not yet used routinely. The aim of this study was to assess the prognostic impact of SUVmax measured on baseline FDG-PET/CT as an index of tumor proliferation and its added value to other prognostic parameters in this population. Methods: A pooled analysis of patient data and centrally reviewed baseline PET/CT scan for 181 patients with high tumor burden follicular lymphoma receiving R-chemotherapy within three prospective trials was performed (PET-FOLL and PRIMA from the LYSA, FOLL05 from the FIL), (Lancet Haematol, 2014). 82% of patients received R-CHOP, 14% R-CVP, 4% R-FM and 16 patients received R maintenance. Baseline SUVmax was computed on quality controlled PET/CT scan and the optimal cut-off for survival prediction was determined by Receiver Operating Curves and X-tile analysis. Multivariate analysis stratified by study were performed between SUVmax and the different components of FLIPI2 and between SUVmax and baseline TMTV. Results: Median age was 55 years; 92% of patients had stage III/IV disease; 37% had FLIPI 3-5; 31% had FLIPI2 3-5. With a median follow up of 64 months, 5y-PFS was 55% and 5y-OS 92%. Only two patients had disease transformation. Median SUVmax was 10 (Q1-Q3:7-14). There was no correlation between the SUVmax and histological grade. The optimal SUVmax cut-off was 9.4. Surprisingly the 47% of patients with a SUVmax ≤9.4 had markedly inferior PFS. 5y PFS was 47.4% vs. 62.4% (HR= 1.62, p=0.032). On multivariate analysis between SUVmax, age, Longest diameter of Largest involved lymph node LodLin> 6cm, positive Bone marrow biopsy and β2 microglobulin, only SUVmax (HR=1.81, p=0.04) and β2 microglobulin (HR=2.48, p=0.006) were independent predictors of PFS (Table1). When SUVmax and β2 microglobulin were combined they identified three risk groups: low SUVmax and high β2 microglobulin with 5y-PFS 32% (HR=3.95, p=0.0005), low SUVmax or high β2 microglobulin with 5y-PFS 54% (HR=2.29, p=0.018) and high SUVmax and low β2 microglobulin with 5y-PFS 73 % (Fig1). In multivariate analysis TMTV>510cm3 remains the only significant predictor against SUVmax≤9.4. There was no difference in the SUVmax values in high or low TMTV groups and similar % of high and low TMTV in low and high SUVmax groups. Furthermore, the 17% of patients with SUVmax≤9.4 and TMTV>510cm3 had a 22% 5y PFS vs 67.4% for the 40% of patients with SUVmax>9.4 and TMTV≤510cm3 (HR=3.96, p<0.001). Conclusions: SUVmax and β2 microglobulin are readily available parameters at staging. A low SUVmax observed on a baseline PET or an elevated β2 microglobulin is predictive of progression in patients with high tumor burden follicular lymphoma having received R-chemotherapy. The risk of progressive disease increases when patients have both these risk factors, and such patients deserve special consideration in treatment planning and follow-up. Figure 1. Figure 1. Disclosures Dupuis: janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Luminari:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria.
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Carpenter, Shannon L., Emily Farrow, Lauren Amos, Neil Miller, Margaret Gibson, Sara Streeter, Byunggil Yoo, Suzanne Herd, Sarah Soden, and Stephen Kingsmore. "Use of Dried Blood Spots for High through-Put, Rapid Turnaround Mutational Analysis in Patients with Hemophilia." Blood 124, no. 21 (December 6, 2014): 5034. http://dx.doi.org/10.1182/blood.v124.21.5034.5034.
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Abstract Introduction: For individuals with hemophilia, mutational analysis could represent a novel method of diagnosis. In addition, mutational analysis ideally would be available to better predict disease manifestations such as inhibitor development and to provide family planning to female carriers. However, many patients do not undergo testing due to high cost and lack of insurance reimbursement. Additionally, the time to receive sequencing results can be several weeks. We are developing a sequencing assay which can identify genetic mutations in the factor 8 and 9 genes using dried blood spots on filter paper with the goal of significantly lowering the turnaround time and cost of testing. Methods: This is a single center, prospective, pilot study. Thus far, we have isolated DNA from blood spots on filter paper for sample preparation. DNA isolation is automated utilizing a Chemagen MSM1 robot (Perkin Elmer); which allows for the extraction of 96 samples at once in approximately 4 hours total time. Library preparation is automated with a NGS Janus Express (Perkin Elmer). The Nextera rapid capture and enrichment work flow is used to prepare samples for next generation sequencing, which is completed on a Miseq instrument (Illumina). Results: We have successfully generated sequencing libraries from samples extracted from blood spots and they are indistinguishable from libraries generated from DNA isolated from whole blood. Using a previously designed targeted panel, we have successfully sequenced and analyzed patients with known F8 and F9 variants within one week of sample receipt. Currently we are able to detect sequence variants and insertions and deletion events up to 40 base pairs. We successfully identified causative mutations in 7 out of 8 individuals with known hemophilia (both A and B). All factor 9 mutations were identified successfully. Point mutations of the factor 8 gene were identified. Of note, a point mutation in a female carrier which was also seen her brother was successfully sequenced. Further method development is underway to detect the known factor 8 inversions from the sequencing data, providing a rapid single molecular test for both Factor 8 and Factor 9 patients. Conclusion: DNA can successfully be extracted and analyzed for mutations in factor 8 and 9 genes from known hemophilia patients using dried blood spots. Once we have finalized the process for identifying inversions, we will compare results from 24 individuals known to be affected with hemophilia (16 hemophilia A, 8 hemophilia B) to 24 banked control DNA samples to provide proof of principle. Subsequently, we plan to expand the project to a larger clinical trial. Table 1: Initial Sequencing Results Table 1:. Initial Sequencing Results Disclosures Carpenter: Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kingsmore:Illumina: Speakers Bureau.
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Sanchez, Maria Belen, Beatriz Moiraghi, Ana Ines Varela, Estrella Levy, Masiel Vera, Bianca Vasconcelos Cordoba, Isabel Giere, et al. "In Pursuit of Surrogate Markers for Treatment-Free Remission in Patients with Chronic Myeloid Leukemia from Argentina Stop Trial." Blood 136, Supplement 1 (November 5, 2020): 24. http://dx.doi.org/10.1182/blood-2020-141067.
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INTRODUCTION: Long-term survival of patients with chronic myeloid leukemia (CML) has significantly improved since the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs). Several considerations about the side effects, risks and cost associated with the lifetime treatment, have led patients and physicians to explore the possibility of TKI discontinuation after achievement of a sustained deep molecular response (DMR), so-called treatment-free remission (TFR). Several clinical trials show that approximately half of patients who achieve a sustained DMR during TKI treatment maintain molecular remission after suspension of TKIs. There is currently no biomarker that reliably predicts TFR in CML, mainly due to different study designs that have generated inconsistent data. Thus, further investigations are needed to identify factors that consistently favor achievement of TFR. With the aim of developing a biomarker for TFR prediction we analyzed the phenotype of Natural Killer (NK) cells and their relation to successful TKI cessation. METHODS: This analysis was conducted as a substudy of the Argentina Stop Trial. Altogether, 50 consecutive chronic phase CML patients who participated in the clinical trial were recruited from 7 Argentinian centers. Peripheral blood samples were collected before stopping TKI treatment, at month 3, 12 and at any time when MR3.0 was lost. Freshly isolated mononuclear cells from 46 patients were immunophenotyped by staining with CD3, CD16, CD25, CD56, CD57, CD158, NKp30, NKp44, NKp46, NKG2A, NKG2C, NKG2D and PD-1 antibodies and NK cells subpopulations were analyzed by flow cytometry (BD FACS Canto™II). Molecular recurrence-free survival was estimated by the Kaplan-Meier method and compared within groups by the log-rank test. The cutoffs of the numerical variables were optimized according to the log-rank test. Quantitative variables were dichotomized according to receiver operating characteristics (ROC) curves in order to describe sensibility and specificity. Multivariate analysis was performed through Cox proportional hazards model. Main results are provided with hazard ratio (HR) at 6 months and 95% confidence intervals (95% CI). RESULTS: At the time of discontinuation the median proportion of NK cells (CD3-CD56+) among lymphocytes was significantly increased in patients compared with controls (15% vs 9%, P = 0.0016). A significant difference between molecular relapsed vs no-relapsed patients was observed when optimal cutoff (0.43) for CD56bright low and high was determined (at 6 months 74% vs 100% respectively, log rank test, p=0.023). At this time of follow up, no significant difference was observed for CD56dim NK cells. Phenotypic markers for adaptive-like NK cells were analyzed, however, no significant differences were observed between the non-relapsing and relapsing groups. Nevertheless, molecular non-relapsing patients had significantly higher frequencies of PD-1+ NK cells as compared with molecular relapsing patients (at 6 months 85% vs 64%, Log Rank test, P=0.009). Based on the ROC and Youden Index analysis, at 6 months the 1.2 cutoff shows an 80% specificity and 50% sensitivity. Moreover, after multivariable Cox proportional analysis, including age, time of treatment, deep molecular response time, Sokal risk, NK cells and PD-1+ NK cells, the last subpopulation was identified as an independent prognostic factor for molecular-relapse-free survival (Hazard ratio = 3.63; 95% CI 1.3 - 10.1; P=0.014). CONCLUSIONS: The clinical impact of NK cells in patients who have discontinued TKIs is controversial. The effects of TKIs against immune cells, including NK cell subsets, could depend on the type of TKIs; this aspect is particularly relevant in Argentinian treated patients real world, since many different copies of TKIs are routinely used in the clinical setting. Our study is the first, to our knowledge, to report a significant increase in PD-1 expression in NK cells at TKI cessation in patients who do not relapse. Accordingly to recent reports, PD-1 expression is more abundant on NK cells with an activated and more responsive phenotype and does not mark NK cells with an exhausted phenotype. To fully understand how PD-1 on NK cells modulates immune responses we are planning to carry out functional studies. In the future, we are also planning a comprehensive study of immune suppressors, including regulatory T cells and myeloid-derived suppressor cells. Disclosures Moiraghi: Novartis: Speakers Bureau; BMS: Speakers Bureau. Varela:Novartis: Consultancy, Speakers Bureau. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Nikiforow, Sarah, Lillian Werner, Joana Murad, Matthew Jacobs, Lauren Johnston, Sarah Patches, Randie White, et al. "Safety Data from a First-in-Human Phase 1 Trial of NKG2D Chimeric Antigen Receptor-T Cells in AML/MDS and Multiple Myeloma." Blood 128, no. 22 (December 2, 2016): 4052. http://dx.doi.org/10.1182/blood.v128.22.4052.4052.
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Abstract Introduction: Conventional CAR-T cells express a single chain antibody variable fragment that restricts recognition to one tumor antigen and a limited set of cancers. This study employs a novel CAR fusing full-length human NKG2D with the CD3z signaling domain. In autologous transduced CM-CS1 T cells, NKG2D CAR receives endogenous costimulation via DAP10 to target multiple NKG2D-ligands that are upregulated in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. Methods: A phase 1 dose-escalation study to establish safety and feasibility of a single infusion of CM-CS1 T cells without lymphodepleting conditioning enrolled subjects with AML/MDS-RAEB or relapsed/refractory progressive multiple myeloma (MM) without standard therapy options (NCT02203825). Eligibility criteria included suitable organ function, no CNS disease, no prior allogeneic SCT or adoptive T-cell therapy, no therapy within 3 weeks prior to infusion, no immune suppression, and no uncontrolled infection. Dose-escalation spanned 4 cohorts [half-log increments from 1x106 to 3x107 CM-CS1 T cells] according to a 3+3 design. DLTs included ≥ Grade 3 non-hematologic toxicity or ≥ Grade 2 autoimmune toxicity related to CAR T cells. Initial assessment was at 28 days. At least 1 AML/MDS and 1 MM subject were mandated in each dose level. Manufacturing included PBMC stimulation with OKT3 and IL-2 followed by 2 rounds of retroviral transduction at DFCI's Cell Manipulation Core Facility. Vector copy number (VCN) and replication-competent retrovirus (RCR) testing were performed on whole blood and PBMCs, respectively, using quantitative PCR. Results: From April 2015 to July 2016, 11 subjects were infused, and 10 completed the DLT period. Eight of 11 were male, 6 had AML/MDS, and median age was 70 (range 44 to 79) (Panel A). Median WBC was 2.3 (range 0.7 to 7.2 K/uL); median ALC was 0.74 (range 0.09-2.37 K/uL). Five had cells manufactured from peripheral blood; 6 underwent apheresis. Median percentage of blasts in bone marrow for AML/MDS patients was 50% (range 4-68%). All myeloma patients had undergone ≥ 5 therapies including ≥1 autologous SCT. Four of the 6 AML/MDS patients had secondary disease, 3 had complex cytogenetics, 3 had p53 mutations, and 1 had a FLT3-ITD mutation. Dose-escalation proceeded from 1x106 to 3x107 CM-CS1 T cells. All 11 products passed release criteria, and there were no infusion reactions. Products consisted of median 97.2% CD3+ cells and 31.0% CD8+ cells, with vector-specific NKG2D expression on median 74.6% of CD3+ and 66.3% of CD8+ cells (Panel B). The first 10 subjects completed their 28 day evaluation period without DLTs. There were no cases of cytokine release syndrome, cell-related neurotoxicity, auto-immunity, or CAR T-related death. SAEs included a Grade 4 intracochlear bleed and an episode each of grade 4 neutropenia and thrombocytopenia deemed related to disease progression. Forty percent of patients experienced some Grade 3 toxicity, all related to underlying disease or a complication thereof (Panel C). At these initial cell doses, no patient to date has had objective tumor response at the 28 day evaluation mark. Nine initiated subsequent therapies; there have been 4 deaths secondary to disease or complications of subsequent therapies. However, cases of unexpected survival without further therapy and responses to subsequent treatments were noted. For example a patient with p53-mutated AML survived 4 months despite 50% blasts at infusion, and another entered PR at 6+months after cells on an IDH-1 inhibitor with <5% IDH and 54% p53 mutation burden at initiation. RCR testing at 3 (n=6) and 6 months (n=1) was negative. As anticipated, no CAR T cell persistence has been detected at or beyond 2 weeks, with 1 exception. CAR T cell DNA has been detected sporadically from 1 hour to 1 week after infusion. Conclusion: In the first 3+ dose-escalation cohorts of patients with AML/MDS and myeloma, a single dose of CM-CS1 T cells without lymphodepletion was feasible and well-tolerated, with no DLTs. CAR T cells generally have not persisted beyond 1 week, consistent with pre-clinical models. Correlative analyses including post-infusion immunophenotyping are in process. Future studies of multiple infusions of NKG2D CAR T cells in both hematologic malignancies and solid tumors at the higher cell doses associated with efficacy in pre-clinical models are in planning. Table Table. Disclosures Murad: Celdara Medical, LLC: Employment. Reder:Celdara Medical, LLC: Employment. Sentman:Celdara Medical, LLC: Membership on an entity's Board of Directors or advisory committees, Other: Holds patents on this technology. Wade:Celdara Medical, LLC: Employment. Schmucker:Celdara Medical, LLC: Employment. Lehmann:Celyad, SA: Employment. Snykers:Celyad, SA: Employment. Allen:Celyad, SA: Employment. Stone:Celator: Consultancy; Jansen: Consultancy; Novartis: Consultancy; Merck: Consultancy; ONO: Consultancy; Sunesis Pharmaceuticals: Consultancy; Roche: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy; Xenetic Biosciences: Consultancy; Agios: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Pfizer: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy. Dranoff:Novartis: Employment. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees.
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BouMjahed, Lama, and Joseph L. Schofer. "Freight Performance Measurement in FAST Act-Mandated State Freight Plans." Transportation Research Record: Journal of the Transportation Research Board 2673, no. 4 (April 2019): 458–72. http://dx.doi.org/10.1177/0361198119835817.
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This paper reviews treatment of performance measures in state freight plans (SFPs) mandated under the FAST Act. This responds to the growing interest in freight performance measurement in government and industry, including concern for assuring supply chain performance to support the economy. To accomplish this, we collected 42 SFPs from state departments of transportation (DOT) websites and reviewed their treatment of freight performance measures in terms of describing and quantifying performance, granularity, multimodality, use of data and analytic methods, treatment of supply chains, and engagement of stakeholders through outreach. This assessment identified positive trends in freight planning practices such as addressing performance and supply chains in broad terms, identifying specific supply chains important to the state, forming freight advisory committees, and engaging them in the development of the freight plans. The novelty of the FAST Act mandate leaves room for further development of performance measurement in freight planning. Few states reached beyond the most readily available, free data, measuring what is most easily measured, and focusing on the highway system. There was limited consideration of supply chain performance. A list of good practices is offered, including selecting measures that are easily understood by key stakeholders, supported by readily available data, responsive to state needs and conditions, covering the most important modes in the state, timely, and appropriately granular to support specific choices.
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Svoboda, Jakub, Susan R. Rheingold, Saar I. Gill, Stephan A. Grupp, Simon F. Lacey, J. Joseph Melenhorst, Irina Kulikovskaya, et al. "Pilot Study of Non-Viral, RNA-Redirected Autologous Anti-CD19 Chimeric Antigen Receptor Modified T-Cells in Patients with Refractory/Relapsed Hodgkin Lymphoma (HL)." Blood 130, Suppl_1 (December 7, 2017): 653. http://dx.doi.org/10.1182/blood.v130.suppl_1.653.653.
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Abstract Background: Cellular therapy using anti-CD19 autologous chimeric antigen receptor modified T (CART19) cells demonstrates promising outcomes in several hematologic malignancies of B-cell origin, but this therapy has not been studied in HL patients (pts). While neoplastic HL Reed-Sternberg (HRS) cells are considered CD19 negative, circulating CD19 positive clonal HRS cell precursors and CD19 positive reactive cells within the HRS tumor microenvironment represent potential therapeutic targets for CART19 in HL. Methods: We designed companion pediatric (NCT02624258) and adult (NCT02277522) open-label pilot studies to estimate the feasibility, safety, and efficacy of CART19 cell infusions in pts with relapsed/refractory HL lacking curative treatment options. To allow transient CD19 targeting and limit the window for acute toxicity and B cell aplasia, we used autologous T-cells electroporated with mRNA encoding chimeric anti-CD19 immunoreceptor scFv (RNA CART19) cells in lieu of permanently modified cells engineered by viral transduction. The scFv is derived from a murine monoclonal antibody. Following pheresis and manufacturing of RNA CART19 cells, pts undergo up to 6 infusions of 8x105-1.5x106 RNA CART19 cells/kg/dose for pts <80kg and 1x108 RNA CART19 cells/dose (±20%) for pts ≥80kg. Intravenous cyclophosphamide (30mg/kg) is administered prior to the first and fourth infusion to enhance engraftment. Safety, response assessments (Cheson 2007 criteria), and ancillary studies are measured at defined time points. The primary objective is to describe manufacturing feasibility, safety, and persistence of RNA CART19 cells in HL. Secondary objectives are to estimate efficacy by overall response rates (ORR) and the effect of RNA CART19 on immune factors. Results: To date, 5 pts have been enrolled and had RNA CART19 manufactured. Four pts were infused with RNA CART19 and are evaluable for toxicity/response. Characteristics of the 5 pts include: median age 24 years (range 21-42), 4 (80%) with stage IV, median number of previous therapies 5 (range 4-9), 4 (80%) had stem cell transplant (SCT): 3 had auto SCT, 1 had both auto and allo SCT. Three pts previously progressed on PD-1 inhibitor. All 5 pts underwent successful manufacturing of RNA CART19. One pt developed MDS prior to RNA CART19 infusions and was taken off study. Four patients who underwent RNA CART19 infusions were treated with cyclophosphamide as per protocol. The median number of infused CART19 cells/kg/dose was 1.5x106 (range 7.3x105 -1.5x106). Each patient (pt) received 6 infusions over 2 weeks. Using qRT-PCR, RNA CART19 was detected in 80% of peripheral blood samples drawn within 2 hours after each infusion (Figure 1). RNA CART19 was also detected in 20% of samples drawn immediately prior each infusion reflecting persistence of RNA CART19 from previous infusion at 48 or more hours ago. No pt had RNA CART19 detected by Day (D) 21. There were no study related deaths or grade (G) 3/4 non-hematologic toxicities. Most common G1/2 toxicities at least possibly related to the RNA CART19 therapy occurring in > 1 pt included transient headache in 3 and insomnia in 2. There was no evidence of cytokine release syndrome or significant elevation in cytokines at any point. The ORR at D28 was 50%: 1 complete (CR) and 1 partial response (PR). One pt had stable disease (SD) and one pt had progressive disease (PD). The CR pt (#3) was noted to have persistent RNA CART19 cells in 3 samples drawn at about 48 hours after the prior infusion compared with the PD pt (#1) who had no RNA CART19 detected by this time point on any measurement. In 2 pts who responded (#3 and #4), number of CD19-positive B-cells by flow cytometry as % of total leukocytes declined by 50% on D28 when compared to baseline. There was no evidence of B cell aplasia. The pt in CR progressed at 3 months and the pt in PR was taken off study. As part of routine clinical care, the 2 responding pts (#3 and #4) are currently in CR on PD-1 inhibitor (one underwent auto SCT). The pt with SD is in PR on lenalidomide and the pt with PD died of disease progression. Conclusion: Targeting CD19 positive cells with non-viral, RNA-electroporated, transiently expressed CART19 cells is a feasible and safe strategy in pts with relapsed/refractory HL. We saw encouraging responses, but these were short-lived. We are planning a study for HL pts utilizing virally transduced CART19 cells that are capable of in vivo expansion in combination with PD-1 inhibitors. Disclosures Svoboda: Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding; Kite: Consultancy; Pharmacyclics: Research Funding. Gill: Novartis Pharmaceuticals: Patents & Royalties, Research Funding. Grupp: Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant. Lacey: Novartis: Research Funding; Genentech: Honoraria. Melenhorst: Novartis: Research Funding. Mato: DTRM: Research Funding; AstraZeneca: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; Acerta: Research Funding; Portola: Research Funding; Kite: Consultancy; AbbVie: Consultancy, Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Dwivedy Nasta: Takeda: Research Funding; Incyte: Research Funding; Immunogen: Research Funding. Landsburg: Takeda: Research Funding; Curis: Consultancy, Research Funding. Levine: GE Healthcare: Consultancy; Tmunity Therapeutics: Equity Ownership, Research Funding; Brammer Bio: Consultancy; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding. Porter: Immunovative Therapies: Other: Member DSMB; Novartis: Honoraria, Patents & Royalties, Research Funding; Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Servier: Honoraria, Other: Travel reimbursement; Incyte: Honoraria. June: Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Schuster: Genentech: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria.
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Smythe, David K. "Inadequate Regulation of the Geological Aspects of Shale Exploitation in the UK." International Journal of Environmental Research and Public Health 17, no. 19 (September 23, 2020): 6946. http://dx.doi.org/10.3390/ijerph17196946.
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Unconventional oil and gas exploitation, which has developed in the UK since 2009, is regulated by four main agencies: The Oil and Gas Authority, the Environment Agency, the Health and Safety Executive and local Mineral Planning Authorities (usually county councils). The British Geological Survey only has an advisory role, as have ad hoc expert committees. I firstly define terms, and summarise the remits of the regulators and background history. Fourteen case histories are then discussed, comprising most of the unconventional exploitation to date; these cases demonstrate the failure of regulation of the geological aspects of fracking operations in the UK. The regulators let inadequacies in geological understanding, and even mendacious geological interpretations by the hydrocarbon operators slip through the net. There are potentially severe implications for environmental safety—if and when permits are granted. Geological pathways, if not properly understood and mitigated, may lead to long-term pollution of groundwater and surface water; methane and H2S emissions. Induced earthquakes have not been well regulated. The case histories demonstrate a laissez-faire and frequently incompetent regulatory regime, devised for the pre-unconventional era, and which has no geological oversight or insight.
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Herfarth, Klaus, Marianne Engelhard, Peter Borchmann, Karin Hohloch, Volker Budach, Andreas Viardot, Mathias Witzens-Harig, Hans Eich, Wolfgang Hiddemann, and Martin Dreyling. "Treatment of Early Stage Nodal Follicular Lymphoma Using Involved-Field Radiotherapy and Rituximab: Preliminary Results of the Mir Trial (phase II study of the German Low Grade Lymphoma Study Group (GLSG))." Blood 120, no. 21 (November 16, 2012): 1634. http://dx.doi.org/10.1182/blood.v120.21.1634.1634.
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Abstract Abstract 1634 Background: The commonly recommended treatment for early stage follicular lymphoma grade 1 or grade 2 (stage I/II) is involved-field radiotherapy (IF RT). However, a prospective German trial showed improved progression free survival compared to historical data using large field radiation techniques as extended-field radiotherapy or total lymphatic irradiation (Stuschke et al, Cancer, 80, 1997). This trial led to the conclusion that large volume radiation techniques may prevent relapses of microscopic lymphatic disease and is confirmed by the a new study, which was presented at Lugano 2011 (Engelhard et al., Ann Oncol, 22 Suppl4, 2011). However, those extensive radiation protocols are associated with significant toxicities, especially grade 3 and grade 4 adverse events concerning the hematopoietic system. It has been shown that the CD20 antibody Rituximab also has an anti lymphoma activity in CD20 positive follicular lymphoma. It might prevent out field recurrences in case of involved field radiotherapy. The German Low Grade Lymphoma Study Group (GLSG) and the German Radiation Oncology Group (ARO) of the German Cancer Society conducted a prospective, multicenter phase II trial investigating the efficacy and toxicity of a combined involved-field radiotherapy in combination with Rituximab treatment (MIR = MabThera and Involved field Radiotherapy) with an accrual of 85 patients (ClinicalTrials.gov Identifier: NCT00509184). Patients and Methods: 85 patients (47 male / 38 female) with early stage CD20 positive follicular lymphoma grade 1/2 were included in the trial at 16 German centers between February 2007 and October 2010. Median age at diagnosis was 55 years (21–75 years). Stage I disease was diagnosed in 48 patients and Stage II in 37 patients. Macroscopically left lymphoma after diagnostic surgery was observed in 55 patients, no macroscopic lymphoma in 26 patients and an equivocal status (e.g. due to postoperative tissue changes) in 4 patients. The treatment included a first block of Rituximab (4 weekly cycles; 375 mg/m2body surface), a 4 week treatment gap with a restaging CT / planning CT of the involved region in week 7 and followed by another block of Rituximab(4 weekly cycles) concurrently with an IF RT of 40 Gy for macroscopic tumor or 30 Gy in case of a complete remission (CR). The fractionation schedule was 5×2Gy per week. Primary endpoint of the study was progression free survival (PFS) at 2 years. Secondary endpoints were CR rate after Rituximab monotherapy (week 7) and after complete treatment (week 18). Additional endpoints were relapse rate, relapse pattern, overall survival, toxicity and quality of life. The protocol was approved by the ethics committee of the University of Heidelberg Medical School and the Paul-Ehrlich-Institute (PEI-registration number 432/06). The trial was in accordance to the Declaration of Helsinki. Recruitment was finished in October 2010. Clinical report form (CRF) collection is currently under way. Results: The treatment was well tolerated. There were 16 serious adverse events (SAE; toxicity grade 3 or higher): 3 infections, 1 hypersensitivity, 2 cardiac disorders, 1 vascular disorder, 1 respiratory disorder, 2 gastrointestinal disorders, 4 bone injuries. Two patients died due to secondary neoplasm. 3/16 were considered to be related to the treatment. Eight patients had to be excluded from the primary response evaluation due to failed inclusion criteria (e.g. stage, histology.) or early withdrawal of their consent. The mean follow-up of the remaining 78 patients has been 22.3 +/− 11.4 months, so far. Of 55 patients with remaining macroscopic lymphoma at inclusion, 26% showed a CR at week 7 after 4 cycles Rituximab (15% missing, CRF data still have to be collected). The CR rate improved to 60% at week 18 at the first follow-up examination at week 18 (15% of data still missing) and to 80% at month 6 (22% of data still missing). A total of 8 relapses have been detected (1 infield relapse) so far. The 2 years actuarial progression free survival and overall survival has been estimated to be 90% and 96%, respectively. Conclusion: The combination of Rituximab and IF RT in early stage nodal follicular lymphoma grade 1/2 is well tolerated and shows promising initial results. So far, 2 years PFS matches with that of large field radiotherapy without the accompanying toxicity and is superior to historic data of IF RT only. Disclosures: Herfarth: Roche: Honoraria, Research Funding. Borchmann:Roche: Honoraria, Research Funding. Budach:Roche: Honoraria. Viardot:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Witzens-Harig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Support of (other) clinical trials and Scientific Advisory Boards Other.
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Tandon, Nidhi, Surbhi Sidana, Morie A. Gertz, Angela Dispenzieri, Martha Q. Lacy, Francis K. Buadi, David Dingli, et al. "Treatment Patterns and Outcomes Following Initial Relapse in Patients with Relapsed Systemic Immunoglobulin Light Chain Amyloidosis." Blood 128, no. 22 (December 2, 2016): 3338. http://dx.doi.org/10.1182/blood.v128.22.3338.3338.
Full textAbstract:
Abstract Introduction Immunoglobulin light chain amyloidosis (AL Amyloidosis) is a plasma cell disorder characterized by deposition of misfolded insoluble protein fibrils (composed of monoclonal κ or λ light chains) in tissues causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT), when eligible, are standard treatment options but relapses remain inevitable for most patients. However, there is a paucity of literature describing relapsed or refractory patients. We performed a retrospective study to analyze the outcomes upon relapse and the impact of type of therapy and retreatment with the same therapy at relapse. Methods Clinical and laboratory data of 1327 consecutive patients with systemic AL amyloidosis seen at Mayo Clinic within 90 days of their diagnosis, between 2006 and 2015, was collected by chart review and analyzed retrospectively. Of these patients, 219 (16.5%) were lost to follow-up. Among the remaining 1108 patients, 366 patients experienced a documented hematological or organ relapse or progression requiring change of first line or start of second line therapy and form the current study population. Overall survival (OS) was calculated from start of second line treatment or progression mandating therapy until death from any cause or the date of last follow up. The OS was estimated using the Kaplan-Meier method and log rank test was used to estimate the difference in survival curves. Results The median age was 62.8 years (36.1 - 85.3); 63.1% were males; 64.7% / 59.3% / 11.4% had cardiac / renal / hepatic involvement and 24.2% / 32.1% / 23.3% / 20.3% had MS I/II/III/IV. The median estimated follow up for this cohort was 69.4 months (95% CI; 64.4, 76.8) from the start of first line therapy and 45.2 months (95% CI; 36.5, 50.6) from the start of second line therapy or progression requiring treatment. The median time to second line treatment or relapse /progression mandating therapy was 16.2 months (1-93) from the start of first line therapy. At relapse, 14 patients underwent ASCT, 165 were treated with proteasome inhibitor (PI) based therapy, 83 with immunomodulator (IMiD) based therapy, 33 with alkylator based therapy, 15 with a combination of PI and IMiD, 10 with steroids, 8 with other therapies and 38 did not receive treatment. Among the 366 patients, 124 (33.9%) required change or reinstitution of therapy during follow up at the time of analysis. The median time to third line treatment or relapse /progression mandating therapy was 31 months (95% CI; 24, 40.5) from the start of second line treatment. The median overall survival (OS) was 76.4 months (95% CI; 65.2, 83.6) from the start of first line therapy and 38.8 months (95% CI; 29.6, 52.6) from the start of second line therapy. The type of therapy at relapse (ASCT vs PI vs IMiD vs melphalan vs steroids and others) did not alter the time to next therapy (ASCT, 43.1m; PI, 31m; IMiD, 37m; melphalan, 20.8m; steroids and others, 20m; p=0.3) and OS (ASCT, 66.9m; PI, 51.1m; IMiD, 51.3m; melphalan, 37.2m; steroids and others, 80.7m; p=0.9) from the start of the second line treatment; as depicted in Figure 1. Retreatment with a different drug class (as the first line treatment) at relapse significantly reduced the time to next treatment (32.3m vs 22 m; p= 0.01) as compared to same therapy; but did not have any impact on survival (30.8m vs 51.1m; p = 0.5); as presented in Figure 2. Conclusion This study provides novel information about outcomes of patients with systemic AL amyloidosis who relapse or progress after first line therapy which could be useful in planning salvage therapies and designing clinical trials. Retreatment with a different therapy at relapse improves time to next therapy but does not impact OS. Hence, we conclude that the patients can fare well post relapse/ progression and can benefit from various treatment regimens including retreatment with the same agent. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; pfizer: Research Funding; Alnylam: Research Funding; Celgene: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding.