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Context. The perhaps only CMML-specific Randomized Clinical Trial (RCT) established hydroxyurea (HY) as the main treatment (Tx) for advanced proliferative CMML (Wattel Blood 1996). In Europe, the only hypomethylating agent (HMA) approved in CMML is AZA in non proliferative CMML-2. Phase 2 trials reported the activity of decitabine (DAC) in advanced proliferative CMML (Braun Blood 2011, Santini Leukemia 2018). We performed a RCT of DAC (±HY during the first 3 cycles) vs HY alone in those pts. Methods. The DACOTA trial (EudraCT 2014-000200-10) accrued pts with previously untreated (or < 6 weeks of HY), proliferative (WBC ≥ 13x109/L) CMML with advanced disease defined per Wattel et al as presence of extramedullary disease or ≥2 criteria among: BM blasts ≥5%, abnormal karyotype (except -Y), ANC ≥ 16x109/L, Hb < 10 g/dL, platelets < 100 x109/L or splenomegaly > 5 cm below costal margin. Pts were randomized 1:1 to DAC (20 mg/m2/d IV 5d/28d) or HY (1g/d, adjusted on WBC, 28d cycles) and treated until death, AML transformation or progression. The primary endpoint was EFS, events being death, transformation to AML, progression of myeloproliferation after 3+ cycles or progression of blasts and cytopenias after 6+ cycles. Response was assessed with IWG 2006 criteria modified to account for improvement of myeloproliferation, after central morphology review. Intent-to-treat analyses were done considering missing responses as failures. Results. From Oct 2014 to Sep 2019, 217 pts from 47 centers were screened and 170 randomized (84 DAC and 86 HY), including 12 pts (6 DAC and 6 HY) who never started Tx. Median age was 73 years (IQR 68-78). WHO was CMML-NA/1/2 in 2, 114 and 54 pts, respectively (resp). Median WBC 34.9 x109/L (IQR 22.9-55.7). Cytogenetic risk (Such Haematologica 2011) was fav 69%, int 12%, adv 18% NA 1%. Mutations in TET2, SRSF2, ASXL1 and signaling genes (CBL, JAK2, FLT3, KIT, NRAS, KRAS and CSF3R) were present in 64%, 51%, 62% and 57% resp. 72 pts had received HY for a median 27 days prior to randomization. Aside from older age in the HY arm (median 74 vs 71.5y in the DAC arm), there was no imbalance between Tx arms. DAC and HY pts received a median of 5 (IQR 3-12) and 6 (IQR 3-14) cycles, resp. As of 15th June 2020, 5 and 10 DAC and HY pts were still on Tx. Reasons for Tx cessation in the DAC arm were death (n=19), AML transformation (n=16), progression (n=9) , hematological toxicity (n=13) or other (n=21). Reasons for Tx cessation in the HY arm were death (n=14), AML transformation (n=13), progression (n=18), hematological toxicity (n=6) or other (n=20). 126 and 85 pts received 3 and 6 cycles, resp. In the ITT population, ORR at 3 cycles was 56% (7CR, 25 mCR±HI, 15 SD+HI) and 30% (0 CR, 8 mCR±HI, 18 SD+HI) in the DAC and HY arms, resp (p=0.0011) and ORR at 6 cycles was 32% (6 CR, 9 mCR±HI, 12 SD+HI) and 17% (2 CR, 4 mCR±HI, 9 SD+HI) in the DAC and HY arms, resp (p=0.033). Median response duration was 15.9 vs 18.2 months (mos) in the DAC and HY arm, resp (p=0.81). Infection and hemorrhage occurred at least once in 49% and 31% of pts, resp. 55% of DAC pts and 38% of HY pts required hospitalization at least once (p=0.05). Non-heme ≥ grade 2 AEs occurred in 79% and 63% of DAC and HY arms, resp (p=0.03). Grade ≥3 cardiac AEs occurred in 13 DAC and 4 HY pts, resp. With a median follow-up of 13.9 mos, median EFS was 12.6 vs 10.3 mos in the DAC and HY arms, resp (reference DAC arm, HR= 1.14 CI95 0.8-1.64, p= 0.46). Median AML-free survival (AMLFS) was 13.6 and 15.8 mos in the DAC and HY arms resp (p=0.86). Median OS was 18.4 and 23.1 mos in the DAC and HY arms, resp (p=0.72). Considering death and AML transformation as competing risks there was no significant difference in cumulative incidence of AML (p=0.1) or death without transformation (p=0.06) between arms. 30 pts from the HY arm received an HMA (DAC n= 13, AZA n= 16, both=1) after study exit. Censoring at HMA onset in the HY arm, median OS was 18.4 vs 30.4 in the DAC and HY arm, resp (p=0.15). 13 pts were transplanted (DAC n= 10, HY n= 3). There was no interaction between Tx arm and CMML-0/1 vs -2, platelets ≥ vs 0.05). Conclusion. RCTs are feasible in advanced proliferative CMML, which remains an unmet medical need. In these pts, DAC did not provide an overall or event-free survival advantage over HY. HY remains a valid option in advanced proliferative CMML. However, one third of HY pts subsequently received an HMA and more DAC pts achieved a response and were bridged to HSCT. Figure Disclosures Itzykson: Abbvie: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Sanofi: Honoraria; BMS (Celgene): Honoraria; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncoethix (now Merck): Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Santini:BMS, J&J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Lionel:Abbvie: Consultancy; Takeda: Consultancy; Celgene/BMS: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Luebbert:Janssen: Research Funding. Park:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Stamatoulas Bastard:Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria; Takeda: Consultancy. Solary:Janssen: Research Funding. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. OffLabel Disclosure: Decitabine for CMML with WBC > 13 x109/L.

Introduction Citrulline, a non-essential amino acid produced exclusively by enterocytes in the small intestine and involved in the synthesis of L-arginine, is not metabolized by the liver. Therefore citrulline serum concentration is highly correlated with functional enterocyte mass, and decreases with digestive toxicity induced by conditioning therapy (radiotherapy and/or chemotherapy) for hematopoietic stem cell transplantation (HSCT) . Acute Graft-versus-host disease (GvHD), one of the major complications of HSCT, is correlated to conditioning-induced gut barrier damage and may be predicted by pre-transplant serum citrulline level (Rashidi, BBMT 2018). It could be interesting to know whether citrulline kinetics could also represent a biomarker for conditioning toxicity, non-relapse mortality (NRM), and GvHD. The aim of this study is thus to define group-based trajectory modeling, to identify clusters of individual serum citrulline kinetics in the early phase of allogeneic HCST, and to test whether these unsupervised trajectories were correlated with these early complications. Materials and Methods Serum citrulline was quantified by liquid chromatography in blood samples collected from consecutive patients who received an allogeneic HSCT in our institution between July 2014 and November 2019. These samples were drawn at different time-points: pre-transplant (D-7, D-3); day of transplant (D0), and post-transplant (D7, D15, D21). Distinct trajectories were identified for serum citrulline by using the semiparametric mixture model described by Nagin (Nagin, Stat Methods Med Res 2018). Results Among 161 patients (pts) included in the study, with a median age of 53 years (17-72), 98 pts (60.9%) received a reduced-intensity conditioning (RIC), 36 pts (22.4%) reduced-toxicity conditioning (RTC), 18 pts (11.1 %) sequential conditioning, and 9 pts (5.6%) myeloablative conditioning (MAC). Donor were identical sibling (22%), matched unrelated donor (52%) and haploidentical sibling (25%). Graft source was peripheral blood mononuclear cells in 144 pts (89.4%) and bone marrow in 17 pts (10.6%) respectively. HCT-CI score was low, intermediate and high-risk in 38%, 32%, and 30% of pts respectively. Disease-Risk Index (DRI) was low/intermediate in 111 pts (69%) and high/very-high in 50 pts (31%). With a median follow up of 29.1 month, 3-year overall survival (OS), disease-free survival (DFS), and NRM rates were 64.5%, 58.3%, and 18.9%, respectively. The median number of citrulline samples per patient was 7 [3-16]. Median citrulline concentrations before conditioning and at D-3, D0, D7 and D15 were statistically different during RIC, RTC, MAC, and sequential conditioning (p In the whole cohort, 3 citrulline trajectories were determined in an unsupervised method. Patients belonging to these 3 trajectories were different according to intensity of conditioning received with lower citrulline trajectories during MAC and sequential conditioning (p After restricting the analysis to pts who received RIC conditioning (n=98), higher pre-HSCT citrulline concentrations were associated with a lower NRM (p=0.042). Unsupervised analysis in this setting individualized 4 clusters of individual trajectories (figure 1), that did neither distinguish age (p=0.28), DRI (p=0.87), HCT-CI score (p=0.81) nor the incidence of acute (p=0.6) or chronic (p=0.4) GvHD. However, the lowest citrulline trajectory contained significantly more haploidentical transplantations (p=0.004) and less pts who received antithymocyte globulin for GvHD prophylaxis (p=0.005). Interestingly in this RIC cohort, cumulative incidence of NRM at 12 months was 23%, 21%, 8%, and 0% respectively according to the 4 citrulline trajectories (figure 2). Conclusion In patients receiving allogeneic HSCT, the variation of serum citrulline concentrations depends on the intensity of the conditioning regimen. In patients who received RIC conditioning, lower plasma citrulline trajectories are associated with higher NRM. In this setting, citrulline may be an attractive biomarker for predicting conditioning toxicity and NRM. Disclosures Hunault: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria.

Introduction: Pre-transplant comorbidities, which may impact the success of allogeneic stem cell transplantation (AlloSCT) can be appreciated through 3 different scoring systems. The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) allows to predict non-relapse mortality (NRM) and survival (Sorror, Blood 2005). Its prognostic value was further augmented by the addition of donor age (< vs ≥40 yo) (Comorbidity/Age index, C/AI, Sorror, JCO 2014) then of pre-transplant ferritin (< or >2500 µg/L) and albumin (3.5g/dL) serum levels as well as platelet count (< vs >100 109/L) (Augmented Comorbidity/Age index, AC/AI, Elsawy, BBMT 2019). The performance of these 3 scores has not been evaluated in haploASCT using post-transplant cyclophosphamide (PTCY), a procedure in constant expansion worldwide. Material and Methods: We studied retrospectively the impact on non-relapse mortality (NRM), overall (OS) and disease-free (DFS) survival of the 3 comorbidity scores on a cohort of 223 patients (pts) having received a haploSCT with PTCY. All pts had pre-transplant ferritin and albumin levels and platelet counts available. These parameters were evaluated at the time of the pre-transplant check-up or just before conditioning (median from transplant: 20 days, range: 4-49). Results: Pts were recruited in 4 French centers (Nantes n=127; Angers n=45; Besançon n=29, Brest n=22). They had received haploSCT between October 2013 and January 2020. There were 136 males and 87 females with a median age of 55 yo (16-71, >40 years n=172). The majority of pts had a myeloid disease (n=157) and received a reduced intensity regimen (n=161, myeloablative n=30; sequential n=32). Respectively, 132 and 91 pts had low/intermediate and high/very-high Disease-Risk Index (DRI). All pts received PTCY, cyclosporine and mycophenolate mofetyl as graft versus host disease (GVHD) prophylaxis. Donors had a median age of 40.8 years (19.4-71.7). Median HCT-CI, C/AI and AC/AI scores were 2 (0-8), 3 (0-9) and 3 (0-11), respectively. The HCT-CI score was 5 in 110, 83 and 30 pts, respectively, while the AC/AI score was With a median follow-up for alive patients of 35.6 months (6-77), 3-year OS, DFS and NRM were 47.8+3%, 46+3% and 29.4+6%, respectively. In univariate analysis, better 3-year OS and DFS were associated with lymphoid diseases (OS: 60.4+6% vs 42.3+4%, p=0.02; DFS: 56.2+6% vs 41.6+4%, p=0.04), low/intermediate DRI (OS: 59.1+4% vs 30.1+7%, p3.5g/dL 50.1+4%, p=0.03; 3.5g/dL 47.4+3%, p=0.05). OS and DFS were not impacted by ferritin levels, platelet count, recipient age, gender, nor any of the 3 comorbidity scores. A lower 3-year NRM was observed in younger pts ( In multivariate analysis, each comorbidity score was compared to DRI, donor and patient age, type of disease and pre-transplant albumin levels. DRI and donor age remained associated with OS and DFS. This was also the case for recipient age, except when considering a high C/AI index score. Finally, an older age of recipients and donors remained associated with higher NRM. Conclusion: HCT-CI, C/AI and AC/AI do not to predict survivals nor NRM in haploSCT with PTCY, suggesting that pre-transplant comorbidities should not be a contra-indication to this procedure. As donor age is the only factor predicting survivals and NRM in this series, while multiple donors are generally available in the haploSCT setting, the selection of a younger donor should be the rule whenever possible for all patients. Disclosures Hunault: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Deconinck:ImmunoGen: Consultancy, Research Funding; Stemline: Consultancy. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Chevallier:Incyte Corporation: Honoraria.

Background: Most IPSS low and int1 (lower) risk MDS patients with isolated del(5q) develop RBC TD or need treatment for symptomatic anemia early after diagnosis (median time to transfusion/treatment of 20 months, López Cadenas et al abstract 3180 ASH, 2016). Lenalidomide (LEN) is a reference treatment in MDS-del(5q) but approved in many countries only when RBC-TD occurs. LEN directly targets the del(5q) clone improving anemia and quality of life. Limited data also suggest a role of LEN in non-TD patients with del(5q) (Oliva et al Cancer Med 2015), but no randomized trial has assessed the efficacy and tolerance of early LEN treatment in this MDS subset. Material: The Sintra-Rev clinical trial is a phase III European multicenter study in low-risk MDS-del(5q) patients with anemia (Hb Results: Main clinical characteristics of the 61 patients (ITT population) included (Feb-2010 to Feb-2018) are summarized in Table 1: 82% females, median age 72 years (range 37-89), median time since diagnosis 3.6 months, median Hb at inclusion 9.8 g/dL (7.1 - 11.7) g/dL and 93% patients had isolated del(5q). Four patients were excluded due either to screening failure (1 pat) or failure to complete at least 12w of treatment (3 pat). Fifty-seven patients were included in the ITT evaluable population for efficacy and 59 for safety (2 patients did not receive any drug). Median time on treatment was 66 weeks (3-121), 95w in the LEN arm and 42w in the placebo arm (p=0.392). Forty-seven percent patients in the LEN arm successfully completed the study compared to 33% in the placebo arm. After a median follow up of 25.6 months (Q1 16-Q3 39), median OS was not achieved. Among the 57 patients evaluable for efficacy, median time to TD was 75.7 mo for the LEN patients and 25.9 mo for the placebo arm (HR 2.703, 95CI1.162-6.286, p=0.021, figure 1). HI-E response was observed in 72.5% of LEN patients compared to 0% in the placebo arm (p Fifty-eight patients developed at least one adverse event (AE) during the trial (no differences between the LEN and placebo arm), related to the drug 86.8% in the LEN and 33.3% in the placebo arm, respectively (p Conclusions: In this interim analysis we confirm that low dose LEN (5 mg) in anemic non-TD low risk MDS del(5q) patients prolongs the period of time to TD (75.7 mo vs 25.9 mo), improves Hb levels (72.5% of ER) and induces clonal responses (70% complete CyR), ie potentially more responses than in historical series of MDS del(5q) treated with LEN at time of TD, with a manageable safety profile, and no increased progression rate. Longer follow up will be required to assess the effect of early treatment with LEN, and particularly the effect of the early reduction of the del(5q) clone size, on long-term outcomes. Disclosures Hernandez-Rivas: Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Sanz:LaHoffman Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Ltd.: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Platzbecker:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Götze:Celgene: Research Funding. Fenaux:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Diez-Campelo:Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: LEN IN ANEMIC BUT NOT TD PATIENTS WITH LOW RISK MDS AND DEL(5Q)

Background: MDS-RS are associated with a low risk of Acute Myeloid Leukemia (AML) progression and prolonged survival in most cases, but recurring anemia whose treatments, including Erythropoiesis Stimulating Agent (ESA), Lenalidomide, hypomethylating agents (HMAs), Luspatercept, and experimental drugs generally have transient effect and/or are not widely available. MDS-RS patients thus eventually have regular Red Blood Cells (RBC) transfusion dependency (TD) associated with mean low hemoglobin levels, and chronic anemia responsible for reduced quality of life, cardiovascular complications, and iron overload with organ dysfunction. We performed a retrospective observational study to describe transfusion characteristics and costs, along with clinical events, in a French population of RBC TD MDS-RS patients. Methods: Adult RBC-TD patients with MDS-RS from 12 hematology departments of the GFM were included. The number of RBC concentrates transfused was assessed over the last 6 months (during which no other treatment than transfusions was received), and patients categorized in low transfusion burden (LTB: 3 to 7 RBC/16 weeks) and high transfusion burden (HTB: ≥8 RBC concentrates /16 weeks). Data about iron chelation, full time hospitalization (differing from day care facility stays for programmed transfusions), causes of hospitalization, treatment of anemia before inclusion and transfusion costs was collected. Results: 100 patients MDS-RS were included, with a median time from diagnosis of 5 years (1 to 21 years). Median age was 78 years (57 to 99). Patients had received a median of 2 lines of treatment (including an ESA in 97% of them). 21% had LTB and 79% HTB. HTB patients had a longer disease duration, more frequent iron chelation (82% versus 50% in LTB patients, p=0.0052) and higher serum ferritin at inclusion (median 1958 µg/l versus 1176 µg/l, p=0.03). During the 6-month study period, 22% of the patients required full time hospitalization (in addition to day care facility for transfusions), including 25% of patients with HTB and 15% with LTB, and 43% during overall disease follow-up. Causes of full time hospitalization (figure) were symptomatic anemia (41%), general condition degradation (5%) or cardiac disease (8%), to both of which anemia potentially contributed, infection (23%), bleeding (8%), pulmonary (2%), 13% for other reasons. 15 HTB patients versus 1 LTB patient were hospitalized for symptomatic anemia. The 6-months average transfusion costs, including cost of the day care facility for RBC transfusion, transportation to and from the hospital, lab tests and iron chelation were $21459/patient, excluding costs of full-time hospitalization for complications. The average cost in HTB and LTB patients was $22829 and $7586/patient, respectively. Conclusion: Most MDS-RS patients currently become RBC-TD, often during several years, and most have high transfusion burden. The average cost of RBC transfusions and iron chelation was $21459/ 6 months. During this short observation time, 22% of the patients required full time hospitalization, due to complications of anemia in at least 50% of the cases, which also increased costs (comparison with rates of hospitalization in an age and sex matched general population will be presented). Poor quality of life associated with chronic anemia should also be taken into account in those RBC-TD patients. Widely available treatments, capable of avoiding RBC transfusion dependence and improving mean hemoglobin levels, are required in those MDS-RS patients. Disclosures Cony-Makhoul: BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Stamatoulas Bastard:Takeda: Consultancy; Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Park:Pfizer: Other: Travel expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.

International audience; Background. Admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) remains controversial , especially when graft-versus-host disease (GVHD) is present. Methods. We performed a retrospective study to assess prognostic factors of survival in all allogeneic SCT recipients admitted to the ICU between 2002 and 2013 in our center which has flexible admission criteria, especially regarding GVHD. Results. Of 349 patients who underwent allogeneic SCT during the study period, 92 patients (26%) were admitted to the ICU. Intensive care unit and hospital discharge rates were 66% and 46%, respectively , whereas 1 year survival was 24%. Acute GVHD, either grade III to IV (30 patients, 33%) or refractory (12 patients, 13%) had a nonsignificant impact on hospital mortality (odds ratio [OR], 2.1; P = 0.1; OR, 5, P = 0.05, respectively). Fifty percent of patients required invasive mechanical ventilation, 30% required vasopressors, 17% required renal replacement therapy, and 28% had liver impairment (bilirubin >34 μmol/L), each of these parameters defining organ failure. Mortality was closely associated with the number of organ failures as hospital discharge rates were 69%, 50%, 42%, and 0% among patients with 0 (26 patients), 1 (26 patients), 2 (26 patients), and 3 to 4 (14 patients) organ failures, respectively (OR, 2.7; 95% confidence interval, 1.6-4.6; P < 0.001 according to the number of organ failures). Conclusions. Early mortality of allogeneic SCT recipients admitted to the ICU is especially influenced by the number of organ failures and therefore patients with 0 to 2 organ failures should be considered if required. Refractory GVHD affects survival but not within the confined ICU admission.

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study (Tefferi et al, Blood Cancer J 2016) supported initiation of a study in TD LR MDS patients. The Phase 2 part of IMerge demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 32%, with median duration of TI being 88 weeks. The responses were seen across different subtypes of LR MDS (Platzbecker et al, EHA 2020, S183). No new safety signal was identified. These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrolment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 130 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of hematologic improvement-erythroid (HI-E), the amount and relative change in RBC transfusions, rate of complete response or partial response, overall survival, progression of MDS, pharmacokinetics, and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Fenaux:Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Steensma:CRISPR: Current equity holder in publicly-traded company; Aprea Therapeutics: Research Funding; Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; H3 Biosciences: Research Funding; Astex Pharmaceuticals, Otsuka: Consultancy; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company. Font:Abbvie: Other: Travel, accommodations, expenses; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Jang:Bristol Myers Squibb: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Johnson & Johnson: Honoraria.

The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-β. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one “epigenetic mutation” and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352).

Introduction: Despite therapeutic advances in recent years, disease relapse is still observed in up to 50-60% of the patients (pts) receiving allogeneic transplantation for high risk AML and MDS. In an initial Phase II trial of 30 pts treated with prophylactic low-dose AZA and escalated doses of DLI to prevent relapse, we reported that such prophylactic treatment can be safely administered and compared favorably to patients receiving no post-transplant maintenance. We here update 16 pts from our center, included in that protocol, as well as a larger cohort of additional patients treated with combined epigenetic and cellular therapy and the resultant effect on their event-free survival and their overall survival. Patients and methods: Fifty-nine pts (median age 59 yrs (range, 37-70); 30 M/29 F), comprising 40 pts with AML and 19 pts with MDS, were treated. Among the AML pts (ELN classification FAV n=2, INT n=17, ADV n=21), high risk criteria were as follows: 15 had complex karyotypes, 7 Flt3-ITD, 1 MECOM (EVI1) rearr., 3 monosomies, 2 t(9;11), and 1 t(11;19)); 9 were in CR≥2, 4 were refractory, and 13 had 2ary AML to MDS/chemotherapy/or MPS. Among the MDS pts, high risk criteria included 6 pts with complex caryotypes, 2 monosomies, 1 MECOM (EVI1) rearr., and 4 had 2ary MDS. IPSS-R median was 5.5 (3 - 7.5). MDS pre-transplant status included 7 CR1, 1 CR2, 5 PR, 1 relapse, 4 upfront, and 1 refractory. The therapeutic protocol administered to the initial 16 pts consisted of AZA, starting between d56 and d100 post-transplant, at a dose of 32 mg/m²/d SC, for 5 consecutive days, every 28 days, for up to a total of 12 cycles followed by DLI commencing after 3 cycles of AZA and 4 weeks following discontinuation of immunosuppressive prophylaxis. Two additional DLI were scheduled every 8 weeks following the 1st DLI. The doses of DLI 1, 2 and 3 were, respectively, 5x106, 1x107, and 5x107 CD3+ cells/kg for matched related donor (MRD), and 1x106, 5x106, and 1x107 CD3+ cells/kg for unrelated donor (UD). In the extended patient cohort, presented here, we slightly modified the schedule: DLI could be given earlier (after one or two cycles of AZA) and haploidentical pts could receive AZA/DLI as well, with DLI at the escalated doses of 1x105, 5x105, and 1x106 CD3+ cells/kg. Immunosuppression included cyclosporine A (CsA) in case of MRD, CsA and mycophenolate mofetil (MMF) in case of UD or haplo. MMF was progressively reduced during the first 2 months. CsA was tapered starting at day 60-100 post-transplant. Patients could start AZA while they were still receiving CsA. The conditioning regimens consisted of MAC for 5 pts, RIC for 46 pts and sequential for 8 pts. Donors were MRD, MUD, UD 9/10, and haplo for 20, 30, 1 and 8 pts respectively. Results: The median number of cycles AZA was 7 (range 1-12), 17 pts received 12 cycles of AZA, while 42 pts (71%) received at least one DLI. The median number of DLI was 1 (range 0-4), 15 pts received ≥ 3 DLI. The median time for the first post-transplant AZA injection was 83 days (range 56-145 d) and the median time post-transplant for those pts who received a first DLI was 148 days (range 78-245 d). The median pt-follow-up was 17 months (range 2-83). Eight pts (13%) relapsed (7 AML and 1 MDS). The cumulative incidence of relapse and NRM at 1 year was 12% and 11.5% respectively. Fifteen pts (25%) died. Causes of death included relapse in 6 pts, infection in 7 pts, myocardial infarction in 1 pt, and GvHD in 1 pt. Overall survival and event free survival for the entire group at 2 years was 71% (95% CI 54-82%) and 67% (95% CI 50-80%) respectively. The cumulative incidence of acute GvHD grade 1-4 and chronic GvHD were 32% (95% CI 16-49%) and 39% (95% CI 20-58%). Among the 8 pts who developed grade 3 acute GvHD, 4 occurred in pts who had received DLI. One pt died from grade 4 digestive GvHD post-AZA alone. Conclusion: We conclude that, despite their very high risk disease, prophylactic/preemptive low-dose AZA and DLI can be readily and safely administered with an acceptable incidence of subsequent GvHD to the AML and MDS pts described here. Significantly, in the poor-prognosis pts under study, the incidence of relapse is lower than expected. Furthermore, considering the immune escape mechanisms prophylactic or pre-emptive either AZA or DLI might be associated to additive non-cross reactive interventions, such as checkpoint inhibitors, in order to further decrease disease relapse and increase overall survival. Disclosures Peterlin: Jazz Pharma: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy; AbbVie Inc: Consultancy. Orvain:Novartis: Honoraria; Incyte: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria.

Introduction: The prognosis of older patients treated for acute myeloid leukemia (AML) relies on cytogenetic/molecular classifications as well as their ability to tolerate intensive induction therapy for which comorbidities have an important impact. A prognostic model has been elaborated to incorporate these two variables, cytogenetic/molecular risk and comorbidities evaluated by the Hematopoietic Cell Transplantation - Comorbidity Index (HCT-CI) (Sorror et al. 2017). The AML-composite model (AML-CM), which also incorporates hypoalbuminemia and high LDH levels at diagnosis, has been recently updated to incorporate the new European LeukemiaNet (ELN) 2017 classification (Sorror et al. 2019). In this study, we aimed to confirm the predictive impact of the revised AML-CM in an independent cohort and to explore which parameters were the most relevant for predicting early mortality and relapse. Patients and Methods: All patients (pts) older than 60 years diagnosed with AML who received intensive induction therapy in our department between 2004 and 2017 were included. Patients with acute promyelocytic leukemia were excluded. They received induction therapy with idarubicin 8 mg/m2 for 5 days and cytarabine 100 mg/m2 for 7 days with or without lomustine 200 mg/m2 on day 1. Patients in first complete remission (CR1) were to receive six consolidation courses with idarubicin 8 mg/m2 for one day and cytarabine 100 mg/m2 for 5 days and maintenance therapy with oral methotrexate and mercaptopurine. The HCT-CI and the revised AML-CM were calculated as previously described (Sorror et al. 2005; Sorror et al. 2019) using individual patient medical records. Early mortality was defined as death within one month after the start of induction therapy. The ELN 2017 classification, the HCT-CI, and the revised AML-CM were considered to determine which parameters - comorbidities or cytogenetic/molecular risk - were associated with each outcome. Results: Ninety-nine pts were included in the study with a median age of 66 years-old (range: 60 - 82). Twenty-seven pts (27%) had secondary AML (prior solid tumor requiring chemotherapy and/or radiation therapy in 11 pts and prior hematological malignancy in 16 patients). According to the ELN 2017 classification, 24 (24%) were favorable, 53 (54%) were intermediate, and 22 (22%) were adverse. The most frequent comorbidities included liver disease (30 pts, low/moderate, 5 pts, severe), previous cancer (22 pts), and arrythmia (22 pts). Thus, 13 (13%), 25 (25%), 44 (45%), and 17 (17%) pts had a revised AML-CM score of 1-4, 5-6, 7-9, and >10, respectively. 78 pts (79%) achieved CR1, with 10 early deaths (10%) due to toxicity (early mortality) and 11 induction failures (11%). Fifteen pts received allogeneic SCT. 54 (55%) relapsed, and 72 (73%) died with a median follow-up of 18 months (range: 0 - 167). Both the HCT-CI and the AML-CM were associated with increased early mortality (OR: 1.4, 95% CI: 1 - 1.8, p=0.03 for HCT-CI and OR: 1.3, 95% CI: 1-1.7, p=0.03 for AML-CM) whereas the ELN 2017 classification had no impact. The predictive value of the AML-CM for early mortality was not superior to the HCT-CI (area under the curve - AUC: 0.76, p=0.01, and 0.76, p=0.01, respectively). The risk of relapse was only associated with an unfavorable ELN 2017 classification (OR: 8.8, 95% CI: 1.1 - 70, p=0.04). It was the most predictive parameter for relapse, in comparison to the HCT-CI and the revised AML-CM, but this did not reach statistical significance (AUC: 0.62, p=0.08). The AML-CM clearly distinguishes 4 groups with different prognosis (Figure, p 10, respectively (OR: 1.4, 95% CI: 1.2 - 1.8, p Conclusion: The revised AML-CM is an effective tool for predicting overall survival in older pts with AML receiving intensive induction therapy. It is a better prognostic system compared to the HCT-CI and the ELN 2017 classification as it combines the evaluation of comorbidities, which predicts early mortality, and cytogenetic/molecular risk, which predicts relapse. Figure Disclosures Orvain: Novartis: Honoraria; Incyte: Honoraria.

Background Atypical CML (aCML) is a rare myeloid neoplasm with molecular heterogeneity and overlapping features of MDS and MPN. Distinction from unclassified MDS/MPNu based on WHO criteria remains difficult, and the management of these closely related entities remains ill-codified. Most patients (pts) are managed with cytoreductive agents, but small series have reported responses to hypomethylating agents or tyrosine kinase inhibitors (TKI), notably ruxolitinib. Allogeneic stem cell transplantation (SCT) is considered the only curative option. To instruct clinical trials with novel agents in this rare and heterogeneous population, real-life cohorts must i) provide prognostic factors and molecular characterization able to stratify patients, and ii) benchmark outcomes with current treatment options. Methods The French National observational study of rare MDS/MPNs performed a retrospective analysis of adult patients with MDS/MPN from 35 centers. Cases were centrally reclassified according to the 2016 WHO criteria to exclude CMML, classical MPNs and CNL. All statistical analyses were done without dichotomizing continuous clinical or biological variables. The prognostic influence of treatments was analyzed considering onset of treatment as a time-dependent covariate (Mantel-Byar method). Results The study population included 136 pts (M/F 83/53), with a median age of 72 years. Only 43 (31.6%) met WHO 2016 criteria for aCML while the remaining 93 were classified as MDS/MPNu. At diagnosis, spleen enlargement or other tumor symptoms were present in 36% of pts, while 32% had constitutional symptoms. Mutations in ASXL1, splice genes (U2AF1, SF3B1, SRSF2 or ZRSR2), SETBP1, EZH2, CSF3R, JAK2 and ETNK1 were present in 68.8%, 50.0%, 30.3%, 15.9%, 12.7%, 12.6% and 7.4% of 63 tested cases, respectively. 25 pts had an AML transformation. With a median follow-up of 29.8 months (0.5-276.4) median overall survival (OS) and AML-free survival (AMLFS) were 25.6 and 20.6 months, resp. Median OS was 20.2 versus (vs) 29.7 months in aCML vs MDS/MPNu, resp (log rank test p=0.2) and median AMLFS was 16.6 vs 27.4 months, resp (p=0.09). In univariate analysis, higher WBC (p=0.003) and lower Hb level (p0.1). Patients with EZH2 mutations had shorter OS (median 9.9 vs 20.6 months in EZH2 wt pts, p=0.03), while other gene mutations had no significant prognostic impact (all p>0.1). All variables with p At any time during follow-up, 89 (65.4%) pts received cytoreductive agents (mostly hydroxyurea), while 23 (16.9%) received TKI (ruxolitinib in 12, imatinib in 8, dasatinib in 3 pts) and 18 (13.2%) HMA, resp. Of note, 8/18 pts received HMA at transformation to AML, while all pts received TKIs prior to AML. Finally, 19 pts (14.0%) received an SCT and 35.3% received ≥2 of the above-mentioned types of treatment. Median time to SCT, HMA and TKI were 10.2, 11.9 and 4.7 months, resp. In multivariate Cox models adjusting for baseline Hb level and dyserythropoieisis, neither cytoreduction (p=0.6) nor SCT (p=0.5) were associated with a significant OS improvement. Treatment with HMA was associated with a significantly worse OS (HR=3.0, p=0.001), but this effect was confounded when transformation to AML, as a time-dependent event, was included in the model (HMA: HR= 1.1, p=0.7, AML: HR=5.1, p Conclusions Anemia and dyserythropoiesis are important prognostic factors in aCML and MDS/MPNu that should be used to stratify pts included in clinical trials. There is currently no standard of care for these overlap syndromes. Treatment with HMAs and TKIs should be restricted to clinical trials. Disclosures Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Roy:Incyte Biosciences: Consultancy. Caers:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Legros:Novartis: Honoraria; BMS: Honoraria; Incyte Biosciences: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Introduction Next generation sequencing (NGS) has allowed to improve knowledge about the genomic landscape of hematological malignancies. Somatic mutations (SM) are valuable new biomarkers but the utility of incorporating routine sequencing to guide diagnosis and therapeutic decisions remains challenging. We report here an observational multicentric study aimed at assessing the impact of SM testing by NGS in a real-life setting on the diagnosis and treatment of chronic myeloid malignancies (CMM). Patients and Method All patients who benefited from molecular assessment, between 10/2014 and 03/2019 in our University Hospital were included. All provided informed consent for data collection. All NGS requests were validated during a regional multidisciplinary concertation meeting. A custom targeted panel of 34 genes (145kbp i.e. ASXL1,BCOR, BCORL1, CBL, CSF3R, DNMT3A, ETV6, EZH2, GATA2, IDH1, IDH2, JAK2, KDM6A, KIT, KRAS, MPL, NPM1, NRAS, PIGA, PTEN, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, TET2, TNFAIP3, TP53, U2AF1, ZRSR2) was applied on DNA extracted from peripheral blood or bone marrow samples. DNA libraries, built with the Haloplex® target enrichment protocol (Agilent Technologies, Santa Clara, CA), were paired-end sequenced (150bp reads) with a MiSeq® Instrument (Illumina, San Diego, CA). Data analysis used an in-house pipeline including three variant callings (GATK HaplotypeCaller, VarScan and SAMTools). In a first group (A), NGS indication was to search for clonal hematopoiesis (CH), defined by the presence of at least one SM, in order to confirm or rule out a diagnosis of Idiopathic Cytopenia of Undetermined Significance (ICUS), Clonal Cytopenia of Undetermined Significance (CCUS), myelodysplastic syndrome (MDS), mixed myelodysplastic/myeloproliferative neoplasm (MDS/MPN), aplastic anemia (AA)/hypoplastic myelodysplasia (hMDS) or myeloproliferative neoplasm (MPN), based on recommendations of the WHO classification. In a second group (B), the theranostic impact of SM was studied. Prognostic SMs according to Bejar (2011) were used for MDS and MDS/MPN excluding chronic myelomonocytic leukemia that were analyzed with Itzykson score (2013) and/or CPSS-Mol score (Elena 2016). Prognostic SMs according to Vannucchi (2013) were used for myelofibrosis. Results The median age of the cohort was 60 years old (range: 10-87) with a median follow up of 1.1 years from molecular assessment to last follow-up. Within group A (94 patients), the most frequent blood count anomalies were cytopenia (68%), thrombocytosis (16%), and monocytosis (13%). The karyotype was normal in 77% and failed in 5% of the cases. Non-specific abnormalities (i.e. loss of chr Y, del 20q), were found in 8% of the cases. Before molecular assessment, the diagnoses proposed were ICUS (n=37), suspicion of MDS/MPN (n=16), AA/hMDS (n=16), or MPN (n=25). CH was detected in 31 patients comforting the diagnosis of CMM for 33% of group A (8 CCUS, 3 MDS, 7 MDS/MPN, 6 medullary hypoplasia, 7 MPN) patients. Considering the patients for whom no CH was detected (n=63), the initial suspected diagnosis of CMM was ruled out in 47 patients (i.e. 50% of group A). For the 16 remaining (i.e. 17% of group A), no firm diagnosis could be retained. Within group B (95 patients), NGS identified prognosis SM in 33% of the patients, i.e. poor prognosis SM in 24, including 8/40 MDS, 10/29 MDS/MPN and 6/17 myelofibrosis and good prognosis SM(SF3B1) in 7 of them, respectively 6/40 MDS and 1/29 MDS/MPN. Prognostic SMs had a therapeutic impact in 18/95 pts (19%). Indeed 13 patients with poor prognosis SM had a therapeutic change including 12 allogeneic stem-cell transplantation and 1 hypomethylating agent. Conversely, 5 patients with a good prognosis SM or absence of poor prognosis SM had a de-escalation of treatment intensity. Conclusion The use of NGS in daily practice had a clinical impact in both diagnostic and therapeutic decisions provided that the prescription is made in a critically explored context and not as a systematic test. In this "real life" cohort, the presence or absence of SM was a useful complement for integrated diagnoses in 83% of the patients, allowing to confirm (33%), or exclude (50%) a suspected condition. Moreover, in this cohort 34% of the patients had a SM with a reported prognostic impact and the treatment was modified in 19% of the cases. Yet, it remains necessary to integrate these results with other diagnostic criteria. Disclosures Peterlin: AbbVie Inc: Consultancy; Jazz Pharma: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy. Moreau:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Chevallier:Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria.

International audience; The benefit of early admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) as soon as they develop organ injury is unknown. We performed a retrospective study on 92 patients admitted to the ICU to determine the impact of time from organ injury to ICU admission on outcome. The number of organ injuries prior to ICU admission was associated with an increased in-hospital mortality (OR 1.7, 95% CI 1–2.7, p = 0.04). Time between first organ injury and ICU admission was also associated with an increased in-hospital survival (OR 1.4, 95% CI 1.1–1.8, p = 0.02). A score combining these two covariates—the number of organ injuries/day (sum of days spent with each individual organ injury)—further improved the prediction of hospital survival. Patients with more organ injuries/day had significantly higher in-hospital mortality rate even after adjustment for refractory acute GVHD and the SOFA (OR 1.3, 95% CI 1–1.7, p = 0.02). Early ICU admission of allogeneic SCT recipients to the ICU as soon as they develop organ injury is associated with decreased in-hospital mortality.

Azacitidine (AZA) prolonged overall survival (OS) in the AZA-AML-001 trial. However, few subjects were randomized to AZA or intensive chemotherapy (IC). The Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) developed a score for older AML patients receiving IC or non-intensive regimens, whereas the E-ALMA study validated a score for survival and response in elderly patients receiving AZA in daily practice. Both identified three groups with different risk estimates. This analysis evaluates the efficacy of frontline AZA in older AML patients (N = 710) unfit for IC from different national registries (E-ALMA + series) stratified by the MRC/LRF risk score. Median OS of patients categorized as good, standard and poor-risk groups by the MRC/LRF score was 13.4 (95% CI, 10.8-16), 12.4 (95% CI, 9.9-14.8), and 8.1 months (95% CI, 7-9.1), respectively (p = .0001). In conclusion, this is the largest retrospective cohort of older AML patients treated with AZA.

Allogeneic stem cell transplantation (AlloSCT) is a curative option for acute myeloid leukemia (AML) patients. In first complete remission (CR1), young patients (< 60 years) with intermediate or unfavorable ELN disease risk are usually considered for AlloSCT. In contrast, because of the expected higher toxicity in older patients, the benefit of this treatment remains a matter of debate after 60 years, especially in the intermediate ELN risk group. In this multicenter analysis from the French Innovative Leukemia Organization (FILO), we investigated whether AlloSCT was beneficial for AML patients over 60 years old in CR1. Inclusion criteria were: patients between 60 and 70 years of age diagnosed with AML from 2007 to 2017; CR1 after intensive chemotherapy; ELN-2010 intermediate or unfavorable risk group. AlloSCT was evaluated as a time dependent variable in survival calculations and in a multivariate Cox model adjusted on age, ELN group, transplantation period and stratified by transplantation center. We also used a multistate model as follow: initial state for all patients was "No Allo - CR" with time 0 at the time of CR. From initial state, patients can transit to "Allo-CR", or move through 2 absorbing states (non-relapse death (No Allo-NRM) or relapse (No Allo-Relapse). Similarly, once transplanted (i.e. in the state "Allo-CR"), patients can move to "Allo-Relapse" or "Allo - NRM" when such events occurred. The model allows the dynamic prediction of probability for a patient to be in a specific state considering specific initial state and time. We analyzed 521 consecutive patients in 6 centers who matched inclusion criteria. Median age was 65 years (range: 60-70). ELN-2010 risk was intermediate and unfavorable in 376 (72%) and 145 (28%) patients, respectively. While all patients had a theoretical indication for AlloSCT in CR1, 199 (38%) were actually transplanted (129 (34%) and 70 (48%) in the intermediate and unfavorable risk group, respectively). In the whole cohort, AlloSCT as time-dependent variable significantly improved relapse-free survival ([RFS] at 5 years, No AlloSCT vs. AlloSCT: 14% vs. 47% p < 0.001) and overall survival ([OS] at 5 years, No AlloSCT vs. AlloSCT: 24% vs. 51% p < 0.001). In subgroup analysis based on ELN-2010 risk classification, AlloSCT significantly improved outcome of both ELN intermediate (No AlloSCT vs. AlloSCT: 5-y RFS: 16% vs. 50% p < 0.001; 5-y OS: 26% vs. 54% p < 0.001) and unfavorable (No AlloSCT vs. AlloSCT: 5-y RFS: 7% vs. 44% p < 0.001; 5-y OS: 17% vs. 46% p < 0.001) risk group patients (Figure A and B). By multivariate time-dependent Cox model, AlloSCT significantly decreased the risk of relapse (HR [95%CI]: 0.29 [0.20-0.41] p < 0.001) and increased the risk of NRM (HR [95%CI]: 2.61 [1.38-4.94] p = 0.003). This led to a significant advantage for AlloSCT in both RFS (HR [95%CI]: 0.48 [0.36-0.64] p < 0.001) and OS (HR [95%CI]: 0.60 [0.44-0.81] p = 0.001). This benefit was observed in both intermediate and unfavorable ELN-2010 risk groups, with lower risk of relapse (intermediate: HR [95%CI]: 0.30 [0.19-0.46] p < 0.001; unfavorable: HR [95%CI]: 0.37 [0.19-0.72] p = 0.004) and better OS (intermediate: HR [95%CI]: 0.67 [0.47-0.96] p = 0.028; unfavorable: HR [95%CI]: 0.51 [0.29-0.91] p = 0.022). Multistate model showed that 5 years after CR1, few patients were still alive in CR without AlloSCT (i.e. in the initial "No Allo-CR" state), whatever the ELN-2010 risk group (intermediate: 9%; unfavorable: 1% Figure C and D). Among patients who were transplanted, the probability for transiting to Allo-NRM state within 5 years post CR1 was 17% and 24% in intermediate and unfavorable ELN-2010 groups, respectively. Corresponding values for patients without AlloSCT transiting to No Allo-NRM state were 11% and 12%. Moreover, considering a landmark at 6 months after CR1, the multistate model showed that patients who received AlloSCT had lower probability of relapse at 5 years (22% and 33% in intermediate and unfavorable ELN-2010 groups, respectively) compared to those who did not (68% and 78% in intermediate and unfavorable groups, respectively). AlloSCT for CR1 AML patients over 60 years of age is routinely feasible and significantly improves outcome in both intermediate and unfavorable ELN-2010 risk groups. Less than 10% of patients are long term disease free survival without AlloSCT, even in intermediate risk group, supporting that AlloSCT remains the first curative option for these patients. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation.

Les syndromes myelodysplasiques (SMD) sont des affections clonales des cellules souches pluripotentes, caracterisees par une hematopoiese inefficace, responsable de cytopenies sanguines qui contrastent avec une moelle generalement riche. De plus, les SMD evoluent frequemment en leucemie aigue myeloide (LAM) et constituent les plus frequents des etats preleucemiques de l’adulte.Les SMD predominent chez le sujet âge, avec une mediane d’âge au diagnostic de l’ordre de 70 [...]

Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100 mg/day ( n = 5) or 150 mg/day ( n = 25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III–IV extra hematological toxicities (skin ( n = 1), and diarrhea ( n = 3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months. Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML.

Acute erythroleukemia (AEL) is a rare disease typically associated with a poor prognosis. The median survival ranges between 3-9 months from initial diagnosis. Hypomethylating agents (HMAs) have been shown to prolong survival in patients with myelodysplastic syndromes (MDS) and AML, but there is limited data of their efficacy in AEL. We collected data from 210 AEL patients treated at 28 international sites. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method and the log-rank test was used for subgroup comparisons. Survival between treatment groups was compared using the Cox proportional hazards regression model. Eighty-eight patients were treated with HMAs, 44 front line, and 122 with intensive chemotherapy (ICT). ICT led to a higher overall response rate (complete or partial) compared to first-line HMA (72% vs. 46.2%, respectively; p, Publication costs were supported by the University of Salzburg.

Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.

Limited data are available on azacitidine (AZA) treatment and its prognostic factors in acute myeloid leukemia (AML). One hundred and forty-nine previously untreated AML patients considered ineligible for intensive chemotherapy received AZA in a compassionate patient-named program. AML diagnosis was de novo, post-myelodysplastic syndromes (MDS), post-MPN, and therapy-related AML in 51, 55, 13, and 30 patients, respectively. Median age was 74 years, median white blood cell count (WBC) was 3.2 × 10⁹ /L and 58% of the patients had ≥ 30% marrow blasts. Cytogenetics was adverse in 60 patients. Patients received AZA for a median of five cycles (range 1-31). Response rate (including complete remission/CR with incomplete recovery/partial remission) was 27.5% after a median of three cycles (initial response), and 33% at any time (best response). Only adverse cytogenetics predicted poorer response. Median overall survival (OS) was 9.4 months. Two-year OS was 51% in responders and 10% in non-responders (P 15 × 10⁹ /L and ECOG-PS ≥ 2 predicted poorer OS, while age and marrow blast percentage had no impact. Using MDS IWG 2006 response criteria, among patients with stable disease, those with hematological improvement had no significant survival benefit in a 7 months landmark analysis. Outcomes observed in this high-risk AML population treated with AZA deserve comparison with those of patients treated intensively in prospective studies.

BACKGROUND: Patients with TD lower-risk (LR)-MDS relapsed or refractory to ESA have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase, characteristics observed in some MDS patients. IMerge is an ongoing global study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1). In the first 32 patients enrolled, 8-week TI rate was 34%, with 24-week TI of 16%, and HI-E of 59%. The most frequently reported adverse events were reversible grade ≥3 cytopenias (Fenaux et al EHA 2018 Abstr S1157). Higher response rates were observed in patients (n=13) who were LEN and HMA naïve without del(5q). We report here results in an additional 25 LEN and HMA naïve patients without del(5q), with longer term follow-up of the 13 initial patients meeting the same criteria. METHODS: IMerge is a phase 2/3 trial (NCT02598661) that includes LR-MDS patients with a high transfusion burden (≥4 units / 8 weeks) who are relapsed/refractory to ESA or have sEPO >500 mU/mL. The additional 25 were required to be LEN and HMA naïve and lack del(5q). Imetelstat 7.5 mg/kg was administered IV every 4 weeks. In addition to the key endpoints noted above, secondary endpoints include safety, time to and duration of TI. Biomarkers are also being explored, including telomerase activity, hTERT, telomere length, and genetic mutations. RESULTS: Overall, for the 38 LEN/HMA naïve and non-del(5q) patients, median age was 71.5 years and 66% were men. 63% of patients were IPSS Low and 37% Int-1. Median prior RBC transfusion burden was 8.0 (range 4-14) U, and 71% had WHO 2008 RARS or RCMD-RS. 9/37 (24%) patients with evaluable sEPO levels had baseline level >500 mU/mL. As of July 2018, with a median follow-up of 25.8 months for the initial 13 patients, and 5.2 months for the 25 recently included patients, the 8-week RBC-TI rate was 37% (14/38). Durability of 24-week TI responses was demonstrated, with a median duration of 10 months and the longest ongoing response now >2 years. Among the patients achieving durable TI, all showed a Hb rise of ≥3.0 g/dL compared to baseline during the transfusion-free interval. Response rates were similar in RARS/RCMD-RS (33% [9/27]) and other patients (27% [3/11]), and those with baseline EPO levels >500 mU/mL (33% [3/9]) and ≤500 mU/mL (32% [9/28]). Reversible grade ≥3 neutropenia and thrombocytopenia were each reported in 58% of the patients. Liver function test (LFT) elevations were mostly grade 1/2. Reversible grade 3 LFTelevations were observed in 3 (8%) patients on study. An independent Hepatic Review Committee deemed the observed LFT elevations were not imetelstat-related hepatic toxicities. SUMMARY / CONCLUSIONS: In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to LEN/HMA, single-agent imetelstat yielded a TI rate of 37%, with a median duration of 10 months and limited side effects. Durable responses were characterized by transfusion independence >24 weeks and accompanied by Hb rise. Updated data will be presented. Disclosures Steensma: Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Platzbecker:Celgene: Research Funding. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Raza:Kura Oncology: Research Funding; Onconova: Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Speakers Bureau; Geoptix: Speakers Bureau; Janssen: Research Funding; Syros: Research Funding. Santini:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Font:Celgene: Membership on an entity's Board of Directors or advisory committees. Samarina:Janssen: Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bussolari:Janssen: Employment, Equity Ownership. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Fenaux:Roche: Honoraria; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Background: Lenalidomide (LEN) is a reference treatment in IPSS low and in1 (lower) risk MDS patients with isolated de(5q) (MDS-del(5q)) and RBC - TD. Most low risk MDS-del(5q) patients with anemia and independent of transfusions develop TD or need of treatment for symptomatic anemia very early after diagnosis (median time to transfusion/treatment of 20 months, López Cadenas et al abstract 3180 ASH, 2016). LEN directly targets the del(5q) clone improving anemia, quality of life and survival in this subset of patients. Limited data also suggest a role of LEN in non-TD patients with del(5q) (Oliva et al Cancer Med 2015). However no prospective randomized study of LEN has been performed in this group of patients. Material: The Sintra-Rev clinical trial is a phase III European multicenter study, in low-risk MDS-del(5q) patients, with anemia (Hb Results: Main clinical characteristics of the 58 patients included are summarized in Table 1: 81% were females, median age was 72 years (37-89), median Hb at inclusion 9.8 g/dL(7.1 - 11.7) g/dL and most patients (86%) had isolated del(5q) cytogenetic abnormality. Three patients were excluded due to screening failures and 58 were finally included in the trial. Seven patients discontinued before 12 weeks: Three developed disease progression (defined as TD), two withdrew consent, one due to changes in patient's status and it was not specified in the remaining patient. Therefore, fifty-four patients were finally evaluable for efficacy and 58 for safety at w12. HI-E was observed in 20/54 patients (37%), minor HI-ER in 6/54 (11%), stable disease in 25/54 (46%) and TD (transfusion dependency) in 3 (6%). In the 26 patients achieving HI-E or minor HI-E, the median Hb level rise was 2.2 g/dL (range 1-4.4) and median Hb level was 12.5 g/dL (9.8-14.2). Cytogenetic response (CyR) was available in 41/54 patients: complete in 16 (30%), partial in 9 (17%), no CyR in 16 (30%) and no available in 13 (23%) patients. 54 patients developed adverse events (AE) in the first 12w, most of them hematological and probably related to the treatment. Hematological toxicity occurred in 74% of patients (neutropenia or thrombocytopenia) and only one third was grade 3/4 (neutropenia 35% or thrombocytopenia 3%). Non-hematological adverse events potentially related to the investigational drug were described in 19 patients (35%) but only 2/19 (11%) were grade 3. Nine serious AE were reported in 7 patients: congestive heart failure (2), vestibular neuritis, polyarthritis, arterial hypertensive crisis, carpal arthritis, respiratory infection, chronic obstructive pulmonary disease exacerbation and blurred vision. Only the last one (blurred vision) was potentially related with the study drug Conclusions: In this preliminary and blinded analysis we confirm a high rate of erythroid and cytogenetic responses early (w12) after study treatment with an adequate safety profile. Unblinded data will be presented at the meeting. Disclosures Platzbecker: Celgene: Research Funding. Götze:JAZZ Pharmaceuticals: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; Novartis: Honoraria; Celgene: Honoraria, Research Funding. Díez-Campelo:Celgene: 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.

Background :AZA improves overall survival (OS) in higher risk MDS, but only 50-60% of the patients respond, and median OS with AZA is only 20-24 months. As OS improvement is obtained at modest response rates, OS rather than response should probably remain the primary endpoint for all combinations with AZA, requiring large phase III trials with significant follow up. On the other hand, combinations that do not increase response will likely not improve OS. We therefore tested, based on a "pick the winner" approach, AZA combinations with the HDAC inhibitor VPA, LEN or IDA to identify, based on response, the most promising combination with AZA in higher risk MDS, that could be subsequently compared with AZA alone in a larger phase III study. Methods : AZA-PLUS (#NCT01342692)was an adaptive two-stage phase II trial based on Jung design (Stat Med.2008;27:568) that randomly assigned higher-risk MDS, low blast count AML (20-30%) and CMML to: AZA (75 mg/m2/d d1-7 of 28-day cycles); AZA plus LEN (10 mg/d on d1-14); AZA plus VPA( 50 mg/kg/d on d1-7; 35 mg/kg/d in patients> 60y) or AZA plus IDA (10 mg/m2on d1 for the first 9 cycles). The primary end point was response rate (RR, including CR, PR, marrow CR, based on IWG 2006) of the combination arms vs AZA alone. Given a 30% RR with AZA alone, we considered that a ≥45% RR would make combination(s) promising. Controlling for type I and type II errors at 0.15 and 0.20, 40 patients per arm were to be enrolled at each stage. Any experimental arms with RR lower than those observed in the AZA arm at the first stage should be stopped. At the second stage, any arm with > 6 more responses than AZA alone should be selected for further testing. Secondary endpoint were ORR (RR+ stable disease with HI (HI) and OS. Results : After inclusion of 40 pts/arm (first stage) all experimental arms had at least the same number of responses as the control arm and were continued in second stage. Overall, 322 pts were enrolled from 06/2011 to 07/2017: 81, 80, 80, 81 in the AZA, AZA+VPA, AZA+LEN and AZA+IDA arms, respectively. Baseline characteristics were well-balanced across arms. Median age was 74.6 y, 213 pts were male, IPSS was INT-2 in 54% and High in 46%. IPSS Karyotype was fav, int and poor in 40%, 26% and 34%, respectively. Pts received a median of 7 cycles and median follow-up was 15.1 months. Prevalence of trial discontinuation due to adverse events was 32%, 29%, 28% and 31% in the AZA , AZA+VPA , AZA+LEN and AZA+IDA arms, respectively (p=0.95). Rates of hospitalization during the first 6 cycles were 38%, 44.7% , 55.1%, 59.7% in the AZA, AZA +VPA, AZA+LEN and AZA+IDA arms, respectively (p=0.028), suggesting increased myelosuppression in the experimental arms, especially in the LEN and IDA arm. In the control arm, 29 responses (CR+PR+mCR) after 6 cycles were observed, with 29, 25 and 29 responses observed in AZA+VPA , AZA+LEN and AZA+IDA arms, respectively. Thus, no combination demonstrated benefit over AZA. The RR was estimated at 34.8% (18.6% CR, 3.1% PR, and 13.0% mCR) and the ORR after 6 cycles was 40.4%. The RR after 6 cycles (35.8% for AZA, 36.2% for AZA+VPA, 31.2% for AZA+LEN, and 35.8% for AZA+IDA) and the ORR after 6 cycles (41.9% for AZA; 41.2% for AZA+VPA, 40.0% for AZA+LEN and 38.3% for AZA+IDA) were close across study arms. By multivariate analysis, factors associated with better ORR were higher Hb level (p=0.05), low fibrinogen (p=0.008) and low LDH (p=0.01). 17 (5%) pts were bridged to allogeneic SCT: 6 on AZA, 5 on AZA+VPA, none in the AZA+LEN arm and 6 on AZA+IDA arm (p=0.03). At the reference date of July 2018, median EFS was 16.6 months for in AZA, 14.5 months for in AZA+VPA, 15.1 months for in AZA+LEN and 13.2 months for in AZA+IDA (p=0.74) (Fig A). Multivariable Cox model selected Hb level (p=0.02), presence of circulating blasts (p Conclusion : Although OS differences may occur with longer follow up, the combination of VPA, LEN or IDA to AZA did not improve response or OS over AZA alone and worsened myelosuppression. With newer, potentially more potent drugs that can be combined with AZA, the "pick the winner " approach may still be useful to select promising combinations based on response in phase II trials. Molecular data of the pt cohort will be presented at the meeting. Figure. Figure. Disclosures Ades: silent pharma: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; JAZZ: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Laribi:Novartis: Other: Grant and personal fees; Sandoz: Other: Grant; Teva: Other: Grant; Hospira: Other: Grant; Takeda: Other: Grant and personal fees; Roche: Other: Grant; Amgen: Other: Personal fees; Gilead: Other: Personal fees. Stamatoullas:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Consultancy. Beyne-Rauzy:Novartis: Research Funding. Cluzeau:MENARINI: Consultancy; CELGENE: Consultancy; JAZZ PHARMA: Consultancy. Quesnel:Sunesis: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Celyad: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

The effect of azacitidine (AZA) in therapy related MDS and AML (t-MDS/AML) is not well established. 54 patients (42 t-MDS and 12 t-AML), 71% of whom had complex karyotype, received AZA for at least one cycle (median 4 cycles). The overall response rate (ORR) was 39% in the whole cohort and 62% in patients who received ≥4 cycles. One, 2 and 3 year OS was 36%, 14% and 8% respectively. Female gender (p=0.01) and ECOG 0-1 (p=0.04) were associated with significantly better OS, while karyotype and marrow blast percentage had no significant impact. By comparison with de novo MDS/AML treated in the same program, t-MDS/AML had a similar response rate (38% vs 45% in de novo MDS/AML, p=0.53), but significantly shorter OS (2 year OS of 14% vs 33.9%, p=0.0005). However, in a multivariate analysis performed in all patients (de novo and therapy related cases), only complex karyotype and high IPSS, and not etiology (i.e. de novo versus therapy related), had a significant impact on OS. Nine (15%) patients received allogeneic stem cell transplantation, 4 of whom were still alive.

Erlotinib was originally developed as an epidermal growth factor receptor (EGFR)-specific inhibitor for the treatment of solid malignancies, yet also exerts significant EGFR-independent antileukemic effects in vitro and in vivo. The molecular mechanisms underlying the clinical antileukemic activity of erlotinib as a standalone agent have not yet been precisely elucidated. Conversely, in preclinical settings, erlotinib has been shown to inhibit the constitutive activation of SRC kinases and mTOR, as well as to synergize with the DNA methyltransferase inhibitor azacytidine (a reference therapeutic for a subset of leukemia patients) by promoting its intracellular accumulation. Here, we show that both erlotinib and gefitinib (another EGFR inhibitor) inhibit transmembrane transporters of the ATP-binding cassette (ABC) family, including P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP), also in acute myeloid leukemia (AML) cells that do not overexpress these pumps. Thus, inhibition of drug efflux by erlotinib and gefitinib selectively exacerbated (in a synergistic or additive fashion) the cytotoxic response of KG-1 cells to chemotherapeutic agents that are normally extruded by ABC transporters (e.g., doxorubicin and etoposide). Erlotinib limited drug export via ABC transporters by multiple mechanisms, including the downregulation of surface-exposed pumps and the modulation of their ATPase activity. The effects of erlotinib on drug efflux and its chemosensitization profile persisted in patient-derived CD34+ cells, suggesting that erlotinib might be particularly efficient in antagonizing leukemic (stem cell) subpopulations, irrespective of whether they exhibit or not increased drug efflux via ABC transporters.

Purpose Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described. Patients and Methods Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program). Results The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care. Conclusion Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.

The deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the progression from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Since hypomethylating agent, notably azacitidine, constitute an efficient therapy for patients with high-risk MDS, we assessed whether such compounds can activate the DDR in malignant blasts. While azacitidine and decitabine had moderate effects on apoptosis and cell cycle progression, both agents induced profound changes in the expression and functionality of DDR-related proteins. Decitabine, and to a lesser degree azacitidine, induced the activation of checkpoint kinases Chk-1 and Chk-2 and the phosphorylation of the DDR-sensor H2AX. In addition, hypomethylating agents were found to cause the dephosphorylation of the transcriptional regulator forkhead box O3, best known as FOXO3A, whose phosphorylation has been related to poor prognosis in AML. The dephoasphorylation of FOXO3A induced by azacitidine or decitabine in malignant blasts was accompanied by the translocation of FOXO3A from the cytoplasm to the nucleus. Upon stimulation with azacitidine, MDS/AML-derived, azacitidine-sensitive SKM-1S cells upregulated FOXO3A and the pro-apoptotic FOXO3A targets BIM and PUMA, and this effect was attenuated or abolished in azacitidine-resistant SMK-1R cells. Altogether, our results suggest that the reactivation of FOXO3A may contribute to the effects of hypomethylating agents in malignant blasts.

Prognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P = .009), bone marrow blasts > 15% (P = .004), and abnormal karyotype (P = .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P = .0003). Performance status ≥ 2, intermediate- and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency ≥ 4 units/8 weeks (all P < 10−4) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10−4). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P = .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10−4). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment.

Incidence on relapse and nonrelapse mortality (NRM) of chronic graft-versus-host disease (GVHD), per National Institutes of Health (NIH) criteria, is not well defined after reduced-intensity conditioning (RIC) regimens. We analyzed the association of chronic GVHD with the risk of relapse and NRM using Cox models in 177 consecutive patients who underwent transplantation for hematological malignancies after RIC. The cumulative incidence of chronic GVHD at 36 months was 74% when using Seattle's criteria compared with 54% with NIH consensus. In Cox model, NRM was significantly higher in patients with late-onset, persistent and recurrent acute GVHD (hazard ratio (HR): 6, 25 and 11; P = 0.014, P0.0001, P0.0001, respectively). The cumulative incidence of relapse was significantly decreased in patients with chronic GVHD compared with no GVHD group using either Seattle's or NIH criteria (HR 0.43 and 0.38; P = 0.022 and 0.016, respectively), whereas the presence of late-onset, persistent and recurrent acute GVHD was not associated with a decreased rate of relapse (HR: not significant, 0.70 and 0.71; P = not significant, P = 0.73 and P = 0.54, respectively). Chronic GVHD per NIH consensus definition is associated with the graft-versus-tumor effect, whereas all forms associated with acute features beyond day 100 are associated with NRM.

The impact of reducing immunoglobulin dosage while switching from intravenous to subcutaneous replacement therapy was evaluated. Sixty-five patients with primary hypogammaglobulinemia on stable intravenous replacement therapy were included in a monocentric longitudinal trial. IgG trough levels were measured at baseline and during 1 year following the switch to the subcutaneous route. Mean IgG trough level after 12 months of subcutaneous therapy was increased by 5.4% (8.37–8.82 g/l, p = 0.3), while immunoglobulin dosage had been reduced by 28.3% (151–108 mg/kg/week, p

Purpose Acute myeloid leukemia (AML) with translocation (t) (8;21) or inversion (inv) (16) is associated with a favorable prognosis when treated with intensive chemotherapy. In elderly patients, these AML types are rare, and intensive treatments are much less tolerated. We conducted a retrospective study to evaluate the characteristics and outcome of AML with t(8;21) or inv(16) in the elderly. Patients and Methods Patients with t(8;21) or inv(16) AML who were age 60 years or older and who received at least one course of induction chemotherapy were included. Postremission therapy consisted of low-dose maintenance chemotherapy (n = 72) or intensive consolidation (n = 56). Results A total of 147 patients were analyzed. The median age was 67 years. Sixty patients had t(8;21), and 87 patients had inv(16). A total of 129 patients achieved complete response (CR) after one or two induction courses (ie, 88% CR rate), and 15 patients (10%) died early (ie, during the 8 weeks after induction). During a median follow-up of 48 months, the 5-year probabilities of overall survival (OS) and leukemia-free survival (LFS) were 31% and 27%, respectively. Multivariate analysis showed a negative impact of high WBC, impaired performance status, and deletion (9q) on OS and LFS. Administration of intensive consolidation was associated with better LFS only in patients with t(8;21). In addition, the need for critical care during induction independently predicted lower LFS. Conclusion Because of a high CR rate, induction chemotherapy should be considered systematically for elderly patients who have AML with t(8;21) or inv(16). The high risk of relapse suggests that alternative strategies of postremission therapy are warranted.

The molecular mechanisms responsible for the evolution from the preleukemic entities of low-risk myelodysplastic syndrome (MDS) to the less favorable forms of high-risk MDS, as well as those enabling transformation to acute myeloid leukemia (AML), are still incompletely understood. Abundant evidence from solid tumors demonstrates that preneoplastic lesions activate signaling pathways of a DNA damage response (DDR), which functions as an 'anticancer barrier' hindering tumorigenesis. Testing the hypothesis that subgroups of MDS and AML differ with respect to DDR, we first assessed markers of DDR (phosphorylation of ATM, Chk-1, Chk-2 and H2AX) in cell lines representing different entities of MDS (P39, MOLM-13) and AML (MV4-11, KG-1) before and after gamma-irradiation. Although gamma-irradiation induced apoptosis and G(2)/M arrest and a concomitant increase in the phosphorylation of ATM, Chk-1 and H2AX in MDS-derived cell lines, this radiation response was attenuated in the AML-derived cell lines. It is noteworthy that KG-1, but not P39 cells exhibit signs of an endogenous activation of the DDR. Similarly, we found that the frequency of P-ATM(+) cells detectable in bone marrow (BM) biopsies increased in samples from patients with AML as compared with high-risk MDS samples and significantly correlated with the percentage of BM blasts. In contrast, the frequency of gamma-H2AX(+) cells was heterogeneous in all subgroups of AML and MDS. Whereas intermediate-1 MDS samples contained as little P-Chk-1 and P-Chk-2 as healthy controls, staining for both checkpoint kinases increased in intermediate-2 and high-risk MDS, yet declined to near-to-background levels in AML samples. Thus the activation of Chk-1 and Chk-2 behaves in accord with the paradigm established for solid tumors, whereas ATM is activated during and beyond transformation. In conclusion, we demonstrate the heterogeneity of the DDR response in MDS and AML and provide evidence for its selective suppression in AML because of the uncoupling between activated ATM and inactive checkpoint kinases.

Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation.

Hypomethylating agents are able to prolong the overall survival of some patients diagnosed with acute myeloid leukemia. The aim of this study was to evaluate the clinical use of azacitidine as front-line therapy in unfit acute myeloid leukemia (AML) patients and to develop a clinical prediction model to identify which patients may benefit more from the drug. One hundred and ten untreated unfit AML patients received front-line azacitidine therapy in Spain, and response and survival were evaluated in them following European LeukemiaNet (ELN) guidelines. A clinical prediction rule was obtained from this population that was validated and refined in 261 patients treated in France, Austria and Italy. ELN response was achieved in 21.0% of the 371 patients (CI95% 17.0-25.5) and did not depend on bone marrow blast cell percentage. Median overall survival was 9.6 months (CI95% 8.5-10.8) and 40.6% of the patients were alive at 1 year (CI95% 35.5-45.7). European ALMA score (E-ALMA), based on performance status, white blood cell counts at azacitidine onset and cytogenetics, discriminated three risk groups with different survival and response rates. Azacitidine seems a reasonable therapeutic option for most unfit AML patients, i.e. those displaying a favorable or intermediate E-ALMA score. (C) 2014 Elsevier Ltd. All rights reserved.

Outcome of patients with high risk MDS and CMML who failed treatment with azacitidine remains poor with a median survival of 6 months, without established therapy available except allogeneic hematopoietic stem cell transplantation. The objective of our study was to evaluate efficacy of decitabine after azacitidine failure in a relatively large patient cohort based on conflicting results with 0-28% response rates (RR) in this setting in small patient series. Thirty-six consecutive high risk MDS and CMML patients who received decitabine after azacitidine failure were retrospectively reviewed. Response was based on IWG 2006 criteria for MDS and CMML with WBC

Importance Bronchiolitis obliterans syndrome has been associated with increased morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). Previous studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome. Objective To evaluate if the early administration of azithromycin can improve airflow decline–free survival after allogeneic HSCT. Design, Setting, and Participants The ALLOZITHRO parallel-group trial conducted in 19 French academic transplant centers and involving participants who were at least 16 years old, had undergone allogeneic HSCT for a hematological malignancy, and had available pretransplant pulmonary function test results. Enrollment was from February 2014 to August 2015 with follow-up through April 26, 2017. Interventions Patients were randomly assigned to receive 3 times a week either 250 mg of azithromycin (n = 243) or placebo (n = 237) for 2 years, starting at the time of the conditioning regimen. Main Outcomes and Measures The primary efficacy end point was airflow decline–free survival at 2 years after randomization. Main secondary end points were overall survival and bronchiolitis obliterans syndrome at 2 years. Results Thirteen months after enrollment, the independent data and safety monitoring board detected an unanticipated imbalance across blinded groups in the number of hematological relapses, and the treatment was stopped December 26, 2016. Among 480 randomized participants, 465 (97%) were included in the modified intention-to-treat analysis (mean age, 52 [SD, 14] years; 75 women [35%]). At the time of data cutoff, 104 patients (22%; 54 azithromycin vs 50 placebo) had experienced an airflow decline; 138 patients (30%) died (78 azithromycin vs 60 placebo). Two-year airflow decline–free survival was 32.8% (95% CI, 25.9%-41.7%) with azithromycin and 41.3% (95% CI, 34.1%-50.1%) with placebo (unadjusted hazard ratio [HR], 1.3; 95% CI, 1.02-1.70;P = .03). Of the 22 patients (5%) who experienced bronchiolitis obliterans syndrome, 15 (6%) were in the azithromycin group and 7 (3%) in the placebo group (P = .08). The azithromycin group had increased mortality, with a 2-year survival of 56.6% (95% CI, 50.2%-63.7%) vs 70.1% (95% CI, 64.2%-76.5%) in the placebo group (unadjusted HR, 1.5; 95% CI, 1.1-2.0;P = .02). In a post hoc analysis, the 2-year cumulative incidence of hematological relapse was 33.5% (95% CI, 27.3%-39.7%) with azithromycin vs 22.3% (95% CI, 16.4%-28.2%) with placebo (unadjusted cause-specific HR, 1.7; 95% CI, 1.2-2.4;P = .002). Conclusions and Relevance Among patients undergoing allogeneic HSCT for hematological malignancy, early administration of azithromycin resulted in worse airflow decline–free survival than did placebo; these findings are limited by early trial termination. The potential for harm related to relapse requires further investigation. Trial Registration clinicaltrials.gov Identifier:NCT01959100

Prognostic significance of monosomal karyotype in higher risk myelodysplastic syndrome treated with azacitidine

The prognosis of patients older than 50 with relapsed or refractory AML is dismal. Azacitidine has been investigated in older AML patients. Here we report the outcome of 130 patients older than 50 years included in a multicenter patient named program of azacitidine after relapse (n=67) or induction failure (n=63) of intensive chemotherapy. Median age was 67 years, cytogenetic risk was high in 28% and performance status ≥2 in 15% of cases. Most (72%) patients received azacitidine at the standard schedule (75mg/m(2)/d, 7 days/month) for a median of 4 courses. The overall response rate was 17% (CR: 10%, CRi: 7%). Median overall survival was 8.4 months. Achievement of CR/CRi was associated with prolonged survival (P=0.0001), whereas hematological improvement according to MDS criteria, achieved in 36% of patients with resistant disease, did not improve survival. In multivariate analysis, high risk cytogenetics (P=0.022) and peripheral blasts >10% (P

To the editor: The International Prognostic Scoring System (IPSS), which is based on cytogenetics, BM blast percentage, and number of cytopenias, has played a major role in prognosis assessment in myelodysplastic syndrome (MDS) since its publication in 1997. The recently published revised IPSS (

To the editor: We previously reported that peripheral blasts, performance status (PS), red blood cell (RBC) transfusion requirement, and International Prognostic Scoring System (IPSS) cytogenetic risk independently predicted inferior overall survival (OS) in 282 consecutive IPSS high- and