Articles de revues : « Myelodisplasia »

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Kaplan, Sümeyye Çoruh. « Neurourological complications in patients with myelodisplasia ». Dicle Medical Journal/Dicle Tıp Dergisi 41, n^o 1 (1 mars 2014) : 234–37. http://dx.doi.org/10.5798/diclemedj.0921.2014.01.0409.

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Bonfichi, Maurizio, Cesare Astori, Emilio Paolo Alessandrino, Paolo Bernasconi Alessandra Balduini, Carlo Castagnola, Ercole Brusamolino, Guido Pagnucco Angelo Canevari, Paola Trucco et Carlo Bernasconi. « Growth Factors in the Therapy of Myelodisplasia : Biological Aspects ». Leukemia & ; Lymphoma 26, sup1 (janvier 1997) : 35–40. http://dx.doi.org/10.3109/10428199709058598.

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Makedonskiy, I. A. « The differential approach to treatment of neurogenic disorders of urination in patient with anorectic disorders and accompanying intraspinal patho ». Neonatology, surgery and perinatal medicine 3, n^o 2(8) (1 juin 2013) : 53–57. http://dx.doi.org/10.24061/2413-4260.iii.2.8.2013.8.

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48 patients with anorectalanorecticabnormalities combined with vertebral, myelodisplasia andneurogenic bladder were examined. With the use of X-ray,ultrasound, urodynamics thereCriteria for therapeutical andsurgical treatment based on urodynamic data were proposedwith the use of X-ray, ultrasound, urodynamics criteria fortherapeutical and surgical treatment based on urodynamicdata. Was proposed and carried out of using of differentkinds of treatment, including periodic sterile catheterizationof urine bladder, pharmacology and different kinds ofsurgical treatment, was proposed and carried out

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Bes, Cemal, et Mehmet Soy. « P0477 RELAPSING POLYCHONDRITIS WITH MYELODISPLASIA AND ARTERIOVENOUS THROMBOSIS : A CASE REPORT ». European Journal of Internal Medicine 20 (mai 2009) : S159. http://dx.doi.org/10.1016/s0953-6205(09)60497-0.

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D’yachkova, N. Yu, T. I. Pospelova, I. B. Kovynev et Yu N. Obgolts. « The analysis of survival of the patients with lymphoproliferative desorders at presence or lack of the myelodisplasia ». Bulletin of Siberian Medicine 7 (30 décembre 2008) : 97–99. http://dx.doi.org/10.20538/1682-0363-2008-0-97-99.

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Capodanno, Isabella, Paolo Avanzini, Fabrizia Franchi et Francesco Merli. « Durable Erythroid and Cytogenetic Response After Short-Term Lenalidomide Treatment In Two Patients with Myelodisplasia and Del(5q) ». Blood 116, n^o 21 (19 novembre 2010) : 4977. http://dx.doi.org/10.1182/blood.v116.21.4977.4977.

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Abstract Abstract 4977 Introduction Lenalidomide (Len) is an immunomodulatory drug that has a selective inhibitory effect on the del(5q) clone. The exact mechanism of action has not been defined: Len is known to have multiple biologic activities and an impressive effect on myelodysplasia (MDS) with deletion of the long arm of chromosome 5, leading to transfusion-independence, a complete erythroid and cytogenetic response in over 65% of cases. Similar responses were also seen in patients with MDS and a complex karyotype including del(5q), which usually have a poor prognosis. Lenalidomide leads to an important myelotoxicity in 50% of patients, so the optimal schedule merits discussion. In this report we describe unexpected erythroid and cytogenetic responses in two elderly patients with del(5q) MDS treated with Len for less than 12 wks. Case Reports Since November 2008 we have been treating two female patients with a diagnosis of MDS and a deletion of the long arm of chromosome 5 [del(5q)] with Len. Both patients had a low-int-1 IPSS risk. At the time of diagnosis severe cardio-pulmonary co-pathologies were present, therefore we observed a very bad tolerance to anaemia. The monthly transfusion requirement before starting treatment was 6 packed RBC units. Len was started at a full dose (10 mg/d for 21 days every 4 wks). Patient 1 received a diagnosis of “5q- syndrome” (Fig. 1). She stopped therapy after only 10 days due to severe agitation and panic attacks; however, one month later we observed a progressive reduction of transfusion need. Two months later, the patient was transfusion-free and the response had been ongoing for 6 months; she obtained a very good partial cytogenetic response. After 6 months the anaemia worsened again; we started Len 10 mg/d, but after 15 days the therapy was stopped due to the same side effects. Forty days later, we observed transfusion-independence for another 6 months, and a very good partial cytogenetic response. When the patient's condition worsened again, she was treated with Len 10 mg on alternative days with a better tolerance. After the first cycle, she presented the same side effects. Again the karyotype analysis showed a very good partial cytogenetic response. In Patient 2 the morphologic analysis was compatible with RAEB-1 and the cytogenetic analysis showed a [del(16)(q22)] together with del (5q) (Fig. 2). Len was stopped after 15 days due to renal impairment, cardiopulmonary and cardiac failure; she was then given only palliative therapy, but four wks later she achieved a complete erythroid response and remained transfusion-free for one year. In January 2010 the patient worsened and started Len again (10 mg/d for 21 dd every 4 wks) with good tolerance, a complete hematologic response and a very good partial cytogenetic response. Hematologic responses are illustrated in Tab. 1 and Tab. 2. In these two patients, after a very short treatment with Len we observed a complete erythroid response and a very good partial cytogenetic response. The median time to achieve the response was 6 wks (range 4–8 weeks). Transfusion-independence was durable (24 and 38 weeks respectively). Discussion Giagounidis et al (Ann. Hematol, 2007) describe two similar cases in which short-time Len treatment was given and a good response was obtained. One of our patients experienced grade III hematologic toxicity during the first cycle of therapy; despite this, we did not observe severe infectious or hemorrhagic complications. Despite the very short duration of Len treatment in our two patients, in both cases we achieved a very good partial cytogenetic response. Conclusions We observed unexpected effects of Len in myelodysplastic patients with del(5q) and a low-int1 IPSS risk who were treated for a very short period; additionally, this response was observed again at least twice when treatment was begun again: although these patients obviously represent only selected cases, the good erythroid and cytogenetic responses suggest that some patients with MDS and del(5q) may benefit from Len treatment even if this must be discontinued. Disclosures: No relevant conflicts of interest to declare.

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Maurillo, Luca, Francesco Buccisano, Maria Ilaria Del Principe, Chiara Sarlo, Luigi Di Caprio, Concetta Ditto, Federica Giannotti et al. « TREATMENT OF ACUTE MYELOID LEUKEMIA WITH 20-30% BONE MARROW BLASTS ». Mediterranean Journal of Hematology and Infectious Diseases 5, n^o 1 (3 juin 2013) : e2013032. http://dx.doi.org/10.4084/mjhid.2013.032.

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Patients with ≥ 20% <30% bone marrow blast infiltration previously regarded as a transitional category between myelodisplasia and acute myeloid leukemia (AML) according to FAB classification, have been subsequently included into AML WHO classification. However, controversies still remain as to whether the natural history and responsiveness to therapy of these patients is comparable to that of patients with > 30% BM blast AML. In the present review, we will discuss the clinical results achieved in the treatment of elderly patients with 20%-30% BM blasts AML using intensive chemotherapy (IC) or hypomethylating agents. Overall, due to concerns of treatment-related morbidity and mortality associated with delivery of IC, approximately only 30% of all patients ≥ 65 years are considered eligible for this approach. Therefore, a great deal of attention has been dedicated to hypomethilating agents such as azacitidine and decitabine. These agents have shown efficacy, with reduced toxicity as compared with IC, when administered to elderly patients not eligible for IC and with 20-30% BM blasts and multilineage dysplasia. Future randomized clinical trials are eagerly awaited to determine whether hypomethylating agents can substitute for IC even in elderly patients with good functional status.

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Pérez, Ana, Olga Salamero, Helena Pomares, Maria Julia Montoro, Montserrat Arnan Sangerman, Laura Gallur, María Laura Fox et al. « Acute Myeloid Leukemia with Myelodisplasia-Related Changes (AML-MRC) Defined Only By Morphological Findings May Not Represent a Poor Prognosis AML ». Blood 134, Supplement_1 (13 novembre 2019) : 2612. http://dx.doi.org/10.1182/blood-2019-129153.

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According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute myeloid leukemias (AML) comprising: AML emerged from a previous myelodysplastic syndrome (MDS) or myeloproliferative /myelodysplastic disease (group 1), AML with MDS-defining cytogenetic abnormalities (group 2), or acute myeloid leukemia (AML) with dysplasia in at least 2 cell lineages without the above mentioned (group 3). In spite that AML-MRC has been considered a high-risk entity with poor prognosis, little is known on the relationship of clinical and biological characteristics with outcomes in these three groups. The aim of this study was to describe the clinical and biological characteristics of patients with AML-MRC and analyze their prognostic variables and outcomes. We retrospectively analyzed AML-MRC cases diagnosed between January-2009 and December- 2018 in two institutions. Descriptive variables were studied to compare the three AML-MRC groups. AML cytogenetic risk and response were defined according to the European Leukemia Net recommendations. Overall survival (OS) was considered as the time from the diagnosis to the last visit. Survival analysis were performed with Kaplan Meier method and comparisons with the log-rank test. Among 575 cases of AML identified, 186 (32.3%) met AML-MRC criteria and were included in the study. The main patient characteristics are shown in Table1. Median age was 72 (range, 22-88) years and 32% were female. Adverse karyotype was present in 29% of patients, being more prevalent in the AML-MRC group 2. Sixty one patients (33%) received an intensive chemotherapy approach and 36 (19%) an allogeneic stem cell transplantation. Patients in group 3 exhibit a higher probability of achieving a complete response than groups 1 and 2 (Table 2). After a median follow-up for survivors of 28.5 months (range, 5-130), 149 (80%) died in this period. Three years Overall Survival (OS) for patients in groups 1, 2 and 3 was 3 (0-117), 5 (0-93) and 10 (0-130) months, respectively (p=0.012) (Figure 1). Type of treatment (intensive, non intensive or best supportive care) and cytogenetic risk also showed impact on OS. Multivariant analysis adjusting these factors showed that patients in group 3 also presented better OS than patients in group 1 (HR=0,42 [IC95% 0,18-0,84], p=0,02), both with around a 30% of patients with adverse cytogenetics. To conclude the present study suggests that group 3 of AML-MRC, for which the diagnosis is based solely on morphologic findings, showed better prognosis than the other groups. A more detailed molecular characterization might contribute to improve prognostic stratification of this heterogeneous AML entity, particularly in patients with non-high risk cytogenetics. Disclosures Salamero: Pfizer: Honoraria; Daichii Sankyo: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Valcárcel:Jazz Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: spouse is an employee in the company, Speakers Bureau; Pfizer: Honoraria. Bosch:AstraZeneca: Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Salar, Antonio, Beatriz Bellosillo, Agustín Seoane, Luz Martinez, Ana Ferrer, Sergio Serrano et Carlos Besses. « A Single-Center Study To Evaluate the Safety and Efficacy of Intravenous/Oral Fludarabine in Untreated Gastric MALT Lymphoma. Impact of t(11;18)(q21;q21) in Molecular Response Rates. » Blood 110, n^o 11 (16 novembre 2007) : 4439. http://dx.doi.org/10.1182/blood.v110.11.4439.4439.

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Abstract Background: The treatment of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in the absence of H. pylori infection or when the lymphoma fails to regress after adequate antibiotic treatment remains controversial. Fludarabine (F) is an active agent for indolent lymphoma, however, its clinical activity in gastric MALT lymphoma has not been studied. The aim of the study is to assess the efficacy and safety of single-agent fludarabine in gastric MALT lymphoma and to analyze the molecular response (MR) after this treatment. Methods: Treatment consisted of fludarabine (25 mg/m2 IV) given on days 1–5, every 4 weeks, for 6 cycles; after the first cycle, oral fludarabine was allowed to be given orally at 40 mg/m2 with the same schedule. Molecular response (MR) was assessed by RT-PCR analysis of t(11;18) or by PCR assays for analysis of IgH gene rearrangements analyzing FR1, FR2 and FR3 in endoscopic biopsies. Results: Eight consecutive patients were included. Median age: 60 years (range: 45–77); 3 pts were in stage I, 2 stage II-1 and 3 stage IV according to Lugano system. Four out of 5 (80%) pts achieved a CR after three cycles and all eight cases (100%) achieved a CR after six cycles, for an overall response rate of 100%. After a median follow-up of 44 months (range 14.5–58 mo) no patient has shown clinical or endoscopic relapse. Hematological toxicity occurred in 75% of pts, mainly mild neutropenia and generally after the third cycle. Three cases received G-CSF (after the 2nd, 3rd and 6th cycle) and three patients required dose modification or delay (3–7 days) in the delivery of the following cycle. No blood transfusions were required. Only one patient had to be admitted because of non-neutropenic fever. None case of myelodisplasia has been detected at last follow-up. Four out of 8 pts (50%) achieved MR during the study-period (see figure). Four out of 5 (80%) pts without t(11;18) achieved MR. In contrast, no patient carrying t(11;18) achieved MR. Sequencing analysis of monoclonal PCR products will be presented. Conclusions: Fludarabine, either intravenous or oral, is safe and achieve a high response rate when given in gastric MALT lymphoma, with many pts achieving MR. In those pts carrying t(11;18), residual disease can be detected by PCR but do not determine relapse at present follow-up. Figure Figure

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Lauria, F., A. Gozzetti, D. Raspadori, A. Petrini et M. Defina. « PATHOGENETIC ASPECTS OF MYELODISPLASTIC SYNDROMES ». Journal of the Siena Academy of Sciences 1, n^o 1 (10 janvier 2012) : 5. http://dx.doi.org/10.4081/jsas.2009.5.

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Guolo, Fabio, Paola Minetto, Luana Fianchi, Michela Rondoni, Giulia Daghia, Stefano D'Ardia, Monica Morselli et al. « Preliminary Results from CPX-351 Italian Compassionate Use Program Show High Response Rate and Good Tolerability in Poor Prognosis AML Patients ». Blood 134, Supplement_1 (13 novembre 2019) : 1363. http://dx.doi.org/10.1182/blood-2019-131329.

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Background: Therapy-related acute myeloid leukemia (t-AML) or AML evolving from a myelodisplastic syndrome are characterized by a low response rate to conventional chemotherapy and high relapse rate with poor overall survival (OS) despite intensive treatment and allogeneic stem cell transplantation consolidation (HSCT). CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin, in a fixed synergistic 1:5 molar ratio. CPX-351 has been approved by FDA for the treatment of patients affected by t-AML or AML with myelodisplasia-related changes (MRC-AML) based on the results of a randomized phase III trial where the drug was compared with conventional 3+7 induction (Lancet et al, JCO 2018). Notably, CPX-351 proved to increase survival probabilities in comparison with standard chemotherapy even among patient achieving complete remission (CR) and proceeding to HSCT, suggesting that CPX-351 may allow deeper responses. However, few information is available on minimal residual disease (MRD) assessment after CPX-351 treatment, or on the impact of molecular alterations on response probability. Aims: The aim of this study was to evaluate the clinical activity of CPX-351 in a real life setting, with particular focus on molecular characterization at diagnosis and MRD evaluation in responding patients. Methods: Seventy five patients were enrolled in a compassionate use program (CUP) in 37 Italian Hematology Centers. CUP started on December 2018 and closed on June 2019. Data collection began on July 2019 and was completed, at the time of writing, for 25/75 patients, enrolled in 9 Centers. Median age was 69 years (56-73), 10 patients were female. Molecular and MRD analysis were performed in each Center as per internal standard. MRD was assessed in most Centers with multicolor flow cytometry. NPM1 mutation was found in 2/22 assessed patients, FLT3-ITD in 3/22, with low allelic burden in 2/3 patients. TP53 mutations have been found in 4/12 patients.Four patients had complex Karyotype, one had isolated del(7q) whereas the remaining 19 had normal karyotype. Six patients had t-AML; 15 patients were previously diagnosed with MDS and 5 of them had already received hypomethilating agents for a median of 5 cycles (2-49). European Leukemia net risk score was low in 2 (8%), intermediate in 12 (48%) and high in 11 (44%) patients. Most patients (20/25) had relevant comorbidities upon enrollment, mostly COPD, diabetes and/or hypertension. As per CUP inclusion criteria, all patients had normal left ventricular function at the time of enrollment (defined by a normal ejection fraction). Results: Induction-related mortality was 2/25 (8%). Fourteen patients experienced grade >1 extra hematological adverse event during induction (mainly infections). Alopecia was observed in 4/25 patients (16%).Response was assessed in 20 patients:2 patients died during induction and 3 patients were not yet evaluated for response at the time of analysis. CR or CRi was observed in 19/22 (86.3%). MRD was performed in 11 patients, with 4 of them achieving flow MRD negativity after first cycle (defined as <0.1%, Minetto et al. BJH 2019). Median time to neutrophil and platelets recovery in responding patients were 29 (18-60) and 24.5 (19-60) days, respectively. Among responding patients, 10 received further CPX-351 consolidation, which was very well tolerated. One patient proceeded directly to HSCT, one is currently waiting for HSCT to be performed and one patient received a conventional chemotherapy consolidation. The remaining patients are currently waiting for administration of consolidation therapy with CPX-351. Four patient had completed so far all planned consolidation therapy with CPX-351 and 2/4 of them were flow MRD negative at the end of therapy. Of note, 3/4 patients with mutated TP53 achieved MRD negative CR. After a median follow-up of 5 months, relapse was observed in 2/20 responding patients and 21 patients are alive at the time of analysis. Conclusions: Our preliminary data confirm the high clinical activity and good tolerability of CPX-351 in a challenging AML cohort. The high median age and the high incidence of severe comorbidities did not result in unacceptable risk of death during induction. With the limitation of very small numbers, CPX-351 showed good antileukemic activity among TP53 mutated patients. Disclosures No relevant conflicts of interest to declare.

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KOZAN, Salih, Deniz TORUN, Yusuf TUNCA, Cengiz BEYAN, Ahmet İFRAN, M. Kürşat KAPTAN, Ali Uğur URAL et al. « Rheumatic and Autoimmune Diseases May Have a Role in Disease Progression of Myelodysplastic Syndrome ». Turkiye Klinikleri Journal of Medical Sciences 32, n^o 4 (2012) : 910–16. http://dx.doi.org/10.5336/medsci.2011-24201.

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Sargin, Gokhan, Taskin Senturk et Irfan Yavasoglu. « Refractory anemia in systemic sclerosis : myelodisplastic syndrome ». European Journal of Rheumatology 2, n^o 3 (27 août 2015) : 120–21. http://dx.doi.org/10.5152/eurjrheum.2015.0100.

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Minetto, Paola, Fabio Guolo, Luana Fianchi, Marino Clavio, Michele Gottardi, Mauro Endri, Sara Galimberti et al. « CPX-351 Induction in Secondary Acute Myeloblastic Leukemia : Extended Follow up from the Italian Compassionate Use Program ». Blood 138, Supplement 1 (5 novembre 2021) : 1262. http://dx.doi.org/10.1182/blood-2021-153028.

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Abstract Introduction: The outcome of patients with acute myeloid leukemia (AML) secondary to myelodisplastic syndrome (MDS) or therapy-related (t-AML) receiving conventional treatment and allogeneic stem cell transplantation consolidation (HSCT) is poor. CPX-351 is a new drug composed by liposomal encapsulated cytarabine and daunorubicin, at a fixed molecular ratio of 5:1. It showed superior results, compared to standard 3+7 induction, in a phase III trial (Lancet et al, JCO 2018) in patients affected by t-AML or AML with myelodisplasia-related changes and it is now commercially available for secondary AML (sAML). We recently published results from CPX-351 Italian Named (Compassionate) Use Program (CUP) which enrolled 73 elderly sAML patients (Guolo et al, Blood Cancer J. 2020) showing that CPX-351 is an effective induction regimen for high risk AML patients treated with a curative aim. With a limited follow up, our data suggested the good activity and tolerability of CPX-351. Good quality remissions with acceptable toxicity in the majority of patients was achieved and CPX-351 increased the feasibility of HSCT in a poor risk AML cohort. Scarce data are available on long term outcome of high risk patients receiving CPX-351 in the real life setting. Here we report the results from the extended follow up analysis of the Italian CUP. Results: Seventy three patients were enrolled between December 2018 and June 2019 in a compassionate use program (CUP) in 33 Italian Hematology Centers. Data collection began on July 2019 and included 71/73 patients (97.2%), enrolled in 31 Centers. As previously reported, median age was 65.5 years (52-79). Sixty-two (88%) patients had at least one relevant comorbidity upon enrollment. Six patients (9%) presented with ECOG 3-4 upon enrollment. With a median follow up of 22 months, median overall survival (OS) was 13 months (21.2 - 22.8 95% IC). Two-years OS was 28.6% in the whole cohort. In order to confirm the positive impact of HSCT in first complete remission (CR) and the correlation with the other variables, a landmark model was applied, including only patients alive and in CR at day 90. In landmark analysis, HSCT performed in first CR after CPX-351 was the only significant predictor of longer survival: median OS was not reached for patients transplanted in first CR Vs 12 months for patients who did not undergo HSCT, p < 0.05, Figure1). Two-year OS for patients who received HSCT was 57.6% vs 15.8% for patients who did not undergo HSCT. Conclusions: Results from the extended follow up of Italian CPX-351 CUP confirm the good activity CPX-351 in such a difficult cohort as sAML. Two-year OS for transplanted patients is high despite the high median age, the high frequency of severe comorbidities in this real life cohort of patients and the high frequency of high risk AML. On the contrary, non-transplanted patients show a poor outcome, thus confirming that CPX-351 induction as an optimal bridge to transplant induction therapy. Figure 1 Figure 1. Disclosures Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Marco: Insight,: Consultancy; Jazz: Consultancy; Janssen: Consultancy. Fracchiolla: Amgen: 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; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Speakers Bureau. Tafuri: Roche: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Rossi: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Pagano: Gilead Science, MSD, Pfizer, Basilea, Janssen, Novartis, Jazz Pharmaceutical, Cidara: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Gilead Sciences, MSD, Pfizer Pharmaceuticals, Astellas Pharma: Speakers Bureau.

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de la Fuente, Cristina, Maria I. Berrocal, J. Rafael Cabrera, Carlos A. Regueiro, Rafael Fores, Carmen Regidor, Isabel Millan et al. « Secondary Malignancies after Hematopoietic Stem Cell Transplantation in Patients Treated with Total Body Irradiation. » Blood 106, n^o 11 (16 novembre 2005) : 2741. http://dx.doi.org/10.1182/blood.v106.11.2741.2741.

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Abstract We have analyzed the incidence and risk factors of developing a secondary malignancy after total body irradiation (TBI) and hematopoietic stem cell transplantation (HSCT). From March 1986 to December 2002, 205 patients received TBI as a part of the HSCT conditioning regimen. TBI was administered in 6 fractions, twice a day, up to a total dose of 12 Gy, with a median dose rate of 11.44 cGy/min. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 119 patients and the other 86 patients received an autologous hematopoietic stem cell transplantation (AHSCT). Median age was 30 years (5–63). We have calculated the cumulative incidence of solid tumors and secondary hematologic malignancies among these patients. Death due to noncancerous causes and patients lost to follow-up were entered as a competitive risk. With a median follow-up of 32 months (0.2–229)- including patients deceased in the first three months- 13 (6.3%) developed a secondary malignancy, 7 of them (3.4%) developed a solid tumor and 6 (2.9%) developed a secondary hematologic malignancy. The 7 patients who developed a solid tumor-1 glioblastoma, 2 head and neck carcinoma, 2 basocelular carcinoma, 1 osteosarcoma and 1 cervical intraepithelial neoplasia- had received an allo-HSCT. The 6 patients that developed a secondary hematologic malignancy- 5 therapy-related leukemia/myelodisplasia (t-AML/MDS) and 1 B cell non Hodgkin’s lymphoma- had received an AHSCT. The overall probability of developing a secondary malignancy after HSCT is 2.5% at 3 years (95% confidence interval (CI) 1.1– 6); 5% at 10 years (95% CI 2.6–9.3), and 9% at 15 years (95% CI 5–16.5). The probability of developing a solid tumor after HSCT is 0.5% at 3 years (95% CI 0.1–3.6), 1.8 % at 10 years (95% CI 0.6–5.5), and 6 % at 15 years (95% CI 2.6–13.7) and the probability of developing a secondary hematologic malignancy is 2 % at 3 years (95% CI 0.8–5.3), and 3,1 % at 10 and 15 years (95% CI 1.4–6.9). Median time to develop a solid tumor was 134 months (29–229). Median time to develop a secondary hematologic malignancy was 31 (3–60) months. Multivariate analysis proved that allo-HSCT was the only risk factor of developing a solid tumor, and that AHSCT and advanced age were risk factors of developing secondary hematologic malignancy (mean age 30 vs. 50 years ). To conclude, the probability of developing a solid tumor after HSCT is higher if an allo-HSCT has been performed and increases with time. AHSCT and advanced age are risk factors for the development of a secondary hematologic malignancy, a risk that decreases 5 years after AHSCT.

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Karduss-Urueta, Amado J., Giovanni Ruiz, Rosendo Perez, Alejo Jimenez, Angelica Cardona, Gloria Suarez, Luis R. Gomez et Pedro Reyes. « Intensification of the Regimen Fludarabine Melphalan with the Addition of 400 Cgy of Total Body Irradiation in Allogeneic Stem Cell Transplantation. It Is Feasible, Has a Good Anti-Leukemic Effect and a Low Toxicity ». Blood 126, n^o 23 (3 décembre 2015) : 1916. http://dx.doi.org/10.1182/blood.v126.23.1916.1916.

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Abstract Fludarabine 120-160 mgs/m2 plus melphalan 140 mgs/m2 (Flu- Mel) is a well known reduced intensity conditioning protocol used in allogeneic transplantation, however it can be no enough intense to treat high risk acute leukemia, specially in the relapse setting. On the other hand, 400 cGy of total-body irradiation (TBI 400) has been successfully added to myeloablative dose of fludarabine busulfan without excessive toxicity. We designed a regimen adding TBI 400 to usual dose of Flu-Mel with the idea to increase its anti-leukemic activity. Below we present our experience Methods and patients Peripheral blood stem cells were mobilized with figrastim for 5 days, later, 1 or 2 apheresis were done to achieve a minimum of 3 million of CD34 + cells/kg. The conditioning consisted of fludarabine 30-40 mgs/m2 for four days, melphalan 140 mgs/m2 one dose, on day - 1, TBI 400 was administered split in 2 fractions. The prophylaxis against graft versus host disease (GVHD) was done with cyclosporine and methotrexate, all patients were given pegfilgrastim 22 patients were transplanted, median age 26.5 years (range 8-49), the diagnosis were; acute lymphoblastic leukemia (13), acute myeloid leukemia (6), chronic myeloid leukemia (1), high risk myelodisplasia(1), mixed acute leukemia(1). 32% were in first remission, 41% in second, 27% were in third or they had active disease. The discrimination according CIBMTR disease risk index (CIBMTR-DRI) was: 54% high risk, 41% intermediate and 5% low Results All donors were matched siblings, a median of 10 millions/kg of CD34+ cells were infused; all patients engrafted, the neutrophil and platelet recovery occurred on days +11 and + 14 respectively. The grade III toxicity was; mucositis, 45% and one case of encephalopathy, there were not any case of sinusoidal obstruction syndrome. The incidence of GVHD acute (GII-IV) and chronic extensive was 10 and 25%. With a median follow up of 11 months (range 6-30) the overall survival (OS)(Kaplan-Meier) at 24 and 36 months is 69 and 55% . Six patients have died, one due to sepsis and five secondary to relapse. The OS according to CIBMTR-DRI at 36 month was 75 and 46% for intermediate and high risk groups Conclusion: The addition of TBI 400 to Flu- Mel regimen is feasibly, the main toxicity is mucositis, the non- relapse mortality is very low and the incidence of GVHD, acute a chronic, is not higher than expected This combination shows an encouraging anti leukemic effect, as it is demonstrated by an OS of 75 and 46% in patients classified in intermediate and high risk CIBMTR DRI groups. This preparative protocol can be a low toxicity alternative to more conventional myeloablative regimen. It warrants further studies Disclosures No relevant conflicts of interest to declare.

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Capelli, Debora, Liviana Giostra, Denise Maravalle, Pietro Leoni et Attilio Olivieri. « Dinamic Evaluation of Quality of Life and Late Effects in a Cohort of Acute Myeloid Leukemia Long Term Survivors ». Blood 126, n^o 23 (3 décembre 2015) : 5584. http://dx.doi.org/10.1182/blood.v126.23.5584.5584.

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Abstract Late effects and quality of life (QoL) in Acute Myeloid Leukemia (AML) long term adult survivors represent an unexplored field of interest. We prospectively evaluated late effects and dynamic QoL in 44 and 29 cured AML patients (17 <60 years, and 12 >60 years), treated at our department between 1997 and 2010 (7 Allogeneic, 16 Autologous Transplant, 21 chemotherapy alone). We administered EORTC QLQ-C30 and FACT-AN questionnaires at two different time points with a median interval of 29 months (range: 12-34 months). We stratifyed QoL scores by age at diagnosis, performance status (PS), Sorror Index, kind of leukemia treatment, comorbidity at diagnosis. We observed a worsening of emotional (-9.03; p= 0.04) and cognitive (-6.94; p= 0.05) EORTC scale scores, while FACTG (+2.9; p=0.03), emotional (+1.1; p= 0.04) and Functional (+2.25; p=0.001) well being FACT scores increased. Multivariate analysis showed that older patients had worse EORTC QLQ-C30 physical and emotional scale scores and higher values of pain symptoms in comparison to younger counterpart, with RR of 20.1 (p = 0.001), 22.7 ( p <0.04) and 18.4 (p=0.03) respectively. Elderly patients also had lower Total Outcome Index and FACT-An subscale scores (RR: 11.9, p= 0.02; and 8.77, p= 0.04 respectively). Sorror index > 2 was related to lower EORTC QLQ-C30 social scale and dyspnea scores (RR: 32.5; p=0.001 and 21.7; p=0.001 respectively) and FACT-An functional well being values (RR=3.9; p=0.001). We evaluated late effects occurring in 44 patients, since the third month after the end of treatment, with a median follow-up of 70 months (range: 12-166 months). The most frequent grade II-IV late toxicity was cardiac (3 arythmia, 9 cardiomyopathy) with 89% incidence in patients with Sorror HCT-CI score>2 at diagnosis vs 8.8% in the remaining patients and 0%, 20% and 55.5% in patients receiving respectively Daunorubicin, Idarubicin and at least two different anthracyclines. Sorror Index>2 was the only factor significantly predicting cardiotoxicity at the multivariate analysis with a RR of 82.7 (p=0.001). Twelve patients developped a transient hemochromatosis secondary to transfusions, treated with phlebotomy in 3 cases. Three patients (2 males and 1 female) had been fertile; all female patients developped menopause after Transplant. Four patients had secondary neoplasia consisting of Multiple Myeloma, breast cancer, myelodisplasia and axillary sarcoma. Our study underlines the role of Sorror Index at diagnosis in defining patients eligibility to cardio-prophylactic therapy. The analysis of larger series of cured AML patients are strongly needed in order to define guidelines for reducing long term treatment AML toxicity. Disclosures No relevant conflicts of interest to declare.

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Rodríguez García, Alba, Maria Linares, Maria Luz Morales, Vanesa Garrido, Irene Baquero, Maria Teresa Cedena Romero, Ricardo Sanchez, Rosa Ayala, Jose Manuel Bautista et Joaquin Martinez Lopez. « Protein Carbonylation Pattern Is Altered in Myelodisplastic Syndromes ». Blood 132, Supplement 1 (29 novembre 2018) : 5502. http://dx.doi.org/10.1182/blood-2018-99-112799.

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Abstract * A.R. and M.L. have contributed equally. INTRODUCTION: Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated hematopoietic stem cells. Oxidative stress could play an important role in the pathology of MDS since a correlation has been observed between high ROS levels and decreased survival in MDS patients. In addition, the oxidation of proteins leads to their aggregation, change and conformational changes that can cause the loss of their functions. Due to alteration of the proteome has been described in patients with MDS, in this study we considered the discovery of protein carbonylation to analyze its oxidation pattern. In addition, as the oxidative stress signaling pathways can regulate the cell cycle through p53, we analyzed p21, an important p53 target during the stress response. Finally, the possible benefit of treatment with Deferasirox as antioxidant therapy was studied. METHODS: Carbonylation pattern was analyzed in the different cell lines (n = 14, 6 MDS, 4 reactive controls and 4 MDS + DFX) by immunohistochemistry by derivatization with 2,4-dinitrophenylhydrazine (DNPH) and detection with anti-DNP antibodies. The degree of protein carbonylation was studied, also by derivatization and detection with anti-DNP, in primary cells of erythroblasts expanded for 11 days, by one-dimensional and two-dimensional electrophoresis (n = 16; 7 MDS, 6 controls, 2 reactive controls and 1 MDS + DFX). Expression levels of p21 were analyzed by qRT-PCR (n=19; 8C, 8 MDS, 3DFX). RESULTS: Immunohistochemical assays revealed a higher level of carbonylation in patients with MDS (Fig. 1a). Interestingly, Deferasirox-treated MDS patients had lower levels than non-treated patients (Fig. 1b). In addition, to evaluate the carbonylation in the erythroid precursors, the pattern of carbonylated proteins in the expanded erythroblasts was analyzed. Again, a higher level of MDS was observed compared to the control group, which was reversed after treatment with Deferasirox. Two-dimensional electrophoresis revealed that differences in carbonylation are due to a limited number of proteins or aggregates, rather than to a large spectrum of proteins. Finally, an increased p21 expression was observed in patients with myelodysplasia and, surprisingly, this effect was reversed with Deferasirox treatment. CONCLUSION: Patients with MDS showed a differential protein pattern respect to control patients, both in the myeloid and erythroid series. The increase in oxidative stress in myelodysplastic patients seems to activate signaling pathways involving p21. Treatment with Deferasirox can reverse the level of oxidation and the increase of p21 in patients with MDS. Disclosures Martinez Lopez: Celgene: Research Funding, Speakers Bureau; Jansen: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

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De Salvo Cardullo, Luigi, Mirian C. Duerto, Dalila DV De Salvo, Rodolfo J. Salas-A, Jesus E. Weir-M, Ana M. Nuñez, Alonso A. Nuñez et al. « Differential Diagnosis of Myelodisplastic Syndrome, with Flow Cytometry. » Blood 114, n^o 22 (20 novembre 2009) : 4860. http://dx.doi.org/10.1182/blood.v114.22.4860.4860.

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Abstract Abstract 4860 Our flow cytometry laboratory processed 38 bone marrow (BM) samples (24 males and 14 females) from patients with Myelodisplasic Syndrome diagnosis, from January 2008 to May 2009. Upon examination, most BM smears corresponded with an hypercellular bone marrow and increased intermediate and immature cells. All patients classified according to OMS for Myelodisplasic Syndromes. Twenty-four (n=24) patients (65%) presented RA, five (n=5) patients (13%) RAEB-1, one (n=1) 1% presented RARS, and eight (n=8) patients (21%) classified as RAEB-II. Cytogenetic result analyses for all patients classified according with the Index Prognostic Standard Score (IPSS). Twenty-five (n=25) patients or 66% corresponded with a good cytogenetic risk; seven (n=7) or 20% corresponded with an intermediate risk and six (n=6) or 14% with poor risk. Cell cytometry results corresponded with increased immature cells. In 20 patients, the DR/CD34 average 27,29% (range 0-67); in 24 patients, the DR/CD33 average 31,80% (range 6-100); in 29 patients, the DR/CD117 average 18,89% (range 0-43); in 7 patients, the CD33/CD34 average 22,14% (range 0-50); in 5 patients, the CD38 average 47,60% (range 32-61); in 4 patients, the BCL2 average 21,75% (14-26 and in 3 patients, the DR/CD64 average 44,33% (range 30-60). All patients with high average of DR/CD64 classified as CMML. Patients with RAEB-II diagnosis classified as MDS in transformation. Most patients displayed 10% CD34+ values higher than normal human average. We conclude the cytometry is an important tool in the differential diagnosis of MDS. Disclosures No relevant conflicts of interest to declare.

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Martinez, Ana Belen Valencia, Alessandro Martino, Francesca Buchi, Erico Masala, Alessandro Sanna, Federico Canzian, Daniela Cilloni et al. « Mechanism of Resistance to Azacitidine in Myelodisplastic Syndromes. » Blood 120, n^o 21 (16 novembre 2012) : 2810. http://dx.doi.org/10.1182/blood.v120.21.2810.2810.

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Abstract Abstract 2810 Azacitidine is a pyrimidine nucleoside analogue of cytidine and it is at present the standard treatment for myelodysplastic syndromes (MDS). A large number of studies performed to evaluate the mechanism of resistance/response to nucleoside chemotherapeutics like cytosine arabinoside or gemcitabine, have demonstrated the importance of the levels of expression of the enzymes involved in their metabolism. Despite the high clinical interest in azacitidine, little is known about its intracellular metabolism and scanty data are available in literature. Recently, differences in the expression of these enzymes has been reported in cell lines differentially sensitive to hypomethylating agents. Clinical responses to azacitidine are heterogeneous, mainly due to clinical characteristics of MDS patients, so there is a need to identify molecular markers that could predict and/or monitor the efficacy of this therapy. A better understanding of the biological mechanisms involved in the activation and DNA uptake of azacitidine is therefore necessary to possibly identify responsive MDS patients. Objectives: To measure the expression levels of the 5 enzymes involved in azacitidine metabolism and to correlate their gene expression with the clinical response to the drug. To test possible causes of differences in gene expression. Material and Methods: DNA and RNA was extracted from mononuclear cells of 39 IPSS high risk MDS patients treated with at least 6 cycles of azacitidine 75mg/m2/7 days every 28 days. Of them, 14 patients were responders and 25 non-responders to azacitidine according to IWG 2006 criteria. Gene expression was assessed with quantitative PCR, using an ABI GeneAmp® 5700. The specific oligonucleotides and TaqMan® probes of every selected gene will be acquired among the Assay-on-Demand® Gene Expression Products (Applied Biosystems). Promoter methylation of UCK1 was evaluated by methylation specific PCR using specific primers. The UCK1 coding region was sequenced by Sanger method. Results: Gene expression of hENT1, UCK1, DCK, RNR1 and RNR2 was compared between the groups of responders and non-responders. Individually, none of the genes was differentially expressed in responders versus non-responders. Nevertheless, a trend for lower expression in non-responders was shown for the UCK1 gene (median responders: 12.4 versus median non responders: 10.7; P = 0.095). In order to verify whether the presence of aberrant methylation could impact in UCK1 gene expression, we measured the methylation status of a putative CpG island in the UCK1 gene promoter region. The CpG island was unmethylated in all the samples analyzed, including responders and non-responder cases, as well as healthy donors. Moreover, to verify whether the difference in gene expression could be due to nucleotide variants in the gene sequence, we sequenced the UCK1 sequence. We found one polymorphic locus (rs2296957) in exon 6 and additional five intronic SNPs (rs3904060 and rs7867616, Intron 1; rs2296956 and rs189473964, Intron 3; rs150900763, 5' UTR) at the intron/exon boundaries. The presence of an individual genotype at these loci was not associated with therapy response and UCK1 gene expression. Conclusions: Our results show that absence of clinical response to azacitidine could be partly correlated with lower expression of UCK1. This is most likely causing a scarce azacitidine monophosphorylation by UCK1 in non-responders patients. The methylation status of the UCK1 gene promoter is not affecting gene expression. In addition, the genetic polymorphisms found in the UCK1 sequence do not associate with therapy response nor with gene expression. Further studies on larger series of MDS cases are needed to confirm these results which could help driving therapeutic decisions. Disclosures: No relevant conflicts of interest to declare.

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Bonini, Alessandro, Paolo Avanzini, Luciano Masini, Francesco Merli, Fiorella Ilariucci, Barbara Gamberi, Alessia Tieghi et al. « Defibrotide Low-Dose Continuous Infusion from Day +1 Until Day +21 after Allogeneic Stem Cell Transplantation as Prophylaxis of Veno-Occlusive Disease (VOD) of the Liver. A Single Centre Experience. » Blood 110, n^o 11 (16 novembre 2007) : 4927. http://dx.doi.org/10.1182/blood.v110.11.4927.4927.

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Abstract Defibrotide has been shown to be effective in the treatment and prophylaxis of the VOD,a relatively common complication after allogeneic hematopoietic stem cell transplantation(SCT).We report our experience in 41 consecutive patients(pts) for a total of 43 SCT.The analysis,closed at day +35 after BMT,is limited to 39 SCT,since 4 pts not affected by VOD died on day +3,+11,+13 and +24,respectively.The pts(mean age 42 yrs,range 16–65) were affected by acute leukemia(14), chronic myeloid leukemia(5),lymphoma(15),multiple myeloma(2),myelodisplasia(1) and solid tumor(2).Other relevant clinical characteristics were:resistant or metastatic disease 9,previous autologous BMT 6,previous allogeneic SCT 2,previous B virus hepatitis 5,liver metastases 1 and lymphoma of the liver 1.All were transplanted from their HLA-identical sibling;the conditioning regimen was defined as reduced in 15(thiotepa,fludarabine and cyclophosphamide),while it was conventional in the other 24 SCT with use of busulphan(oral 13 and iv 11) and cyclophosphamide(VP16 added in few cases;never TBI). Thirteen received bone marrow and 26 peripheral blood as source of stem cells.No T-cell depletion was done and the GVHD prophylaxis regimen was CsA+MTX for 36 pts, CsA alone for 2 pts and FK506+MTX for 1 patient.For VOD prophylaxis no Heparin was administered,while Defibrotide was given at the dosage of 10 mg/Kg in continuous iv infusion starting on day +1 until day +21 after the SCT.Defibrotide was very well tolerated,and no hemorrhagic complications were observed.Blood coagulation significant alterations were:prolonged PT(4/39),prolonged aPTT(3/39),fibrinogen elevated(23/39,never over 800 mg/dl),low level(less than 50%) of ATIII,and/or protein C,and/or protein S(2/39).By using the VOD Baltimore criteria,only 1 case of VOD was observed at day +29 in a patient who died at day +36 with VOD,aspergillosis and CMV pneumonia.The bilirubin was more than 2 times the normal value in 20/39;US scan of the liver and Doppler,performed in 15 pts with a possibile sign of VOD,was positive only in the patient who died for VOD.We documented 29 infectious complications(14 FUO,9 gram positive bacteremias,2 pneumonia and 4 invasive aspergillosis).We observed acute GVHD in 10 pts(9 grade I–II and 1 grade III).Five pts died between +36 and +100 but none for VOD(3 for progression of their disease and 2 for aspergillosis).Since in this at risk transplanted population only 1 VOD has been observed,Defibrotide low-dose continous infusion, not associated with Heparin,seems able to play a relevant role in the VOD prophylaxis.On considering the favourable results obtained by us and Others,the absence of toxicity and the low cost of Defibrotide,we intend to continue this experience with defibrotide as VOD prophylaxis,even if we foretell a large randomized study to find better indications.

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Alvarez, Patricia, Pilar Saenz, David Arteta, Antonio Martiez, Miguel Pocovi, Laureano Simon et Pilar Giraldo. « A Low Density DNA Microarray for Comparing Gene Expression Profiles in Hematological Malignancies. » Blood 108, n^o 11 (16 novembre 2006) : 4291. http://dx.doi.org/10.1182/blood.v108.11.4291.4291.

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Abstract High density microarrays (HDM) are powerful tools for simultaneously profiling the expression levels of thousands of genes. The application of this technology to study of neoplastic hematological disorders.has identified new sub groups of disease not related previously and new prognosis markers. However there is a limited experience in the gene expression studies using low density microarrays (LDM) in neoplastic hematological disorders. A gene expression analysis system based on a LDM containing 538 oligonucleotides has been developed. Whole technical process was optimized to improve the analysis of differential expression. We have analyzed mRNA from cell line cultures (Jurkat, U937), whole blood samples from healthy subjects and different hematological malignancies (HM) using this chip. A hierarchical clustering procedure applying Welch t-statistics with Bonferroni correction was used to analysis gene expression data The LDM generated a linear response of 2 magnitude orders and a CV values less than 20% for hybridization and label replicates. This procedure detects 0,2 fmols of mRNA. We have found genes with statistically significant differences between Jurkatt and U937 cells cultures, and blood samples from 15 healthy donors, 59 lymphocyte leukemia and 13 myeloid leukemia and myelodisplasia syndrome patients. A classification system based on gene expression data was constructed with an accuracy of 97%.to predict healthy or lymphocyte leukemia status. To identify different subsets of patients in the B-CLL group, whole blood samples from 12 B-CLL patients were collected and defined as stables, according to clinical and analytical criteria at the time of diagnosis, “stable” (n=6) if disease stability was maintained for more than five years after the diagnosis and “progressive” (n=6) if the disease progressed less than one year after the diagnosis. Applying Welch statistical test without correction and a p<0.05 yielded two lists of 29 and 19 probes differentially hybridized from VSN and quantile-robust normalized data, respectively. The supervised hierarchical clustering of B-CLL samples with 29 statistically significant probes shown that samples grouped together based on their stable or progressive behavior. Eighteen probes were statistically significant in both normalized data. In order to confirm the data expression of POU2F2, PSMB4, FCER2, LCP1, and ABCC5 genes represented by 5 of the 18 statistically significant probes, real-time RT-PCR was performed. Three out of 5 genes -POU2F2, PSMB2, and FCER2- were over-expressed in B-CLL stable patients. Differences were statistically significant (P<0.05) and, therefore, results obtained from the chip for POU2F2, PSMB2, and FCER2 genes were confirmed. In conclusion, a viable LDM for gene expression analysis and a simple procedure has been developed useful for analysis of whole blood samples, without any cellular or sample manipulation prior to RNA extraction with variability and reproducibility similar to others commercial HDM. The application to different samples is capable to establish significant differences in gene clusters and could be useful for clinical application in HM

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Bonini, Alessandro, Annalisa Imovilli, Angelo Ghirarduzzi, Mauro Silingardi, Annalisa Pilia, Luigi Gugliotta et Francesco Merli. « Defibrotide Low-Dose Continuous Infusion After Allogeneic Stem Cell Transplantation as Prophylaxis for Veno-Occlusive Disease of the Liver. » Blood 116, n^o 21 (19 novembre 2010) : 3483. http://dx.doi.org/10.1182/blood.v116.21.3483.3483.

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Abstract Abstract 3483 Defibrotide (DF) has been shown to be effective in the treatment and prophylaxis of the veno-occlusive disease (VOD) of the liver, a relatively common complication after allogeneic stem cell transplant (SCT). We report our experience in 46 consecutive adult patients (pts). The pts (mean age 41 yrs, range 16–66) were affected by leukemia (22), lymphoma (15), multiple myeloma (4), myelodisplasia (2), solid tumor (2), Fanconi anemia (1). Risk factors for VOD were: resistant disease 9, previous transplant 8, B virus hepatitis 6, liver metastases 1, lymphoma of the liver 1, increased transaminases before conditioning 7. All were transplanted from their HLA-identical siblings; the conditioning regimen was reduced in 17, while it was conventional in 29. All the pts received a combination of drugs as conditioning regimen, 23 of them received Busulfan and 8 of them oral Busulfan. 15 received bone marrow and 31 peripheral blood as source of stem cells. None was T-cell depleted; the GVHD prophylaxis regimen was: CsA alone or combined with MTX 45, FK506+MTX 1. For VOD prophylaxis no heparin was administered, while DF was given at the dose of 10 mg/Kg in continuous iv infusion starting on day +1 until day +21 after the SCT. DF was very well tolerated and no hemorrhagic complications were seen. Blood coagulation significant alterations were: prolonged PT (4/46), prolonged aPTT (3/46), elevated fibrinogen (24/46), (never over 800 mg/dl), low level (less than 50%) of ATIII and/or protein C and or protein S (2/46). By using the VOD Baltimore criteria, only 1 case of VOD was observed on day +29 in a patient who died at day +36 with VOD, aspergillosis and CMV pneumonia. The bilirubin was more than 2 times the normal value in 26/46; US-scan of the liver and Doppler, performed in 16 pts with a possible sign of VOD, was positive only in the patient who died for VOD. We documented 32 infectious complications (16 FUO, 9 gram positive bacteremias, 3 pneumonia and 4 invasive aspergillosis). We documented acute GVHD in 14 pts (12 grade I-II and 2 grade III). Five pts died between +36 and +100 but none for VOD (3 for progression of their disease and 2 for aspergillosis). Our laboratory data demonstrated modest alterations of the coagulative parameters, low consumption of coagulative factors and reduced fibrinolysis. Since in this at risk transplanted population only 1 VOD has been observed, DF low-dose continuous infusion, without heparin, seems able to play a relevant role in the VOD prophylaxis. On considering the favourable results by us and others, the absence of toxicity and the low cost of the drug, we intend to continue this experience with DF as VOD prophylaxis, even if we foretell a large randomized study to find better indications. Disclosures: No relevant conflicts of interest to declare.

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Turkina, Anna G., Olga Vinogradova, Alexandra Vorontsova, Ekaterina Chelysheva, Olga Lazareva, Galina Gusarova, Elena Aseeva et Nina Khoroshko. « Clinical Significance of Additional Chromosomal Abnormalities In Ph-Positive and Ph-Negative Cells In Patients with Chronic Myeloid Leukemia Treated by Tyrosine Kinase Inhibitors ». Blood 118, n^o 21 (18 novembre 2011) : 1683. http://dx.doi.org/10.1182/blood.v118.21.1683.1683.

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Abstract Abstract 1683 Introduction. Additional chromosomal abnormalities (ACA) in Ph'-positive (Ph'+) cells firstly described more than 30 years ago were associated with progression of chronic myeloid leukemia (CML) and often were founded in advanced stages of the disease. Prognostic significance of ACA in Ph'+ cells in the era of tyrosine kinase inhibitors (TKI) are not yet fully clarified. The ACA in Ph'-negative (Ph'-) cells seem to have no adverse prognostic impact, but it is not possible to exclude the development of myelodisplasia within the long lasting persistence of such clones. Long-term cytogenetic monitoring can better understand the biological aspects of CML. Aim. To estimate the clinical significance of ACA in Ph'+ and Ph'- cells in CML patients (pts) treated by TKI 1st and 2nd generation (TKI-1 or 2). Materials and methods. The complete peripheral blood count, morphological and cytogenetic examination of bone marrow (BM) cells have been done for 435 CML pts in different disease stages: chronic phase (CP)/accelerated phase (AP)/blast crisis (BC) pts were 336/78/21 respectively. The median (Me) age was 50 years (y) (16–61), Me follow-up- 97 months (mo) (5−265). Results and discussion. The ACA in Ph'+ cells were revealed by conventional cytogenetic study generally in 50 (11,5%) of 435 CML pts. ACA in Ph'+ cells were a rare event for CP and AP: 9% and 14% of pts respectively and more frequent for BC: 43% of pts. The most frequent ACA was the additional Ph'-chromosome (addPh'+) found in 50% of cases. 17pts had addPh'+ alone, while 13pts had also other ACA: trisomy 8 (8 cases), deletion or monosomy 7 (3 cases) and complex abnormalities (2 cases in CP & AP); dominated by male (M: F=23: 7). The duration of IM treatment in 16pts with addPh'+ was from 6mo to 5,5y. The follow-up duration of pts with addPh'+ was from 26 to 176 mo (Me 107 mo). All 16 pts have achieved complete hematological response (CHR) after 3 to 6mo of Imatinib (IM) treatment, but all pts with standard IM doses had primary cytogenetic resistance. Complete cytogenetic response (CCyR) was achieved in 56%pts without ACA, in 24% with ACA, and only in 7% with addPh'+. Due to IM resistance, 14 pts were switched to TKI-2 (Dasatinib – 10pts, Nilotinib – 3pts, Bosutinib – 1pt); 3 of these pts later progressed to AP; for 2 of them T315I mutation was found. All of the 11 pts still in CP have achieved CHR; partial cytogenetic response was founded in 45% and CCyR in 36% cases. At present, 43% pts with ACA died: 11% in CP, 82% in AP and all in BC. The 8-year overall survival (OS) for CML CP pts with ACA was 83%, no statistically significant (p>0,5) difference with the general CML CP pts group, treated by TKI. The assessment by multifactorial Cox model with variable risk factors revealed the increased probability of fatal outcome in CML CP more than 16 times higher in pts with ACA vs. patients without ACA. The variant chromosome abnormalities were rare: 13pts (3 %), but in 77% of them there was cytogenetic resistance pts and high risk of progression. ACA in Ph'- cells were founded in 13 (3%) pts only after the achievement of major cytogenetic response. 10 of them received IM 600–800mg daily; 3pts received 2nd generation of TKI. All those patients got the MCR only after 18–36 mo of treatment and 11 (85%) of 13pts achieved the CCyR. Ph'- clone was constantly founded only in 1 patient, in all other cases it was not constant but persisted from one analyses to other. No myelodisplastic changes were founded in the BM of 5 examined pts after IM treatment within 3–7y. All pts with ACA in Ph'- cells are alive. Conclusion. The durable persistence of Ph'+ cells in CML CP pts is a marker of therapy resistance but not all cases are associated with disease progression. The addPh'+ during IM treatment was associated with cytogenetic resistance. The dose escalation of IM was ineffective in the majority of cases, only TKI-2 therapy could restore Ph'- neg. hematopoiesis and suppressed addPh'+ clone more effectively. This finding should be tested in large-scale studies. The male predominance in pts with addPh'+ also needs further investigation. In contrast to other reported data, we founded that the prognosis for 77% of pts with the variant chromosome abnormalities was poor and associated with cytogenetic resistance and high risk of progression on TKI-1 and 2 therapy. In most pts with ACA in Ph'- cells a dose escalation of IM and switching to TKI-2 was needed but generally the disease prognosis was favorable. Disclosures: Turkina: Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Vinogradova:Novartis: Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Chelysheva:Novartis: CML registry, Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Lazareva:Novartis: CML registry, Research Funding, Speakers Bureau. Gusarova:Novartis: Honoraria, Speakers Bureau. Khoroshko:Novartis: Speakers Bureau; Bristol: Speakers Bureau.

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Clark, Otávio, et Enéas José de Matos Faleiros. « Cost of the treatment of myelodisplastic syndrome in Brazil ». Revista Brasileira de Hematologia e Hemoterapia 33, n^o 1 (2010) : 31–34. http://dx.doi.org/10.5581/v33n1a11.

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Clark, Otávio, et Enéas José de Matos Faleiros. « Cost of the treatment of myelodisplastic syndrome in Brazil ». Revista Brasileira de Hematologia e Hemoterapia 33, n^o 1 (2010) : 31–34. http://dx.doi.org/10.5581/1516-8484.20110011.

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Petrini, M., E. Capochiani, F. Caracciolo, S. Galimberti, L. Loni et B. Rosaia. « 178 Oral idarubicin administration as monochemotherapy in myelodisplastic syndromes ». Leukemia Research 21, n^o 1 (avril 1997) : S47. http://dx.doi.org/10.1016/s0145-2126(97)81387-2.

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Visani, Giuseppe, Pietro Maria Stefani, Saveria Capria, Lara Malerba, Piero Galieni, Francesco Gaudio, Giorgina Specchia et al. « Bendamustine, Etoposide, Cytarabine and Melphalan (BeEAM) Followed By Autologous Stem Cell Transplantation Produce a 3-Year Progression-Free Survival Of 75% In Heavily Pre-Treated Hodgkin and Non-Hodgkin Lymphoma ». Blood 122, n^o 21 (15 novembre 2013) : 2134. http://dx.doi.org/10.1182/blood.v122.21.2134.2134.

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Abstract Background We previously demonstrated (Visani et al, Blood 2011) the safety of a new conditioning regimen with bendamustine, etoposide, cytarabine, and melphalan (BeEAM) prior to autologous stem cell transplant (ASCT) in resistant/relapsed lymphoma patients (EUDRACTnumber2008-002736-15). Furthermore, this regimen showed significant anti-lymphoma activity (80% CR). At the time of publication (2011), disease type (NHL versus HL) and disease status at transplant (chemosensitive versus chemoresistant) were the only statistically significant variables influencing PFS (p=0.01; p=0.007). However, median follow-up for surviving patients was short (18 months), therefore, it was not possible to draw final conclusions on the efficacy. Aims We evaluated the efficacy of the BeEAM regimen in terms of disease-free (DFS) and overall survival (OS) after a median follow-up of 41 months. Methods Forty-three patients (median age 47 years, range 18-70) with resistant/relapsed NHL (28) or Hodgkin lymphoma (HL, 15) were consecutively enrolled in the study. Twenty-one patients had primary refractory disease, whereas 22 had relapsed disease, 5 of whom where in second or subsequent relapse, at the time of enrolment. The study was designed according to Fleming’s method. The primary objective of the study was to determine the 36-months event free survival rate. We fixed the lowest acceptable rate as 40% and the successful rate as 60%, with a significance level a=0.05 and a power 1-b =0.80. At the time of publication, the median follow-up was 18 months, and therefore it was not possible to establish if we had met the primary end-point of the study. Results we updated the follow-up at 41 months after transplant. Thirty-one out of 43 patients are still in CR (72%), as documented by both PET and CT scan. Two patients with HL were refractory and rapidly died, whereas 10/43 patients (23%) relapsed after a median time of 7.5 months (range:3-23) from transplant. Five patients died (3 NHL, 2 HL), whereas 5 patients are still alive after relapse. Median PFS and OS were still not reached. Conversely, 3-year PFS was 75%, allowing our study to met its primary end-point. Interestingly, disease type (HL versus NHL) at transplant is no longer influencing PFS (p=0.7), and still does not influence OS (p=0.1). On the other hand, disease status at transplant (chemosensitive vs chemoresistant) is still a strong predictor of both PFS and OS (p=0.03 and p=0.009, respectively). At present, one patient developed myelodisplasia after transplant. No other late effects were observed up to now. Conclusions The new BeEAM regimen met the primary end-point of the study and confirms its safety, after 41 months of follow-up. Interestingly, NHL and HL were not statistically different in terms of both PFS and OS at 41 months of observation. These data confirm the high efficacy of this regimen in heavily pretreated non-Hodgkin, as well as Hodgkin lymphoma. Acknowledgments supported in part by AIL Pesaro Onlus. Disclosures: Ocio: Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding.

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SAGESHIMA, Junichiro, Tooru MURAKAMI, Tomonori KAWASE, Yasuo ISHII, Taketoshi HAYASHI, Hiroshi HONDA, Yasuo OOKUBO et al. « AN OPERATING CASE OF LUNG CANCER WITH MYELODISPLASTIC SYNDROME (MDS) ». Journal of the Japanese Practical Surgeon Society 57, n^o 3 (1996) : 575–78. http://dx.doi.org/10.3919/ringe1963.57.575.

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Tendas, A., L. Cupelli, M. Giovannini, G. Catalano, L. Scaramucci, A. Perrotti, P. Niscola et P. De fabritiis. « P-166 Disability and disease burden in outpatient myelodisplastic syndromes ». Leukemia Research 37 (mai 2013) : S98. http://dx.doi.org/10.1016/s0145-2126(13)70214-5.

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Arana Trejo, Rosa Ma, Enrique Gómez, Susana Guerrero, Alicia Cervantes, Irma Cortes, Adrian Pérez, Elizabeth Sánchez, Javier Pizzuto et Susana Kofman Alfaro. « Chromosomal abnormalities in myelodisplastic syndromes (MDS) in the Mexican population ». Leukemia Research 18 (janvier 1994) : 45. http://dx.doi.org/10.1016/0145-2126(94)90227-5.

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Attolico, Imma, Giancarlo Discepoli, Roberta Nuccorini, Sara Pascale, Sabrina Coluzzi, Michele Pizzuti, Angela Amendola et Attilio Olivieri. « Late Onset of Secondary AML with 5q- in CLL with 13q- Abnormality ; Coexistence of the Two Neoplastic Clones and the Therapeutic Potential of Lenalidomide. » Blood 114, n^o 22 (20 novembre 2009) : 4394. http://dx.doi.org/10.1182/blood.v114.22.4394.4394.

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Abstract Abstract 4394 Therapy-related acute myeloid leukemia (AML) and myelodysplastic syndrome (t-AML/MDS) are common after alkylating agents. t-AML/MDS related to alkylating agents are associated with monosomies or deletions of the long arm of chromosomes 5 and 7. Among patients with chronic lymphocytic leukemia (CLL), the potential for disease transformation to diffuse aggressive non-Hodgkin's lymphoma (Richter's syndrome) or the evolution to prolymphocytic leukemia is well known. However, the development of therapy related myelodysplastic syndrome (t-MDS) or t-AML is uncommon. In most trials, an incidence rate of 1% has been reported. We describe here a patient who developed t-AML twentyone years after treatment with chlorambucil and fludarabine for CLL, carrying a typical CLL-associated Chromosomal abnormality (CA), associated with a typical AML-related CA. In 1988 a 42-year-old man was found to have B-cell CLL (Binet stage B). Examination of the marrow showed infiltration by small lymphoid cells that expressed CD5, CD19, CD23, and weak surface immunoglobulin with lambda light chain restriction. The residual hematopoiesis was otherwise normal in morphology. During subsequent years he received courses of therapy with chlorambucil and fludarabine which resulted in partial remission. In June 2009 he developed pancytopenia (WBC 11.4×10e9/L, PMN 0.1×10e9/L, Hgb 7.7g/dL, PLT 26×10e9/L). Physical examination showed small, diffuse lymphadenopaties and splenomegaly. Peripheral blood film examination and immunophenotype were consistent with diagnosis of CLL. Bone marrow examination showed trilineage myelodisplasia with 25% blasts and 62% lymphocytes that expressed CD5, CD19, CD23 and sIg lambda, confirming the diagnosis of concurrent AML with multilineage dysplasia and CLL. Cytogenetic analysis showed a hyperdiploid karyotype with a number of chromosomes comprised between 47 and 55. FISH analysis of bone marrow showed del 5q in 50% of nuclei and biallelic deletion of 13q14 in 70% of nuclei. FISH analysis on peripheral blood confirmed deletion 13q14 in 80% of nuclei, and del 5q in 10% of nuclei; trisomy of 18 in 50% of nuclei was also present. Although patients with CLL have an increased risk for the development of second malignancies, solid tumors are most common. With regard to second hematologic malignancies, the risk of multiple myeloma in patients with CLL is increased 10-fold over the incidence of myeloma in the general population. However, AML develops in 1% or fewer of patients with CLL, despite the frequent and long-term use of alkylating agents for therapy, the older age of many of these patients, and their relatively long survival with this disease process. In a retrospective review by Robertson et al of 1,374 CLL patients who received care at the M.D. Anderson Cancer Center from 1972 to 1992, only three cases of MDS or AML were found. Seventy-two percent of these patients had received prior alkylator therapy. Anecdotal cases of myelodysplasia or AML occurring in untreated patients with CLL have been reported, as have cases of concomitant diagnoses of CLL and AML, although these are quite uncommon. These cases of secondary leukemia were generally refractory to therapy, with a median survival after diagnosis of approximately 1 month. Lenalidomide (Revlimid) is an immunomodulatory drug that yields a high frequency of erythroid, pathologic, and cytogenetic response in patients with myelodysplastic syndromes (MDS) with an interstitial deletion of the long arm of chromosome 5 (del 5q). Responses of AML with del 5q are also reported. Whether both the diseases will respond to this drug it is matter to prospectively investigate in these cases. Disclosures: No relevant conflicts of interest to declare.

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Benevolo, Giulia, Ludovica Riera, Barbara Nicolino, Andrea Evangelista, Eloise Beggiato, Chiara Aguzzi, Maura Nicolosi, Chiara Frairia et Umberto Vitolo. « Prognostic Value of JAK2V617F, Calr and MPL Mutational Status on Outcome and Thrombotic Risk in a Retrospective Cohort of 138 Patients with Essential Thrombocythemia ». Blood 124, n^o 21 (6 décembre 2014) : 5553. http://dx.doi.org/10.1182/blood.v124.21.5553.5553.

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Abstract Background: Life expectancy in Essential Thrombocythemia (ET) patients is superimposed to normal population. The main causes of death are thrombotic events and evolution into myelofibrotic phase or secondary myelodisplasia/acute leukemia. Approximately 50% to 65% of patients with ET carry activating mutations in the Janus kinase 2 gene (JAK2), and an additional 5% in the thrombopoietin receptor gene (MPL) whereas 10 to 20% of patients have mutated calreticulin gene (CALR). Non-mutated JAK2, CALR and MPL ET (triple negative-TN) are about 10%. Patients and methods : In this study we analysed the prognostic value of JAK2V617F, CALR and MPL mutational status on outcome and thrombotic risk in a retrospective cohort of 138 ET patients defined according to WHO criteria, diagnosed from 1974 to 2013 in a single Italian centre (Turin). JAK2V617F mutation was assessed by Quantitative Real–Time PCR on DNA from peripheral blood or bone marrow samples. JAK2 negative cases were then analyzed for CALR mutations by Gene Scan Analysis in combination with direct sequencing or MPL W515L/K by Allelic Discrimination Real-Time PCR assay. Overall survival (OS), cumulative incidence of myelofibrotic transformations (CI-MT) and thrombosis (CI-TB) were calculated from the date of diagnosis. The between-group comparison for OS was performed with the log-rank test, whereas for CI-MT and CI-TB we using the Gray’s test considering death as competing event and adjusting for presence of cardiovascular risk factors . Results: Among 138 ET patients, 103 (74.6%) carried the JAK2V617F mutation, 3 (2.2%) carried activating mutations of MPL exon 10, 16 (11.6%) carried mutations of CALR exon 9, and only 16 patients (11.6%) had none of these markers (TN). An high incidence of elevated haemoglobin levels and/or haematocrit (males >16.5 g/dl or 49% and females >16.0 g/dl or 48%) was significantly associated with JAK2 positivity [13 pts JAK2+ (14.77%) vs 0 pts JAK2- (Fisher test p=0.019)]. Similarly, the CI-TB, analysed with a competing-risk approach, was higher in patients with a JAK2 mutation [(5-year CI-TB: 23.7% JAK2, 0% CALR, 0% MPL, 12.5% TN; P<0.001)]. With a median follow-up of 48 months (IQR: 27-78; range 1-269), we observed 4 (3%) deaths, 9 (7%) myelofibrotic transformations and none leukemic evolution. The overall survival at 5 years was 98.4% (95%CI: 89.1-99.8) and the cumulative incidence of myelofibrotic transformations was 2.1% (95%IC: 1.0-8.6). The CI-MT was significantly higher in MPL-positive patients [5-year CI-MT: 0% JAK2, 0% CALR, 33.3% MPL, 8.3% TN; (P=0.006)]. Not significant difference on OS was found [5-year OS: 100% JAK2, 100% CALR, 100% MPL, 85.7% TN; (P=0.66)]. We did not include leukemia transformation, because of lack of event. Conclusion: In our retrospective cohort of ET patients, we found a significant correlation between JAK2 positivity and high risk of thrombosis. We also found a significant incidence of elevated haemoglobin levels and/or haematocrit in JAK2-positive patients. These data support the correlation between JAK2 positivity and cumulative risk of transformation to Polycythemia Vera. The correlation between MPL mutational status and evolution to myelofibrosis found in our study needs to be confirmed in a larger series of patients. Disclosures No relevant conflicts of interest to declare.

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Pirrotta, Maria Teresa, Monica Bocchia, Alessandro Bucalossi, Marzia Defina, Francesco Forconi, Simona Sammassimo et Francesco Lauria. « Phase II Pilot Study of Gemtuzumab Ozogamicin (GO), Fludarabine, Cytarabine and Idarubicin Combined Regimen as Induction Therapy Plus GO Alone as Consolidation Therapy for Elderly Acute Myeloid Leukemia Patients. » Blood 106, n^o 11 (16 novembre 2005) : 4613. http://dx.doi.org/10.1182/blood.v106.11.4613.4613.

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Abstract The prognosis of acute myeloid leukemia (AML) in older adults is generally poor. Standard cytotoxic chemotherapy is scarcely tolerated and usually followed by low complete remission (CR) rate and short remission duration. Gemtuzumab ozogamicin (GO), is an anti-CD33 antibody conjugated to calicheamicin, that has shown activity as single agent in relapsed AML with a favorable safety profile. Few data have so far reported on GO associated with conventional chemotherapy in the elderly and less is known on the role of this antibody-targeted therapy as single consolidation treatment in this patients population. We here report a pilot experience on the feasibility and outcome of an age-adjusted combination regimen with GO, fludarabine (FLUDA), arabinisyl-cytosine (AC) and idarubicine (IDA) (GO-FLAI regimen) followed by two courses of GO alone as consolidation treatment in a group of elderly AML patients. We treated with GO-FLAI regimen 12 patients: 5 with primary leukemia, 5 with a prior history of myelodisplasia and 2 with relapsed disease. They received FLUDA 25 mg/m2, AC 1 g/m2 and IDA 5 mg/m2 for 3 days; on the fourth day GO was administered at 3 mg/m2. Two cycles were planned. After induction therapy, patients achieving a response received two courses with GO at 3 or 6 mg/m2. The median age was 71.5 years (range 65–80), the male/female rate was 6/6. Eigth patients had normal kariotype, 4 had one ore more cytogenetic abnormalities. After induction regimen 9/12 patients reached a CR (75%), 1/12 (8%) patient obtained a partial remission (PR), and 2/12 (16%) patients were resistant to the treatment. The most common adverse events at this stage of treatment were fever and chills during the administration of GO, infections secondary to neutropenia (66%) and transient grade I/II gastrointestinal toxicity. No hepatic veno-occlusive disease nor grade III/IV bleeding were recordered. The median time to recovery from severe neutropenia (ANC < 0.5 x 109/L) was 16 days and from severe thrombocytopenia (platelets < 20 x 109/L) was 14 days. No patient died of GO-FLAI related mortality. As consolidation treatment, all responders patients (9 CR plus 1 PR) underwent two additional GO administration at 3mg/m2 (6/10 patients) or 6mg/m2 (4/10 patients). All 10 patients maintained their response after the two courses of GO for a median of 5.5 months (range 1-15) with 4/10 patients relapsing after 5, 7, 7 and 9 months respectively. Median overall survival was 10 months (range 1-23) from diagnosis. All GO administrations were performed in an out-patient setting, treatment was generally well tolerated and myelosuppression was moderate both at the 3 and 6 mg/m2 dose schedule. Nevertheless it has to be noted, that two patients (1 CR, 1 PR) died because of a CNS hemorrhage despite a number of platelets ≥ 20 x 109/L (one patient after receiving 1 course of GO at 3mg/m2 and one patient after receiving 2 courses at 6 mg/m2, respectively).We conclude that GO-FLAI regimen followed by two GO administrations is a feasible, fairly effective and well tolerated treatment for AML elderly patients. In particular the CR rate appears consistent with previous studies employing conventional chemotherapy only. Further studies are required to assert, after a longer follow-up, if this induction and consolidation target-based regimen can improve DFS, which is the major problem of elderly AML patients.

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Bilori, Bilori, Hideki Makishima, Bartlomiej P. Przychodzen, Mohamed Ashkar, Rohan Garje, Swapna Thota, Brittney Dienes et al. « Clinical and Molecular Features Of Young Patients With Myelodisplastic Syndromes (MDS) ». Blood 122, n^o 21 (15 novembre 2013) : 1566. http://dx.doi.org/10.1182/blood.v122.21.1566.1566.

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Abstract MDS typically affects older adults, and hereditary factors have been considered less contributory to disease pathogenesis. Moreover, their impact is obscured by the complexity of the clinical presentation and history. Similarly, familial MDS and pediatric MDS is rare and likely distinct from adult MDS occurring in younger adults. Younger MDS patients (pts), excluding those who present with treatment-related disease, may represent a distinct subtype of MDS characterized by a specific molecular pattern of lesions. We compared two groups of MDS pts focusing on pathological diagnosis at presentation, family history of solid malignancies and blood disorders (Leukemia and MDS) in first and second degree relatives, cytogenetic abnormalities and somatic mutations. Our analysis of 1030 MDS pts included MDS, MDS/myeloproliferative neoplasm (MPN) and secondary acute myeloid leukemia (sAML) pts. Overall the median age at presentation of this population was 71years (range 14-100); we classified the younger subset as those falling into the lower 8thpercentile of age to identify. Accordingly, the younger population was characterized by age less than 50 years (range 14-49; median age 41), and the older population age ≥ 50years (range 50-100; median age 75). Treatment-related MDS was excluded. Younger MDS pts more frequently presented with higher-risk disease compared to the older population (46% vs. 31%; P=.004). There was no significant difference between the two groups with regard to family history of cancers (40 vs. 47%; P=.21) and blood disorders (10 vs. 6%; P= .1). When we compared cytogenetic abnormalities between these patient subsets, there was no difference in detection of rate of abnormal cytogenetics (53% vs. 52%; P=.5) or complex karyotype (23 vs. 25%; P=.86). However, del 20q was more common in the older subset (19 vs. 6%; P=.03). We then investigated somatic mutational patterns using new generation deep sequencing for the 60 most commonly encountered MDS mutations (defined in the 200 MDS exome cohort presented in other abstract from our group). Data were available for 26 younger pts and 179 older pts. By analyzing comprehensive mutational spectrum, the average number of somatic mutational events (mean; 2.4/case) was significantly higher in the older subgroup compared to the younger (1.8/case; P<.001). RUNX1, PHF6, TP53 (12% each) are the most frequently affected genes in MDS associated with the younger population. Interestingly, germline mutations of these 3 genes are all associated with congenital syndromes, which lead to susceptibility for hematological neoplasms. Conversely, somatic mutations of TET2 (24%) and ASXL1 (15%) were most prevalent in the older MDS cohort. Notably, these 2 genes associated with older populations were less prevalent in younger MDS cases (<4%; P=.02 and < 4% P=.11 for TET2 and ASLX1 respectively). In contrast, there was no significant difference between these subgroups (old vs. young MDS) in the frequency of RUNX1 (9 vs. 12%; P=.67), U2AF1 (11 vs. 12%; P=.88), BCOR family (9 vs. 15%; P=.35), PRC2 family (10 vs. 4%; P= .34), RAS family (11 vs. 12%; P=.88), or many other gene mutations. In sum, 8% of MDS pts present at a younger age in our cohort. MDS in younger pts presents with more advanced disease and is less commonly affected by del20q- and TET2 mutations, consistent with less common myeloproliferative features in this population. Disclosures: Makishima: AA & MDS international foundation: Research Funding; Scott Hamilton CARES grant: Research Funding.

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Rus, G. Pérez, J. del Toro, E. Prieto, J. Sánchez Fayos et P. L. Cuesta. « 57 Myelodisplastic syndromes prognostic factors in 133 patients with cytogenetic study ». Leukemia Research 21, n^o 1 (avril 1997) : S15. http://dx.doi.org/10.1016/s0145-2126(97)81266-0.

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Elez, Marija, Lavinika Atanaskovic, Svetlana Mirosavljevic, Gordana Ostojic, Biljana Todoric-Zivanovic et Dragana Stamatovic. « Matched unrelated donor hematopoietic stem cell transplantation - our results ». Medical review 70, suppl. 1 (2017) : 63–65. http://dx.doi.org/10.2298/mpns17s1063e.

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Introduction. Allogeneic stem-cell transplantation is only potentially curative therapy for variety of hematology malignancies, such as acute and chronic leukemia, myelodisplastic syndrome and aplastic anemia, but also promising treatment option for other disorders. If we know that only 25% of patients have an human leukocyte antigen identical sibling donor, it is obvious that matched unrelated donor hematopoietic stem cell transplantation is an alternative for the rest of the patients. Material and Methods. Since 2013, matched unrelated donor hematopoietic stem cell transplantation has been performed routinely in the Military Medical Academy. Results. We hereby present the outcome after 77 procedures in 75 patients. Considering primary diseases, 35 patients had acute myeloid leukemia, 25 patients had acute lymphoid leukemia, 5 patients had chronic myeloid leukemia, 9 patients had myelodisplastic syndrome and we performed the transplant on 1 patient with chronic lymphocyte leukemia, 1 patient with aplastic anemia and 1 patient with T lymphoblastic lymphoma. Conclusion. It is difficult to make clear conclusions based on this heterogeneous group of patients, but it seems that these results are encouraging. Future research will be performed to evaluate matched unrelated donor and identical sibling hematopoietic stem cell transplantation in the homogenous groups with respect to primary diseases.

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Scaldaferri, M., E. Sciorsci, F. Re, C. Calvo, M. Chiumente, D. Barilà, A. Chiesa, M. Ferroni, S. Stecca et F. Cattel. « CPC-079 Management of Myelodisplastic Syndromes and Lymphomas : The Example of Lenalidomide ». European Journal of Hospital Pharmacy 20, Suppl 1 (mars 2013) : A193.2—A193. http://dx.doi.org/10.1136/ejhpharm-2013-000276.536.

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Belli, Carolina B., Mabel Lardo, Guillermo Arrossagaray, Juan Francisco Sakamoto, María Gabriela Flores, Pedro Negri Aranguren, Raquel Maria Bengio, Irene Larripa et Pedro Raul Perez Bianco. « Evaluation of Prognostic Variables and Scoring Systems in Normal Karyotyped Myelodisplastic Patients ». Blood 112, n^o 11 (16 novembre 2008) : 5101. http://dx.doi.org/10.1182/blood.v112.11.5101.5101.

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Abstract Myelodysplastic Syndrome (MDS) comprises a group of heterogeneous hematological disorders with variable risk of leukemic evolution (LE) and short survival (SV). According to French-American-British (FAB) classification, MDS are divided into five morphological entities and the World Health Organization reclassified them eliminating Refractory Anemia (RA) with Excess of Blast in transformation (RAEBt) and Chronic Myelomonocytic Leukemia (CMML), among other changes. Around 40–60% of patients shows normal karyotype at diagnosis and, despite this finding which is associated with good prognosis, some of them show poor outcome. The aim of this study was to evaluate different variables and prognostics scoring systems in an overall population (OP) of normal karyotyped MDS patients and in the reduced population (RP) after eliminating RAEBt and CMML subgroups. This retrospective study was performed in a population of 152 MDS patients with normal karyotype at diagnosis distributed according to FAB into 59% RA/RA with ringed sideroblast, 23% RA with excess of blasts, 5% RAEBt and 13% CMML. The OP’s median age was 67 (20–89) years with a sex ratio (M/F) of 1.53. The median follow-up was 25.7 (1–266) months (m) and there were 31 (20%) events of LE and 65 (43%) related-MDS death during this period. The OP showed a median SV of 57 m and time to LE (25%) of 44 m vs. 63 and 124 m, respectively for the RP. Age, sex, percentage of bone marrow (BM) blast, hemoglobin (Hb) level, platelets count and number of cytopenias were significant predictive variables for prognosis in both populations (Kaplan-Meier and Long-Rank test, p<0.05). Despite all applied scoring systems allowed to difference groups of risk, patient distribution among them showed variations which were more evident in the Intermediate ones. Multivariate analysis (Cox proportional Hazard Model, p<0.05) established that age, Hb level and % BM blast were the most important predictors for SV. Therefore, a new scoring system was developed coding % BM blast 0 if <5, 0.5 if 5–9, 1 if 10–19 and 1.5 if ≥20, age 0 if ≤60 and 0.5 if >60 years, Hb level 0 if ≥10 and 0.5 if <10g/dL. Three groups of risk were defined: Low (0+0.5), Intermediate (1+1.5) and High (>1.5) with median SV of 131, 32 and 13 m for the OP vs. 131, 43 y 18 m for the RP, respectively. Additionally, confirmed that IPSS includes better variables for LE, determining 3 groups of risk: Low, Intermediate and High (Intermediate-2 + High) with time to LE (25%) of >130, 22 and 4 m for the OP vs. >130, 39 y 21 m for the RP, respectively. Results showed that SV and LE risk should be evaluated separately in patients with normal karyotype using different variables to predict each one, at least in MDS-FAB classified patients or in those that present less than 20% of BM blasts and monocite counts lower than 1000/μL. These results would be helpful to develop better risk-adapted therapeutic strategies for MDS patients with normal karyotype.

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San Miguel, J. F., M. Gonzalez, M. C. Ca�izo, J. P. Anta, J. Hernandez, F. Ortega et Lopez Borrasca. « The nature of blast cells in myelodisplastic syndromes evolving to acute leukaemia ». Blut 52, n^o 6 (juin 1986) : 357–63. http://dx.doi.org/10.1007/bf00320782.

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Chiappella, Annalisa, Alessia Castellino, Maria Giuseppina Cabras, Anna Marina Liberati, Andrea Evangelista, Chiara Bottelli, Flavia Salvi et al. « Prolonged Survival with Low Incidence of CNS Relapse and Late Toxicities in a Retrospective Series of 278 Young Patients with High-Risk (aa-IPI 2–3) Diffuse Large B-Cell Lymphoma Treated with Intensified Chemotherapy with or without Rituximab At Diagnosis ». Blood 118, n^o 21 (18 novembre 2011) : 1606. http://dx.doi.org/10.1182/blood.v118.21.1606.1606.

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Abstract Abstract 1606 Introduction. Diffuse Large B-cell Lymphoma (DLBCL) patients at high-risk (age-adjusted International Prognostic Index (aa-IPI) 2–3), had a dismal prognosis if treated with conventional chemotherapy. The introduction of intensive regimens and the addition of monoclonal antibody anti-CD20, improved prognosis, but some issues remain unresolved such as: the risk of central nervous system (CNS) relapses and the incidence of late toxicities. We analyzed a series of young DLBCL patients at high-risk consecutively treated in four prospective trials by the Italian Lymphoma Foundation (FIL) with the aim to assess the risk of CNS relapses and late toxicities in this series of patients with a prolonged follow-up Methods. From 1986 to 2006, 278 patients with DLBCL with aa-IPI 2–3 at diagnosis, were enrolled in four consecutive trials previously reported. Thirty-two into a phase II study, treated with 12 weekly infusion of MACOP-B; 39 into a phase II trial with eight weekly MACOP-B infusions followed by high-dose cytarabine, mitoxantrone and dexamethasone (MAD) plus standard BEAM and autologous stem cell transplantation (ASCT); 95 in a phase III trial that randomized high-dose sequential (HDS) chemotherapy plus ASCT (45 patients) vs six courses of dose-dense intensified CHOP (iCHOP) (50 patients); 112 into a phase II trial with four courses of iCHOP in combination with Rituximab followed by Rituximab-MAD + BEAM and ASCT. CNS prophylaxis was not mandatory in the four protocols. Updated data regarding of survival, CNS relapses and late toxicities were recorded on June 2011. Results. Clinical characteristics were: aa-IPI 2 in 55%, aa-IPI 3 in 45%, PS > 2 in 66%, LDH upper normal value in 89%, number of extranodal sites > 2 in 35%, bone marrow involvement in 27% of patients, with no statistical differences between the four trials. With a median follow-up of five years, 5-year Overall Survival (OS) was 63% (95% CI: 57–69%) in the whole series; 5-year OS by treatment was 41% (95%CI: 24–74%) in MACOPB, 54% (95%CI: 37–68%) in MACOPB+MAD+BEAM and ASCT; 53% (95%CI: 38–67%) in HDS+ASCT; 58% (95%CI: 43–70%) in iCHOP; 79% (95%CI: 70–86%) in R-iCHOP+R-MAD+BEAM and ASCT. In a multivariate analysis, the risk of death was significantly reduced in R-iCHOP+R-MAD+BEAM and ASCT (p<.001) and was adversely influenced by age with a progressive increase of five years at diagnosis (p.008) or aa-IPI3 (p.001). Four patients experienced CNS relapses, three of them in R-iCHOP+R-MAD+BEAM and ASCT and one in MACOPB. Only one of the four patients received CNS prophylaxis with intrathecal Methotrexate, even if all of them were at risk for CNS relapse according to Italian Society of Hematology guidelines (Barosi, Hematol 2006). Cumulative incidence of CNS recurrence at 10 years for R-iCHOP+R-MAD+BEAM and ASCT regimen was 3.6% (0 to 7.8). Most frequent late toxicities were dyslipidemia and secondary amenorrhea. Regarding to secondary malignancies, myelodisplasia or acute myeloid leukemia were recorded in three patients, two of them treated with R-iCHOP+R-MAD+BEAM and ASCT, at a median time of seven years off therapy. The actuarial risk of secondary malignancies at 10 years for R-iCHOP+R-MAD+BEAM and ASCT was 4.2% (0 to 10). Conclusions. The addition of Rituximab to dose-dense iCHOP plus high-dose chemotherapy plus BEAM and ASCT improved the outcome in young untreated DLBCL patients at poor prognosis, with an acceptable risk of secondary malignancies and late toxicities. A careful identification of patients at risk could avoid the risk of CNS relapse. Disclosures: Vitolo: Roche Italy: Speakers Bureau; Celgene: Speakers Bureau; Jannsen-Cilag: Speakers Bureau.

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Bolaman, Ali Zahit, Hacer Kale et İrfan Yavaşoğlu. « Düşük Risk Myelodisplastik Sendromda Darbepoetin ve Koloni Uyarıcı Faktör Tedavisinin Anemi Üzerine Etkisi ». LLM Dergi 4, n^o 3 (15 octobre 2020) : 39–44. http://dx.doi.org/10.5578/llm.69997.

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Corinaldesi, Giorgio, et Christian Corinaldesi. « Myelodisplastic Syndrome : Is It Associated or Is It a Precursor of Myeloid Malignancies?. » Blood 110, n^o 11 (16 novembre 2007) : 4592. http://dx.doi.org/10.1182/blood.v110.11.4592.4592.

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Abstract Myelodisplastic syndrome (MDS) is a clonal haematopoietic stem cells disorder considered a pre-leukemic disease (about 30% of MDS turn into acute myeloid leukaemia (AML)) which is frequently associated with cytogenetic abnormalities and chromosomal instability: monosomy 7 or 7q - syndrome, 5q- syndrome, trisomy 8, inv(16), t (8;21), t (15;17), t (12;21), t (9;11), or sub microscopic DNA mutation of gene such as RAS, p53, FLT3, HSPA9, FMS and refractory cytopenias, with dysmyelopoiesis and increased apoptosis. We have identified 15 people aged between 54/67 years with MDS and we have examined their clinical presentation and their associated disorders. RA: refractory anaemia (7 patients) RARS: refractory anaemia with ringed sideroblasts (1 patient) 5q-syndrome (1 patient) RAEB refractory anaemia with excess blast: type 1 (5–10%) (3 patients); type 2 (11–20%) (1 patient) E) RAEB-T refractory anaemia in transformation (1 patient) F) CMML chronic myelomonocytic leukemia (1 patient) The disease is characterized by chronic tiredness, headache, shortness of breath, increased susceptibility to infection especially in the lung with a prolonged fever, easy bruising, nosebleeds, pinpoint red spots, bleeding, splenomegaly, hepatomegaly, abdominal distress and pain are also common. VEGFR-1 and VEGFR-2 are strongly expressed in megakaryocytes, HLA-DR2 and HLA-DR15 are higher, immune dysfunction in MDS increases activated cytotoxic T-cells with higher percentage of CD8+CD28-, CD8+CD28- CD57+ with an increased level of CD4, and Fas ligand/Apo-1 (CD95). The RA, RARS, 5q-syndrome are more indolent disease with a lower rate of progression to AML and a prolonged clinical course; the RAEB, RAEB-T are slightly more advanced with a short course; in the CMML the progression is faster and it is frequently associated with the secondary chromosomal perturbation t(5;12), (q33;p13), or with the loss of specific portion 3p-, 7q- (7q22-7q33-). The goals of the therapy are to control symptoms and to decrease the progression to myelogenous leukaemia; our results show that a low intensity treatment in the low and intermediate groups with 5-azacitidine 75 mg/m2/day produces a high rate of response (72%, of which: complete remission: 18%, partial remission: 34%, improved: 20%), relapse 24%, disease-free survival at 3 years of 64%; with a low incidence of side effects (nausea 68%, vomiting 60%, chest pain 28%); on the other hand in the high risk group the 5-azacitidine with gentuzumab reverted to normal about 90% of the patients (complete remission: 6%, partial remission: 28%, improved: 56%), disease free survival at 3 years 52%, relapse 48%; however, the only curative treatment is stem cells transplantation from a tissue matching donor. Finally, it is very important to provide a supportive care with erythropoietin, G-CSF or GM-CSF, red cells transfusions, administration of broad-spectrum antibodies mostly for controlling symptoms, but also for preventing or treating complications.

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Caliendo, Irene, Rosanna Di Concilio, Paolo Danise, Anna Guerriero, Anna Maria Aurino, Maria Amendolara, Giovanna d'Urzo, Luigia Luciano, Marcello Ingenito et Giovanni Amendola. « Myelodisplastic Syndrome with Trysomy 21 IN A Patient with Constitutional Submicroscopic 21Q22 Deletion. » Blood 114, n^o 22 (20 novembre 2009) : 4831. http://dx.doi.org/10.1182/blood.v114.22.4831.4831.

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Abstract Abstract 4831 Introduction Previous studies showed that chromosomal and genomic aberrations leading to activation of oncogenes or haploisufficiency of tumor suppressor genes are well-known pathogenic mechanisms in cancer. Additional copies of chromosme 21 are frequently found in Myelodisplastic Syndrome (MDS) and in Acute Myeloid Leukemia (AML); the presence of these chromosomal abnormalities and the high incidence of acute leukemias in subjects with constitutional trisomy 21, suggest that genes on chromosome 21, including RUNX1/AML1, play a particular role in leukemogenesis and hematopoiesis. We describe a patient with syndromic trombocytopenia ( average platelet count= 70000/mm3), psychomothor delay, microcephaly and low stature, that developed a progressive anemia and became transfusion-dependent at seventeen years of age. Materials and methods Cytogenetic analysis was performed on bone marrow cells and on peripheral blood lymphocytes, with standard techniques and evaluated with Giemsa-trypsin-Giemsa banding according to International System for Human Cytogenetic Nomenclature (ISCN 2005). Fluorescent In Situ Hybridization (FISH) experiments was performed on bone marrow samples with LSI AML1/ETO Dual Color, Dual Fusion Translocation and, at the same time, the High-resolution oligo array-CGH (Agilent Human Genome CGH Microarray 44B) was performed on the DNA of the patient. Results The bone marrow cells showed marked dysplastic morphology and the following abnormal karyotype: 46,XX[14]/47,XX,+21[6]; the peripheral blood karyotype was normal. The High-resolution oligo array-CGH demonstrated a constitutional de novo microdeletion of one chromosome 21. The interstitial deletion was found to be approximately 4,4Mb (Megabases), extending from 32,29 Mb to 36,51 Mb on band 21q22.11-12, involving MRAP, IFNAR2, IFNGRR2, KCNE2, KCNE1 and RUNX1 genes. The FISH performed on bone marrow cells, revealed two orange signals representing normal copies of ETO and one green signal for AML1 in 60% interphase cells and two orange signals and two green signals in the remaining 40% cells. The first pattern of signals, for AML1, is related to cells with karyotype 46,XX, while the second pattern of signals is related to cells with karyotype 47,XX,+21. These results indicate that in the myelodisplastic clone the third chromosome 21 are not deleted on band 21q22. Conclusion Three cases were recently published of syndromic thrombocytopenia with 21q22 constitutional deletion, including RUNX1, and variable degree of dysmorphic features and mental delay. One of the three patients developed LMA at the age of six years. Our results further support the fundamental role, in the pathogenetic mechanism of syndromic trombocytopenia and MDS/AML, of the numerical abnormalities of chromosome 21 associated with submicroscopic rearrangement of RUNX1 and other dosage-sensitive unknown genes on chromosome 21. Disclosures No relevant conflicts of interest to declare.

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Costa, Larissa da, Ana Paula de Azambuja, Erica Sabrine Ângelo Lisboa, Silvia Natalia Bueno, Elenaide Nunes Coutinho, Bruno Francisco Buzinetti Spinelli, Larissa Alessandra Medeiros, Vaneuza de Araujo Moreira Funke et Mariester Malvezzi. « Evolution of myelodisplasic syndrome with ring sideroblasts (MDS-RS) to systemic mastocytosis and aleukemic mast cell leukemia ». Hematology, Transfusion and Cell Therapy 42, n^o 4 (octobre 2020) : 387–89. http://dx.doi.org/10.1016/j.htct.2019.08.003.

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Beneforti, Linda, Erica Dander, Silvia Bresolin, Clara Bueno, Geertruy te Kronnie, Anthony Ford, Pablo Menendez et al. « Bone Marrow Mesenchymal Stromal Cells and Inflammation Contribute to ETV6-RUNX1+ Preleukemic Cells Persistence and DNA Damaging ». Blood 132, Supplement 1 (29 novembre 2018) : 3918. http://dx.doi.org/10.1182/blood-2018-99-114791.

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Abstract INTRODUCTION ETV6-RUNX1 (ER), generated from translocation t(12;21), is the most frequent fusion gene in pediatric cancers, exclusively leading to B-Cell Precursor Acute Lymphoblastic Leukemia. Translocation occurs in fetal hematopoietic stem-progenitor cells (HSPC) but it is insufficient for disease. ER, in fact, is an aberrant transcription factor that expands a silent preleukemic clone with enhanced self-renewal and partial B cell differentiation. Secondary hits are thus required to complete transformation. Epidemiological and experimental data indicate that infections/inflammation play an important role in the preleukemia to leukemia transition. We previously demonstrate that TGFβ1, a pleiotropic cytokine produced after inflammation, favored the persistence of ER+Ba/F3 cells and selected putative preleukemic stem cells in ER+umbilical cord blood (UCB) CD34+cells. We also demonstrated that ER+Ba/F3 showed altered expression of adhesion molecules and impaired migration towards CXCL12. Migration, physical interactions and response to soluble factors determine HSPC fate in the Bone Marrow (BM) niche. BM Mesenchymal Stromal Cells (MSC) are non-redundant regulators of HSPC in the niche; in addition, they possess pro- and anti-inflammatory properties, representing a bridge between hemopoiesis and inflammation. Finally, dysfunctions in MSC can induce myelodisplasia and secondary myeloid leukemia, while MSC inflammation cause genotoxicity in HSPC predicting myeloid leukemia evolution in predisposing syndromes. On that basis, we questioned if interaction between ER+cells, MSC and inflammation could favor preleukemic clone persistence and progression. METHODS The murine proB cell line Ba/F3 was transfected to generate an inducible ER-V5tag expressing model (Ford A, Palmi C, 2009). BM-MSC were characterized and cultured for controlled passages. UCB-CD34+cells were immunomagnetically isolated and lentivirally transduced with pRRL-eGVP or pRRL-ER-eGFP constructs. Cells were treated with IL6/IL1β/TNFα inflammatory cytokines. RESULTS Gene Expression Profile shows that ER affects pathways involved in inflammatory response, cell cycle, apoptosis and migration in Ba/F3. In particular, ER+ cells overexpress CXCR2, a chemokine receptor also implicated in cancer, (MFI: ER=1378±807 vs ctr=284±167, p<0.05) and highly migrate toward its ligand CXCL1 (% migrated cell/input: ER=21.5±6.7 vs ctr=2.2±1.8, p<0.01). Interestingly, MSC increases CXCL1 secretion after inflammatory stimulation (murine MSC, pg/mL: basal=78±28 vs +infl.ck=30162±4760, p<0.01). In accordance, ER+ Ba/F3 are highly attracted by inflamed MSC supernatants (% migrated cell/input: ER=30.2±9.1 vs ctr=14.3±9.6, p<0.01) in a CXCR2-dependent manner. Coculturing control and ER+ Ba/F3 with MSC and inflammatory cytokines favored the persistence of preleukemic cells in the coculture (% ER+ fold increase: +MSC vs +MSC+infl.ck = 2.62±0.94, p<0.01). The effect is mediated by soluble factors and results from decreased survival in control (% ann-V negative cells: +MSC=68.4±5.7 vs +MSC+infl.ck=48.2±1.3, p<0.05) but not ER+ Ba/F3; cell proliferation was reduced in both, but the effect was stronger on control Ba/F3 (CSFE MFI fold increase +MSC vs +MSC+infl.ck: ER=2.2±0.6, p<0.001; ctr=4.4±1.8, p<0.05). However, CXCL1 is not implicated. Phosphorilation of histone H2AX and AID mRNA levels, which are basally higher in ER+ Ba/F3, further increase in both normal and ER+ Ba/F3 cocultured with MSC and inflammatory cytokines, confirming the genotoxicity of MSC inflammation (γH2AX MFI fold increase +MSC vs +MSC+infl.ck: ER=2.5±1, p<0.05; ctr=2.8±1.2, p<0.01) (AID mRNA fold increase basal vs +MSC+infl.ck: ER=6.3±1.6, p<0.05; ctr=14.6±11). Finally, preliminary data show a higher migration towards inflamed MSC also in ER+ UCB-CD34+cells (% migrated cell/input: ER=21.2±2.4 vs ctr=5.2±0.6, p<0.01). CONCLUSIONS ER expression increases migration towards inflamed BM-MSC supernatants in murine proB cells. Interestingly, MSC and inflammation create favoring microenvironmental conditions for preleukemic cells persistence and DNA damage accumulation. Preliminary results show that inflamed MSC highly attract human ER-expressing UCB-CD34+as well. Collectively, our data support the importance of ER-driven alterations in hematopoietic/BM stromal cells interactions in the leukemogenic process. Disclosures No relevant conflicts of interest to declare.

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Bergua Burgues, Juan Miguel M., Isabel Cano-Ferri, David Martínez-Cuadron, Blanca Boluda, Pilar Martínez-Sánchez, Rebeca Rodríguez-Veiga, Jordi Esteve et al. « Outcomes after Plerixafor Plus FLAG-IDA (PLERIFLAG) Versus FLAG-IDA +/- Gentuzumab for Adult Patients with First Relapsed/Refractory AML : A Propensity Score Analysis from the Pethema Registry ». Blood 134, Supplement_1 (13 novembre 2019) : 1321. http://dx.doi.org/10.1182/blood-2019-128568.

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BACKGROUND AND OBJECTIVES: Chemosensitization using plerixafor combined with FLAG-IDA (PLERIFLAG regimen) showed promising results (48% CR/CRi) in a phase 2 trial for primary refractory and early relapsed (duration of first CR <12 months) Adult AML patients. We aim to compare retrospectively results of the PLERIFLAG cohort versus historical cohorts of patients salvaged with FLAG-IDA (Fludarabine, Idarubicine, Cytarabine, G-CSF as priming agent), or FLAGO-IDA (Gemtuzumab plus FLAG-IDA) registered in the PETHEMA epidemiologic AML registry (NCT02006004). To match different cohorts, we used two risk-score classifications: EPI/HOVON (De Breems, JCO 2005) and SALFLAGE (Bergua, BJH 2016). The purpose is to analyse the complete remission (CR+CRi) rate, the rate of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). The disease-free survival (DFS) and overall survival (OS) were adjusted using established risk factors (time to relapse (TTR), karyotype, FLT3-ITD, previous stem cell transplant (SCT)) using propensity score analysis. Patients: Of the 540 patients in the data base we analysed 300 patients relapsed or resistant to induction therapy, which had all data available. 241 patients were treated with FLAG-IDA, 41 with FLAGO-Ida, and 42 with PLERIFLAG. Differences between treatment cohorts were tested using Fisher exact test. Treatment cohorts (PLERIFLAG vs FLAG-IDA vs FLAGO-IDA) were similar in Age (p=0.5), Sex (p=0.5), FLT3-ITD mutated (p=0.5), EPI/HOVON cytogenetics score (p=0.5) and previous myelodisplasia (p=0.2). The three cohorts differed in time to relapse (p=0.001), previous stem cell transplantation (0.001), HOVON score (p=0.03) and SALFLAGE score (0.001). RESULTS There were no differences in terms of CR+CRi between the three types of treatment adjusted by Hovon risk score (Pleriflag: 48%, FLAG-IDA: 50% or FLAGO-IDA: 58%; Chrochan Maentel-Haenszel test, p=0.466) or SALFLAGE score (Chrochan-Maentel-Haenszel test, p=0.23). More patients were allografted in the PLERIFLAG (61%) group even not achieving CR/Cri, as compared to FLAG-IDA (38%) or FLAGO-Ida (61% vs 38% vs. 18%, p=0.0001). To compare PLERIFLAG against the other two types of salvage treatment we performed a Propensity Score in a proportion 1:3. We adjust variables like age, previous allogeneic transplant, time to relapse (refractory, <12 months and >12 months), karyotype using MRC, and FLT3-ITD status. Karyotype risk was considered by HOVON criteria (inv16, t(8;21) vs others), and SALFLAGE (inv 16, intermediate risk, and unfavourable risk by MRC risk plus t(8;21)). The propensity score analyses showed that Compared to FLAG-IDA, PLERIFLAG was associated to increased survival (median OS 10.56 months vs. 5.6, p=0.03), but not improved EFS (2.83 months vs 1.41 months, p=0.8). The benefit in OS but not in EFS could be explained in part by frequent use of Allo SCT in patients who had not achieve CR/CRi in the PLERIFLAG cohort. In conclusion, our historical control study show that PLERIFLAG regimen is an acceptable therapeutic option for first relapsed/refractory adult AML patients. Disclosures Esteve: Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau. Salamero:Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Daichii Sankyo: Honoraria. Perez Encinas:CELGENE: Consultancy; JANSSEN: Consultancy; GILEAD SCIENCES: Research Funding. Montesinos:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau.

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Cancian, Mauro, Elisabetta Cosi, Marco Pizzi, Sandro Giannini, Irene Bertozzi, Fabrizio Fabris et Maria Luigia Randi. « Systemic Mastocytosis and Essential Thrombocythemia : Case Report and Literature Overview ». Medicina 55, n^o 9 (25 août 2019) : 528. http://dx.doi.org/10.3390/medicina55090528.

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Mastocytosis is a rare disease in which heightened amounts of mast cells accumulate in the skin, bone marrow, and other visceral organs. Upon activation, mast cells release a wide variety of preformed or newly synthesized mediators which can induce allergic symptoms and inflammatory reactions. Mastocytosis is diagnosed by biopsy and can be divided into cutaneous and systemic mastocytosis (SM). The first one affects the skin and is relatively benign, whilst SM, which involves bone marrow and other organs, may be aggressive and associate with both myelodisplastic and myeloproliferative diseases. Here we present a case of SM associated with essential thrombocythemia and complicated by severe osteoporosis, successfully treated with hydroxyurea, low-dose aspirin and zolendronic acid.

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Masljak, Z., V. Loginsky, Ya Vygovska, A. Mazurok et Z. Salamantchouk. « 98 Expression of the myeloid antigens on bone marrow cells in patients with myelodisplastic syndromes ». Leukemia Research 21, n^o 1 (avril 1997) : S26. http://dx.doi.org/10.1016/s0145-2126(97)81314-8.

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Salvi, Flavia, Daniela Gioia, Daniela Cilloni, Ernesta Audisio, Margherita Bonferroni, Gianni Cametti, Antonella Darbesio et al. « Prognostic Role of Transfusion Requirement and Validation of the IPSS Prognostic System in Myelodisplastic Syndromes. » Blood 108, n^o 11 (16 novembre 2006) : 2622. http://dx.doi.org/10.1182/blood.v108.11.2622.2622.

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Abstract BACKGROUND. The International Prognostic Scoring System (IPSS) of myelodysplastic syndromes (MDS) is based on bone marrow blast count, cytogenetic features and number of peripheral cytopenias. Transfusion requirement has been recently proposed as an important risk factor (Malcovati et al JCO23, 7594, 2005), and a new prognostic system (WPSS) has been suggested, based on WHO diagnostic subgroups, cytogenetic abnormalities and transfusion requirements (2005 ASH meeting abs.789). AIM OF THE WORK. To confirm the prognostic role of transfusion requirement and to compare the prognostic value of WPSS to that of IPSS. PATIENTS AND METHODS. The Piedmont MDS register is active since 1999. Clinical and laboratory data of patients were centrally recorded through our web site. Transfusion requirement data were retrospectively obtained from blood banks when possible. IPSS was calculated according to Greenberg et al. (Blood 89, 2079Blood 89, 1997). WPSS was calculated according to Malcovati et al. (2005 ASH meeting abst 789) by summing the score values of the following three variables: cytogenetic abnormalities scored according to the IPSS: 0 for good; 1 for intermediate; 2 for poor; transfusion requirement: 0 for absent; 1 for regular; WHO category: 0 for RA, RARS, 5q-, and unclassifiable; 1 for RCMD and RCMD-RS; 2 for RAEB-I; 3 for RAEB-II. WPSS score values were stratified into the proposed five risk groups: very low (score 0), low (1); intermediate (2); high (3–4); very high (5–6). RESULTS. From June 1999 to December 2004, 762 MDS patients were registered from 37 different institutions. Transfusion information was available for 376 patients. Data on both cytogenetics and transfusion requirements were available for 202 patients who are the object of the present analysis. 132 patients (65 %) needed regular transfusions, while the remaining 70 ones (35 %) did not. In univariate analyses all variables of both IPSS and WPSS scoring systems statistically influenced overall survival (OS). The time from diagnosis to the first transfusion was variable: less than six months in 97 cases (48 %); 6 to 12 months in 15 (7 %); more than 12 months in 20 (10 %). The OS of the 132 transfused patients was significantly worse than that of the 70 non-transfused ones, but the OS of patients who began to require transfusions more than 12 months after diagnosis was not significantly worse than that of not transfused patients. Only patients with an early transfusion requirement (within the first 12 month) had a poor outcome. When considering the prognosis of WHO subgroups the difference in OS between the subgroups 0 and 1 did not reach a significant level (p>0.05). In stepwise multivariate analysis the best prognostic factors were blast count, peripheral cytopenias and cytogenetic abnormalities. When the IPSS variables were included into the Cox model, neither WHO subgroups nor transfusion requirement retained an independent prognostic value. CONCLUSIONS. The prognostic value of transfusion requirement was confirmed, but only patients requiring transfusion within the first 12 months since diagnosis showed a poor outcome. In our experience IPSS model fits prognosis better than WPSS.

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