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Background and aims: intensive chemotherapy (IC) has been used since the early 90's in the treatment of higher risk MDS, yielding 40 to 50% complete response (CR) but prolonged myelosuppression and 10 to 30% early deaths. IC is also recommended before allogeneic (allo) SCT when marrow blasts are increased (De Witte et al, Blood, 2017). CPX-351, a liposomal combination of cytarabine and daunorubicin, proved greater efficacy than classical IC with 3+7 in secondary-AML, including in patients with 20-30% marrow blasts and those who subsequently received allo SCT (Lancet et al, Lancet Haematol, 2021). We evaluated response to CPX-351 in a group of untreated higher risk MDS patients, most of whom were candidates for allo SCT. Methods: This prospective study, involving 12 GFM centers, included int-2 or high IPSS MDS, previously untreated with HMA or chemotherapy, and aged Results: 31 patients were included between July 2020 and January 2021. Median age was 62 years (range 31-69); WHO classification: 26 MDS-EB2, 5 CMML-2; IPSS: int-2: 84%, high: 16%; R-IPSS: intermediate: 29%, high: 55%, very high: 16%; karyotype: 2 very good, 22 good, 3 intermediate, 2 poor, 2 very poor. 27 patients received one induction cycle and 4 (in stable disease (SD) after the first cycle), a second induction cycle. Response rates, eventually evaluated a median of 53 days (range 28-112) from onset of induction, were with ELN 2017 criteria: CR: 52%, CRi: 13%, MLFS: 23%, SD: 13% and with IWG 2006 criteria : CR: 23%, mCR: 45%, mCR + HI-P: 6%, mCR + HI-P + HI-N: 6%, mCR + HI-N: 3%, PR: 3%, SD: 13%. Minimal residual disease assessment by NGS and flow cytometry will be presented at the meeting. 24/27 patients with baseline marrow blasts >10%, reached 20G/L and >50G/L were: 16 (range 0-55) days and 28 (range 8-51), respectively and to ANC >1G/L: 26 (range 2-60) days. Only one patient had grade ≥ 3 mucositis and 4 had grade ≥ 2 alopecia during induction treatment. No patient died during induction treatment or required management in the intensive care unit. With a median follow-up of 201 days (range 102-350), 22 of the 30 patients initially considered for allo SCT received transplant after no (10 pts), 1 (9 pts), 2 or 3 (3 pts) consolidation cycles and 5 are planned for allo SCT. Reasons for not being transplanted were, investigators' choice (n=1), relapse (1), no donor (1) and invasive fungal infection (n=1). None of the 4 non transplanted patients received consolidation cycles. Reasons for not receiving consolidation cycles were persistent cytopenia (n=5), cardiac toxicity (n=2), failure to achieve CR or PR (n=2). At the time of analysis (June 2021), 4 patients had relapsed, after 3 to 6 months of response. Conclusions : CPX-351 is effective in higher risk MDS/CMML, especially to achieve blast clearance, and as a bridge to allo SCT. Figure 1: waterfall plot according to IWG 2006 and ELN 2017 criteria Figure 1 Figure 1. Disclosures Fenaux: Novartis: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria; Takeda: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. OffLabel Disclosure: CPX-351 use off-label for myelodysplastic syndroms in a prospective trial

Introduction Anemia is a common complication of hematological chemotherapy for acute leukemia and following hematopoietic stem cell transplantation (HSCT). Exposure to allogeneic blood transfusions has been associated with unfavorable outcome in several studies in a non-surgical settings. Retrospective studies in hematological intensive unit have suggested that single red blood cell (RBC) unit transfusion policy may reduce the number of RBC used in comparison with a classical double RBC unit transfusion policy, without clinical impact. The aim of the study was to demonstrate that single RBC transfusion was non inferior to the standard double RBC transfusion arm in terms of severe complication or mortality for inpatient with hematological malignancies. Key secondary endpoint, was the comparison of the numbers of RBC units transfused in each arm. Method In a phase 3 multicenter randomized trial, 245 adults' patients with acute leukemia requiring intensive chemotherapy or patients receiving autologous or allogeneic HSCT were randomly assigned (1:1) to receive either single RBC unit (1 RBC arm, n=125) per transfusion or double RBC (2 RBC arm, n=120) per transfusion when hemoglobin level was below 8g/dL. The primary composite endpoint was the percentage of patients who developed a grade ≥3 complications defined as stroke, transient ischemic attack, acute coronary syndrome, heart failure, elevated troponin level, intensive care unit transfer, death, new pulmonary infiltrates, and/or transfusion-related infections during hospital stays. The secondary endpoint was the number of red cell units transfused per patient per hospital stay. The primary endpoint was compared between groups by non-inferiority analysis for the proportion risk difference using Farrington-Manning method with a non-inferiority margin of 0.1, in ITT dataset. Results Hematological disease were as followed: AML (59%), ALL (13.1%), Lymphoma (16.4%), others (11.5%). The median age was 55 years. Baseline characteristics were well balanced between the 2 arms (Figure 1A). A total of 981 and 592 transfusions have been necessary in the 1 RBC arm and 2 RBC arm, respectively. The median of RBC unit per transfusion was 1(1-1) and 2(2-2) in the 1 RBC and 2 RBC arm, respectively. The mean pre transfusion hemoglobin level was 7.49 +/- 0.83 g/dL in the 1 RBC arm and 7.46 +/- 0.67 g/dL in the 2 RBC arm (p=0.275). Hemoglobin level at discharge was 9.35 +/-1.14 g/dL in the 1 RBC arm and 9.58 +/-1.13 g/dL in the 2 RBC arm (p=0.118). The median (IQR) of red-cell units transfused per patient was 7 (4-12) in the single arm and 8 (4-12) in the double arm (p=0.65). The median number of platelet transfusion event was 7 (3.5-11.5) in the 1 RBC arm and 7 (3-13) in the 2 RBC arm (p=0.69). The median (IQR) number of red cell unit transfused per cycle and per day was 7 (3-9) and 0.28 (0.17-0.37) in the 1RBC arm and 6 (4-10) and 0.27 (0.20-0.38) in the 2 RBC arm (p=0.61 and p=0.47). The predefined non-inferiority criteria was achieved with 28 patients developing a serious complication in the 1 CGR arm (22.4%) and 28 patients in the 2 RBC arm (23.3%) (Risk difference 0.009; 95% Confidence interval [-0.0791- 0.0978] (Figure 1B). Conclusion: Single RBC transfusion policy is non inferior to double RBC transfusion policy in hematological intensive care unit for patient receiving a bone marrow transplant or intensive chemotherapy. Single RBC unit transfusion can be used safely in daily clinical practice. The single RBC transfusion policy does not reduce the number of RBC transfusion. Figure 1 Figure 1. Disclosures Jardin: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties. .

Background Post-transplant cyclophosphamide (PTCy) is a powerful strategy to prevent occurrence of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Initially developed in the setting of haploidentical HSCT, PTCy has been increasingly used for fully HLA-matched transplants with favorable results. The purpose of this retrospective multi-center study is to evaluate PTCy-based GvHD prevention for patients with acute leukemia receiving a traditionally prohibitive highly mismatched HSCT and to describe their outcome. Methods This is a registry-based study employing the data set of the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT). We retrospectively assessed the outcome of adult patients with acute myeloid or lymphoblastic leukemia (AML/ALL), transplanted between 2010 and 2020 with grafts from HLA-mismatched donors with more than 5/10 mismatches using PTCy-based GvHD prophylaxis. Results The study cohort consisted of 59 patients, with a median time of follow up of 20 (95% CI, 14-39) months. The median age was 47 (range, 18-69) years. Forty-four patients had a diagnosis of AML, 14 of ALL and one case of mixed phenotype acute leukemia. At time of transplant, 39 (66%) were in first or second complete remission, 4 (7%) were in later remission and 16 (27%) had active, relapsed or refractory, disease. Conditioning regimens were myeloablative for 54% of cases and peripheral blood was the preferred source of stem cells (64%). All donors were related. Most patients (85%) received a 4/10 HLA-matched transplant, the most commonly mismatched loci were C and DQB1, often with a double mismatch involving the same locus. Two cases of fully mismatched donors were also recorded. PTCy was always associated with other immunosuppressive treatments, especially with the standard combination of calcineurin inhibitors and mycophenolate mofetil. In only 8 cases in vivo T-cell depletion was realized with anti-thymocyte globulin. A large proportion of patients (86%) attained engraftment with a median time of 19 (range, 11-37) days. Only 8 patients did not reach engraftment and all of them died of infection or disease relapse in the first one-hundred days (range, 6-99) after HSCT. Thirty-three patients (58%) did not present any sign of acute GvHD (aGvHD). Cumulative incidence of grade II-IV and grade III-IV aGvHD at day 180 were 30.3% and 14.3%, respectively. At 2 years, the cumulative incidence of chronic GvHD (cGvHD) was 21%, and 7% for extensive cGvHD. Twenty-four patients died during the study period, mostly because of leukemia progression (n=13, 54%), infectious complications (n=6, 25%) and interstitial pneumonia (n=2, 8%). Other causes of death were hemorrhage, GvHD, and another non HSCT-related that accounted for one case (4%) each. At 2 years, the overall survival (OS), leukemia-free survival (LFS), and a GVHD and relapse free survival (GRFS) were 56%, 54% and 47% respectively. Rates of relapse incidence and non-relapse mortality were 28% and 19%, respectively. Conclusion According to this preliminary data overview, transplantation in a highly mismatched framework is possible, without unfavorable OS, LFS and GVHD rates. Despite the important limitation of the retrospective non-controlled nature of this analysis, these findings suggest that PTCy-based strategies could help overcome the barrier of HLA-matching and configure a new setting of transplantation, encouraging more in-depth investigations. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Angelucci: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Gilead: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Astellas: Honoraria.

Aims: Combining 2GTKI+pegylated IFN-a (Peg-IFN) represents an attractive approach for first-line treatment of CP CML, while providing somewhat light additional AEs, it induces high rates of deep molecular responses. We evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82) and analysed here the proportion of patients reaching Treatment-Free Remission (TFR) and outcome. Methods: Newly diagnosed CP CML pts ≤65 years, without vascular history were randomized 1:1 to get NIL 300 mg BID alone [M0 to M72 (unless TFR), arm A] vs Peg-IFN alone for 30 days (M-1→M0) 30 mg/wk, prior to NIL 300 mg BID + Peg-IFN 30 mg/wk 2 wks, upgraded to 45 mg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone until M72 unless TFR. The primary endpoint was the rate of MR4.5 by M12, and after amendment, the trial was extended to 72 months follow-up in order to add, as a secondary endpoint, the TFR rate in pts reaching MR4.5 ≥2 y. The trigger for treatment resumption was loss of MMR. All molecular assessments were centralised until M36, and in case of TFR, MR4.5 was centrally confirmed at M0 TFR, and further molecular follow-up was then performed locally. All molecular quantifications are expressed as BCR-ABL1/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control in the central lab and in the local labs all involved to the pluri-annual French external quality controls. Results are analysed in intention-to-treat. Results: As previously reported, 200 pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. The median follow-up (FU) since diagnosis is now 47.5 (33.77-62.39) Mo. and the median FU since discontinuation is 9.86 (5.8-23) Mo. in arm A and 15.57 (12.62-22.77) Mo. in arm B. Sokal and ELTS scores were high in 25% and 2.5%, intermediate in 33% and 16.5% and low in 42% and 81% pts respectively, equally balanced. All pts harboured a "Major" BCR transcript. We have previously shown that by M12, the rate of MR4.5 was 15.9% vs 21.5% (primary endpoint met, p=0.049) and that the overall cumulative incidence of MR4.5 was somewhat superior in arm B (54.6 [43.7-65.5] %) vs A (44 [31.5-54] %), p=0.05. Two pts died, one from myeloid blast crisis before TFR (arm A), one from a solid tumour (arm A). Overall, 40 pts (20%) reached the TFR criteria, 21 in arm A with a median FU of 9.86 (5.8-23) Mo. and 19 in arm B with a median FU since Nilo cessation of 15.57 (12.62-22.77) Mo, partly related to slightly different time for obtaining sustained MR4.5 in favour of arm B (16 vs 13 Mo.). For these 40 pts reaching TFR criteria, there was no statistical difference in terms of age at diagnosis and age at TFR, gender, Sokal, ELTS, FU since diagnosis, undetectability at cessation, BCR-ABL1 levels at 3 Mo. after cessation between the 2 arms. The survival without loss of MMR after cessation is illustrated in Figure 1. It looks superior in arm B over arm A, but did not reach statistical difference (p=0.445), but the FU is very short after cessation yet, especially in arm A. Once NIL was resumed in the pts that failed TFR, all pts recovered MMR within 6 Mo., with no difference between arms (p=1.00). In univariate analysis, we did not identify significant factor impacting on the TFR success (age at cessation, sex, undetectability at cessation, Sokal, ELTS) except the BCR-ABL1 value at M3-TFR (undetectable versus detectable, HR 7.15 [2.06-24.75], p=0.002), and the duration of MR4.5 before discontinuation (HR 1.11 [1.03-1.19], p=0.004). During this TFR phase 7 SAEs were reported in arm A (2 pregnancies, 1 obstructive sleep apnea, 1 fever episode, 1 carotid stenosis and 1 femoral stenosis in the same patient at 2 Mo. after cessation, 1 lung carcinoid tumor) and 2 in arm B (1 persistent atrial fibrillation, 1 cholecystectomy). Conclusions: The combination of NIL + Peg-IFN induces higher MR4.5 rates by M36 in newly diagnosed CP CML pts that may translate in higher successful TFR rates, however a longer follow-up is needed to see consistent significant differences. Updated data will be presented. Figure 1 Figure 1. Disclosures Nicolini: Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Guerci-Bresler: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Charbonnier: Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees.

On behalf of the GRAALL group. Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4. Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44. Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C). Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia

Introduction Based on the results of the ALFA-0701 trial (Castaigne et al. Lancet 2012), the addition of fractionated doses of the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin (GO, Mylotarg®) to conventional chemotherapy has been approved in 2017 for frontline treatment of adults with CD33-positive acute myeloid leukemia (AML). Prolonged event-free survival (EFS) was observed in patients with AML of favorable or intermediate risk, while not in those with adverse cytogenetics. Nevertheless, more frequent added toxicities could make the addition of GO a questionable option in patients over 60-65 years of age. In this ALFA-1401/Mylofrance 4 trial (NCT02473146), we investigated if the replacement of the anthracycline by GO might also improve EFS in older patients. Methods Between January 2016 and March 2019, 225 patients were randomized 2:1 to receive an experimental GO-cytarabine combination (154 patients) or a standard anthracycline-cytarabine treatment (71 patients). Patients aged 65 to 80 years old (later extended to patients aged 60-64 years old), with previously untreated de novo AML of favorable or intermediate cytogenetics were eligible for the trial. Standard treatment arm consisted in a 7+3 using idarubicin at 12 mg/m 2/d on day 1 to 3 and cytarabine 200 mg/m 2/d on day 1 to 7. Experimental arm (GO arm) consisted of two doses of GO 3 mg/m 2/d on day 1 and 4 and cytarabine 200 mg/m 2/d on day 1 to 7. Post-remission therapy comprised two courses of intermediate-dose cytarabine (IDAC) at 1.5 g/m 2/12h on day 1, 3 and 5. In the GO arm, a third dose of 3mg/m 2/d GO was administered on day 1 of the first IDAC course. The first IDAC course could serve as second induction in patients not responding to the first one. The decision to perform allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission was left to the discretion of the physician. The efficacy analysis was conducted in the modified intent-to-treat (mITT) population excluding patients who did not meet the cytogenetic eligibility criteria. The primary study endpoint was EFS. Secondary endpoints were response rate defined by complete remission (CR), CR with incomplete platelets recovery (CRp) and CR with incomplete hematological recovery (CRi), early mortality, relapse incidence, overall survival (OS) and safety. Results Among the 225 randomized patients, 214 (71 standard arm, 143 GO arm) were included in the mITT population. There were 126 men and 88 women. Median age was 70 years (61-80). Cytogenetics was of favorable and intermediate risk in 14 and 200 patients, respectively. One hundred and eighty-one patients reached CR/CRp/CRi, 64 (90%) in standard arm and 117 (82%) in GO arm (p=0.17). Median follow-up time was 38 months. At 2 years, estimated EFS was 38% [95% CI, 28-51] in the standard arm vs. 29% [22-37] in the GO arm (Hazard Ratio (HR), 1.37 [0.98-1.93]; p= 0.067) (Figure 1A). Overall, 118 patients relapsed, 36 (51%) in standard arm and 82 (57%) in GO arm. At 2 years, estimated cumulative incidence of relapse was 48% [36-61] in standard arm vs. 61% [52-70] in GO arm (csHR, 1.32 [0.90-1.93]; p= 0.078). Overall, 122 patients died, 38 (54%) in standard arm, 84 (59%) in GO arm. Sixty-day mortality was 4% in standard arm vs. 10% in GO arm (p=0.13). At 2 years, estimated OS was 65% [55-77] in standard arm vs. 52% [45-61] in GO arm (HR, 1.27 [0.86-1.87]; p= 0.23). In subgroup analysis for EFS (Figure 1B), we found a significant interaction with gender, GO having a detrimental effect in women which persisted after adjustment on known prognostic factors. A total of 33 patients received allo-HSCT in first remission, 19 (30%) in standard arm and 14 (12%) in GO arm (p=0.006). When censoring these patients at transplant time, HR of GO on EFS was 1.27 ([0.88-1.83]; p=0.19). Regarding safety, 76% and 80% of patients had at least one grade 3 to 5 adverse event (p=0.81), including infection in 30% vs. 21% and bleeding in 7% vs. 29% in standard arm and GO arm respectively. Serious adverse events were reported in 34% of patients in standard arm vs. 49% in GO arm (p=0.031). Sinusoidal obstruction syndrome occurred in 2 patients in the GO arm. Conclusion Frontline use of GO instead of idarubicin, when combined to cytarabine, does not benefit older patients with de novo standard-risk AML. At the reduced dose schedule used in this study, GO remains associated with significant toxicities while non-significant higher relapse incidence, shorter EFS and shorter OS were observed. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: ABBVIE: Consultancy; PFIZER: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Barbieux: ASTRA-ZENECCA: Consultancy. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; Daiichi Sankyo: Honoraria; BMS-Celgene: Honoraria.

To the editor: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare form of acute myeloid leukemia (AML) that has been recognized as a distinct entity in the 2008 World Health Organization classification of hematopoietic tumors.[1][1] BPDCN is characterized by frequent skin and bone

Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .047). LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856.

Cyclosporine A (CsA) alone or in combination with mycophenolate mofetil (MMF) has been used as graft-versus-host-disease (GvHD) prophylaxis since the early development of reduced intensity conditioning (RIC). The association of CsA+MMF, while commonly used after transplantation from a matched unrelated donor (MUD), has never been tested in a large randomized prospective trial. We retrospectively investigated the outcomes of adult patients with AML in complete remission (CR) undergoing a MUD transplant using CsA+MMF or CsA alone as GvHD prophylaxis, transplanted between 2007-2017 and registered with the ALWP of the EBMT. Of the 497 patients who were evaluated, 183 received CsA alone and 314 received CsA+MMF. The median age at transplant was similar, being 59 (range, 20-75) years in the CsA group and 60 (range, 21-75) years in the CsA+MMF group. All patients underwent a RIC regimen with fludarabine and busulfan and received anti-thymocyte globulin as part of the conditioning. The median follow-up was 33 (range, 18-60) months in the CsA group and 34 (range, 18-75) months in the CsA+MMF group. Disease status at transplant was first complete remission (CR1) for 81% (n=149) in CsA group and 86% (n=268) in CsA+MMF group (p=NS). Poor risk cytogenetics was reported for 19% of patients who received GvHD prophylaxis with CsA alone and for 15% of patients receiving CsA+MMF (p=NS). Peripheral blood stem cells (PBSC) was the graft source in 93% of patients receiving CsA alone and in 96% of patients who received CsA+MMF (p=0.17). Female to male mismatch was present in 13% and 15% of patients in the CsA goup and CsA+MMF group respectively, (p=NS). All but 2 patients engrafted. The 100 day cumulative incidence (CI) of grade II-IV and grade III-IV GvHD were 30% and 10%, respectively. The 2-year CI chronic GvHD was 35% and CI of extensive cGvHD was 15%. The 2-year CI of non-relapse mortality (NRM) and relapse were 19% and 25%, respectively. Of the 81 patients who died in the CsA group, disease recurrence (n=31), GvHD (n=20) and infection (n=17) were the most common causes of death. One hundred twenty seven patients died in the CsA+MMF group; cause of death was relapse for 53, GvHD for 28 and infection for 28 of them. The 2-year GVHD-free relapse-free survival (GRFS), leukemia- free survival (LFS), and overall survival (OS) were 45%, 56% and 60%, respectively. On multivariate analysis (MVA), no statistically significant differences were found among the two GvHD prophylaxis groups with respect to relapse, NRM, LFS, OS, acute and chronic GvHD. A positive cytomegalovirus serology of the donor was associated with higher NRM [HR=2.03, p In a subgroup analysis of patients in CR1 who received PBSC, (CsA alone, n=138; CsA+MMF, n=257), no differences were detected between the two groups for relapse, NRM, LFS, OS, or aGvHD, but patients who received CsA alone tended to have a higher cGvHD (41% vs 33%, p=0.05). However, on MVA, although the risk of cGvHD was lower in the CsA+MMF group, this finding was not statistically significant [HR=0.67, p=0.08]. Adverse cytogenetics was an independent risk factor for relapse [HR=2.22, p In this study, we observed comparable outcomes in patients with AML in CR1 who underwent MUD transplantation and RIC with CsA+MMF or CsA alone as GvHD prophylaxis. This suggests that both strategies may be considered valid approaches. Additional randomized trials are needed to further assess which patients could benefit from the addition of MMF in GvHD prophylaxis. Disclosures Blaise: Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Socie:Alexion: Consultancy. Chevallier:Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Background High-resolution sequencing has improved prognostication of AML. A multistage model (MM), based on a knowledge bank (KB) of 1540 patients (pts) treated between 2004 and 2010, has been set up to improve outcome prediction and tailor therapeutic decision, including SCT (Gerstung, Nat Genet 2017). Validation of overall survival (OS) predictions by this KB has been reported (Huet, Blood 2018). Given progresses of SCT over the last decades, whether such a KB approach can be harnessed to personalize SCT decision in first remission (CR1) remains unclear. We addressed this question in younger AML pts treated intensively. Methods From 03/2009 to 09/2013, the multicentric ALFA-0702 study (NCT00932412) enrolled 713 pts with de novo AML aged 18-60 years old, excluding APL and CBF AML. Pts with protocol-defined non-favorable risk AML were eligible for SCT from a matched donor (Thomas, J Clin Oncol 2017). High throughput sequencing of 41 genes and ligation-dependent RT-PCR was done in 656 pts (92%). Risk stratification was assessed according to ELN 2017 (Döhner, Blood 2017). Of the 100 variables used by the MM, 3 clinical (splenomegaly, LDH and Hb levels) and 24 genetic variables (genes mutated in at most 5.3% in the KB) were unavailable. After imputation of missing data based on the KB, individualized 5y-OS predictions were done for each patient in 3 scenarios: no SCT, SCT in CR1 or SCT after first relapse, as previously described (Gerstung, Nat Genet 2017). Results Median age at diagnosis was 46 years. Median follow-up was 4.2 years. Overall, 302, 282 and 72 pts were never transplanted, transplanted in CR1 or after relapse, respectively (resp). ELN 2017 risk was favorable (Fav), intermediate (Int) and adverse (Adv) in 31%, 31% and 38% of the 647 evaluable pts, resp. 5y-OS was 77.7%, 58.3% and 42.2% in Fav, Int and Adv pts, resp (Fav versus [vs] Int P Considering SCT in CR1 as a time-dependent variable, there was a significant interaction between ELN 2017 risk and SCT in CR1 (P We investigated the ability of the KB approach to determine the subset of patients that may benefit from SCT in CR1 rather than at relapse (per Gerstung, Nat Genet 2017). An estimated 128 patients (ELN 2017 Fav/Int/Adv in 34.6%, 45.7% and 19.7%) would have a 10% improvement in 5y-OS if allografted in CR1. However, in these 128 pts, the effect of SCT in CR1 on OS did not differ from that in the other 528 pts (interaction test P=0.31). We therefore sought alternative ways to inform SCT decision based on KB predictions. The KB approach predicted a 5y-OS We next combined ELN 2017 risk and KB-predicted OS into a single rule to guide SCT decision. Only pts with both ELN 2017 Int/Adv risk and a KB-predicted 5y-OS Conclusion The Knowledge bank approach predicts OS of younger adults with AML more accurately than ELN 2017. ELN 2017 and KB risk predictions may be combined to optimize indications of SCT in CR1. Figure Disclosures Berthon: JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; PFIZER: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD. Pigneux:Jazz: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Roche: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Daichi: Honoraria; Astellas: Honoraria; Pfizer: Honoraria. Recher:Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Thomas:ABBVIE: Honoraria; INCYTE: Honoraria; DAICHI: Honoraria; PFIZER: Honoraria. Dombret:Institut de Recherches Internationales Servier (IRIS): Research Funding; CELGENE: Consultancy, Honoraria; AGIOS: Honoraria.

The combination of 2GTKI+pegylated IFN-α (Peg-IFN) is an attractive approach for first-line treatment of CP CML, inducing high rates of deep molecular responses in phase II trials. Thus, we evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82). Newly diagnosed CP CML pts ≤65 y, without prior history of arterial occlusion were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone for 30 days (M-1→M0) 30 μg/wk as priming, prior to NIL 300 mg BID + Peg-IFN 30 μg/wk 2 wks, upgraded to 45 μg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone for 4 more years unless pts enter treatment-free remission (TFR). The primary endpoint is the rate of MR4.5 by 1 y. As a secondary endpoint, pts reaching MR4.5 ≥2 y are allowed to stop NIL and enter a TFR phase in both arms. The trigger for treatment resumption is loss of MMR. All molecular assessments are centralised, quantifications are expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Two hundred pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. Median follow-up is 43.8 (34.3-55.9) Mo. Results are analysed in intention-to-treat. Sokal and EUTOS LTS scores were H in 25% and 2.5%, Int. in 33% and 16.5% and L in 42% and 81% pts respectively equally balanced. Median age is 46 (18-66) y, 18 pts (9%) had ACAs, all pts have a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (in B) and 88% of pts in A and 90.4% of pts in B at M1. CCyR rates at M3 were 63% vs 75% in A and B (p=ns), and BCR-ABL1 ≤1% at M6 were 87% in A vs 93% in B (p=ns). By M12, the rates of MMR were 68.1% vs 70.1% (p=0.44), MR4 were 34% vs 47.5% (p=0.041), MR4.5 were 15.9% vs 21.5% (p=0.049), MR5 11.7% vs 23.71% (p=0.023), in A vs B respectively. By M36 the rates of MMR were 83% vs 86.6% (p=0.31), MR4 were 70.2% vs 71.13% (p=0.50), MR4.5 were 37.2% vs 49.5% (p=0.05), MR5 33% vs 42.3% (p=0.12), in A vs B respectively The overall cumulative incidence of MR4.5 is superior in B (54.6 [43.7-65.5]%) vs A (44 [31.5-54]%) close to significance (unilateral Fisher test, p=0.05, see Figure). Seven patients were mutated by Sanger in A (5 Y253, 1 E255K, 1 T315I) vs 2 in B (2 T315I). One pt (A) progressed toward AP and then myeloid BC with a Y253H mutation, is still alive in CMR on Ponatinib. Twenty nine (29%) pts were withdrawn from study in A (toxicity 9, cancer 3, resistance 14, investigator decision 2, lost for FU 1) vs 26 (26%) pts for B (toxicity 13, resistance 8, investigator decision 5), 1 pt died from cervix cancer (A). Median overall doses of NIL delivered by M36 were 600 mg/d in both arms (p=ns). The median overall dose of Peg-IFN delivered in B by M24 was 37.5 mg/wk. The overall rate of grade 3-4 hematologic toxicities was 22%; with 2% and 7% thrombocytopenia, 4% and 6% neutropenia, and 1% and 1% pancytopenia in A vs B respectively. Major grade 3-4 non-hematologic toxicities consisted in 9% of cardiac disorders in A (2 coronaropathies, 1 myocardial infarction, 2 thoracic pains, 2 atrial fibrillation, 1 bradycardia, 1 palpitations, 1 pericarditis) vs 8% in B (2 coronaropathies, 1 myocardial infarction, 3 atrial fibrillation, 1 palpitations, 1 pericarditis), 4% vascular disorders in A (1 thrombophlebitis + PE, 1 transient ischemic attack, 1 PAOD, 1 carotid stenosis) vs 3% in B (1 thrombophlebitis, 1 PAOD, 1 transient ischemic attack). Three % of gastro-intestinal disorders were observed in A (2 pancreatitis, 1 anal fissure) vs 6% in B (2 pancreatitis, 1 anal fissure, 1 abdominal pain, 2 cholecystectomies); 5% auto-immune disorders in B (1 recurrent pericarditis, 2 hemolytic anemia, 1 ITP, 1 thyroiditis); 5 and 8 pregnancies (2 pts + 3 partner Arm 1, 3 pts + 5 partner Arm B), despite recommended contraceptive methods. Secondary tumours were diagnosed in 4% (1 breast, 1 cervix, 1 thyroid, 1 neuroendocrine) in A vs 2% of pts (1 neuroendocrine and 1 testis) in B. Of note 8% psychiatric episodes were reported in B pts (2 unsuccessful suicide attempts), vs 2% in A. We observed 9% lipase elevations in A, 6% in B, 2% cholestatic episodes in A, 6% in B; 3% of transaminase elevations in A vs 2% in B. Infections were detected in 3% A vs 7% in B. The combination of NIL + Peg-IFN seems to provide somewhat higher MR4.5 rates by M36 in newly diagnosed CP CML pts without inducing significant higher toxicities than NIL alone. Whether this will translate in higher TFR rates is under evaluation. Final updated results at M36 will be presented Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Novartis: Research Funding, Speakers Bureau; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Huguet:Servier: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Charbonnier:Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy; Pfizer: Consultancy. Legros:Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria. Coiteux:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy. Roy:Incyte Biosciences: Consultancy. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Ame:Incyte Biosciences: Honoraria, Speakers Bureau. Rea:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria; BMS: Honoraria. Dulucq:Novartis: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. OffLabel Disclosure: Pegylated Interferon alpha 2 a is not licensed in this setting

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.

Metabolic syndrome (MetS) is defined as a clustering of five factors including (1) fasting hyperglycaemia (2) hypertriglyceridaemia (3) low HDL cholesterol (4) hypertension (5) obesity (high waist circumference). According to the International Diabetes Federation harmonised definition, a large waist circumference plus any other two features meet criteria for diagnosis of MetS. It is associated with raised risk of cardiovascular disease (CVD) by 3-fold and is increasingly recognised in patients after HCT. Recent guidelines for long-term HCT survivors recommend screening for MetS. We performed a large cross-sectional service evaluation of HCT survivors in centres working in accordance with international screening guidelines. We have previously presented interim results regarding the prevalence of MetS and associated risk factors and now present the final results. This was an EBMT approved cross-sectional, non-interventional study of consecutive HCT patients (allo and auto) aged 18+ years and a minimum of 2 year post-transplant attending routine follow-up HCT and/or late effects clinics in 9 centres. Centres completed proformas incorporating routine recording of the MetS parameters (given above) as well as performance status (ECOG); evidence of cardiovascular events; family history of premature CVD; and relevant drug history. Univariate comparison of patients and HCT characteristics between the 2 groups (MetS vs no MetS) was performed using non-parametric Mann-Witney U test for continuous variables and Chi-square test or Fisher test for categorical variables. All tests were two-sided. Multivariate logistic regression analyses were performed to predict MetS and cardiovascular events. Variables with a p-value Table 1 gives the population demographic, age, primary disease and transplant details. The prevalence of MetS was 30.4% (allo 29%, auto 35.6% ns). There was a significant difference in prevalence by age at follow-up (p This large study in HCT survivors confirms high prevalence of metabolic syndrome following both allogeneic and autologous HCT of 30.4% overall rising to 39% in those aged over 50 years at follow-up. The data support MetS being an age-related late effect of HCT that is strongly associated with not only cardiovascular events but also the occurrence of second cancers. Further analysis examining the relationship between intensity of treatment and prevalence of MetS and CVE is needed. The data supports routine screening for MetS of both allo and auto HCT patients. Early intervention of reversible features of MetS with lifestyle and medical management may reduce the risk of cardiovascular events, but this needs be tested in a randomised controlled trial setting. Meanwhile, screening and management should be robustly integrated within routine HCT long-term follow-up care. Table 1. Table 1. Disclosures Cortelezzi: janssen: Consultancy; novartis: Consultancy; roche: Consultancy; abbvie: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau; Bristol Myers: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Molmed: Consultancy; Janssen: Honoraria, Research Funding, Speakers Bureau. Kroeger:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; JAZZ: Honoraria; Sanofi: Honoraria; Neovii: Honoraria, Research Funding. Snowden:Jazz & Sanofi: Other: Speaker fees at ASH; Jannssen/J&J: Other: Speaker fees.

Background. Tyrosine kinase inhibitors (TKI) are standard front-line therapy for patients with BCR-ABL1/Philadelphia positive ALL (Ph+ ALL), but the relative merits of available TKIs remain uncertain. Nilotinib is a potent inhibitor of BCR-ABL1 with broader activity against ABL kinase domain mutations than imatinib and greater selectivity than dasatinib or ponatinib. As there is a paucity of data on nilotinib as first-line therapy for Ph+ ALL, the EWALL (European Working Group for Adult ALL) conducted an international clinical trial to evaluate efficacy and safety of the combination of nilotinib with low intensity chemotherapy. Patients and Methods. After a prephase with dexamethasone (DEX) and cyclophosphamide, nilotinib (400 mg BID) was given concurrently with the same chemotherapy backbone employed in the EWALL-PH01 assessing the combination with dasatinib (Rousselot et al, Blood 2016;128:774-82). Induction consisted of nilotinib combined with weekly vincristine (VCR, 1mg iv) and oral dexamethasone 40mg 2 days (20 mg over 70y). Nilotinib was continued throughout six consolidation cycles, followed by 24 months maintenance therapy with nilotinib, 6-MP, MTX and DEX/VCR boosts. Stem cell transplantation (SCT) was permitted as considered appropriate. BCR-ABL1 RTQ-PCR and kinase domain resistance mutations were centrally monitored. Primary endpoint was event-free survival (EFS) at 12 months, secondary endpoints included rates of CR, major and complete molecular response, relapse free survival (RFS), EFS and overall survival (OS). Results. 72/79 enrolled pts. were evaluable for response, 3 withdrew consent, 4 did not meet eligibility criteria. Median age was 65.5 (55-85) years, male/female ratio 0.85, ECOG status 0 or 1 in 89% of pts., median CIRS comorbidity score 5(0-19). Baseline vascular risk factors including high blood pressure (grade ≥2) were present in 36% of pts.. Sixty-eight of 72 pts. (94.4%) achieved CR, one died during induction and one was refractory, 2 pts. discontinued study therapy. Non-hematologic adverse events (AE) grades 3/4 during induction (in ≥ 5% of pts. irrespective of causality) included infections (n=20), elevated transaminases or bilirubin (n=18) and gastrointestinal AEs (n=12). The spectrum of AEs was similar during consolidation, without concerns related to cardiovascular events. 24 pts. (61y; 55-69y) underwent allogeneic (9 MUD, 12 SIB, 3 Haplo) and 3 autologous SCT. 21 pts. received reduced intensity conditioning (including 8Gy TBI, n=11) regimens. Among all pts., relapse was the main cause of treatment failure (n=23; 17 BM, 2 CNS, 3 other sites, 1 na), 11 pts. died in CR (6 after HSCT), 34 are in ongoing CR. Based on Kaplan Meier analysis, EFS (events being resistant disease, relapse or death) at 12 months was 74%, with median follow-up of 39 (24-66) months for surviving pts., EFS and OS at 4 years was 42%, and 47%, respectively. By landmark analyses using median time to HSCT as cutoff, cumulative incidence of relapse in transplanted vs. non-transplanted pts. was 32% and 47%, OS at 4 years was 61% and 39%, median OS was not reached versus 3.6 years, respectively (p=ns). The proportion of pts. with a BCR-ABL1/ABL1 ratio ≤0.1% increased from 41% after induction to 86% after consolidation 2; that of pts. with undetectable or non-quantifiable BCR-ABL1 transcripts (sensitivity ≥10-4) increased from 14% to 58%. Conclusions. Nilotinib combined with low-intensity chemotherapy is well tolerated and highly effective in elderly pts. with Ph-positive ALL. OS and EFS compare favorably with previous similar studies testing imatinib or dasatinib. With 32% of pts. undergoing allogeneic HSCT and 61% survival at 4 years, transplantation is a viable option in this elderly cohort of pts.. Disclosures Ottmann: Celgene: Consultancy, Research Funding; Novartis: Consultancy; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Fusion Pharma: Consultancy, Research Funding. Pfeifer:Novartis: Research Funding. Cayuela:Cepheid: Other: financial sponsor to attend John Goldman Conference 2017. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Sanhes:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goekbuget:Pfizer: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Celgene: Consultancy; Kite / Gilead: Consultancy; Amgen: Consultancy, Other: Travel support, Research Funding. Dombret:Jazz Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Ambit (Daiichi Sankyo): Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Ariad (Incyte): Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Shire-Baxalta: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Cellectis: Consultancy, Honoraria, Other: Travel expenses; Otsuka: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau.

Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative option for acute myeloid leukaemia (AML). A major improvement of conditioning regimen has been realized in the last two decades, offering the opportunity for older patients to undergo HSCT with an acceptable toxicity profile. Unfortunately, relapse remains the main cause of death, and only few studies analyzed the survival of patients presenting with post-HSCT AML relapse and their treatment options. The purpose of this study was to analyze the survival of patients with post-HSCT AML relapse, to describe the treatment options and to search for factors associated with poor prognosis at relapse. In this study, we collected the data of all the patients transplanted between January 2005 and December 2014 at Bordeaux university centre and showing AML relapse after HSCT. Between 2005 and 2014, out of 312 HSCT for AML, one hundred patients relapsed at our center with a median time from transplant of 123.5 days (11-2726 days). Median age was 55 years old (range 17-65), 44 patients were male. Donors were matched related for 49 patients, unrelated for 35 patients, and cord blood units were used in 16 patients. Conditioning regimen was reduced for 70 patients and myeloablative for 30 patients. According to the Disease Risk Index, 4 patients were considered at low risk, 29 patients at intermediate risk, 43 patients at high risk and 11 patients at very high risk. Thirty one per cent of patients had refractory disease. Before relapse, 31 patients developed Acute Graft Versus Host Disease (GVHD) and 9 patients developed Chronic GVHD. At relapse, 62 patients were still on cyclosporine and 22 on steroids. Eighty four patients presented an isolated bone marrow relapse, while 5 patients showed isolated extramedullary relapse, and 11 mixed relapse. With a median follow-up from relapse of 106 days (0-3619 days), the 1 and 2-year overall survival (OS) were 24% and 13%, respectively. At final follow-up 8 patients were still alive. For alive patients, median follow-up from relapse was 1524 days (980-3619 days). Median age was 39 years old (20-57 years old), DRI was considered at intermediate risk for 2 patients, at high risk for 5 patients and at very high risk for 1 patient. No patient was FLT3 mutation. In univariate analysis, factors associated with better OS at relapse were age < 45 years old, male gender, performance status at relapse > 70%, and no initial FLT3 mutation. Male gender, performance status at relapse, early relapse and no initial FLT3 mutation were associated with a better OS in multivariate analysis. Seven patients responded to immunosuppression tapering and 19 patients to first line treatment containing local radiotherapy, chemotherapy and/or Donor Lymphocyte Infusion (DLI). Developing GVHD after immunosuppression tapering or DLI was associated to disease response: Seven patients responded after immunosuppression only of whom 4 after developing GVHD (p=0.0013). Twelve patients responded after DLI of whom 7 after developing GVHD (p=0.05). Patients receiving an association of chemotherapy and DLI showed a better response and a better survival compared to chemotherapy only (p= 0.03). Patients with FLT3 mutation did not respond to any treatment. This study confirms the severity of AML relapse after HSCT with a poor long term OS. The particularly poor impact of FL3 mutation suggests the use of targeted therapy in a prophylactic setting. Immunomodulatory approaches resulted in disease response in some patients and should be evaluated prospectively to identify clinical and biological factors predictive of the response. Disclosures No relevant conflicts of interest to declare.

Prognosis of graft failure patients is dismal, and another transplant is the sole option for long-term survival. Currently, there is no consensus concerning the best option for treating patients undergoing primary graft failure and finding a new donor within an acceptable delay is challenging. In the last years, haploidentical transplants with post-transplant cyclophosphamide (PT-Cy) have shown acceptable results in the treatment of many hematological diseases, including some cases of graft failure. To address the interest of haploidentical transplants as a salvage option in this context, we retrospectively collected and analyzed data from 26 primary graft failure (PGF) patients transplanted between 2011 and 2017 in 15 centers belonging to the Francophone Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Inclusion criteria were the occurrence of PGF defined as non-achievement of a minimum absolute neutrophil count of 500/μL without evidence of disease relapse at D+28 after transplantation and the use of a haploidentical transplantation with PT-Cy as graft-versus-host-disease (GvHD) prophylaxis. Continuous variables are presented as medians and inter-quartile range. They were compared between groups using the Wilcoxon rank sum. Categorical variables are presented with counts and percentages and were compared using the Fisher exact test. All tests were 2-sided, and a p-value below 0.05 was considered to be significant. Analyses were performed using the R statistical platform (version 3.4.1). This study was performed according to the Declaration of Helsinki and was approved by the SFGM-TC scientific council. Nineteen patients had a diagnosis of myeloid malignancy (8 acute myeloid leukemias, 4 myelodysplastic syndromes, 4 myeloproliferative neoplasms, 1 unclassified myeloid disorder), 3 had a lymphoid neoplasm, and 4 had a bone marrow failure syndrome (2 acquired and 2 congenital). Twenty-four patients had previously received an allogeneic transplantation, and 2 had already failed two previous allogeneic transplants. Male/female ratio was 2.25. Median age at haploidentical transplant was 42 years (2-58). Fifteen patients received peripheral blood as stem cell source, and 11 received bone marrow. Eleven transplants were female to male. Twelve patients received an ABO-matched graft, 6 had a major ABO-incompatibility, 7 a minor incompatibility and one missing data. The median number of infused CD34+ cells was 5.2 x106/kg (1.2 - 12.5). There was no ex-vivomanipulation of cells. CMV matching was available for 22 transplantations, of which 6 were high-risk (seropositive recipient with a seronegative donor). Fludarabine-based reduced intensity conditioning was used in all but one patient who received clofarabine + 4Gy TBI. Twenty patients received TBI 2Gy. Three patients received ATG. Fourteen patients received the Baltimore regimen (53%). The median delay between the previous and the salvage transplantation was 77 days (39-1161). All patients received PT-Cy associated with cyclosporine, and 24 patients also received MMF for GvHD prophylaxis. Median follow up was 487 (16-2010) days. The cumulative incidence (CI) of neutrophil recovery at day 30 was 81%, and the median time to neutrophil engraftment was 19 (13-34) days. Four patients (15%) presented primary graft failure and died within a median time of 5 (3-8) weeks after transplantation of infectious complications. Cumulative incidence of grade II-IV aGvHD at day-100 was 13%, and 1-year CI of cGvHD was 32%. One-year CI of relapse was 16%. Overall survival was 58% at 1 year (Figure 1; confidence interval: 39-85). Among the 22 patients who engrafted, 6 patients died. HSCT complications accounted for 80% of the causes of deaths (4 multiorgan failure, 1 GvHD, 1 interstitial pneumonitis, 1 bacterial infection, 1 post-transplant lymphoproliferative disorder). To the best of our knowledge, this is the first cohort describing the outcomes of haploidentical transplants with PT-Cy rescuing patients with primary graft failure. Our cohort presents promising outcomes in a particularly challenging situation, suggesting that haploidentical transplants with PT-Cy might appear as a valid salvage strategy for patients with PGF. Prospective well-designed trials are urgently needed before the inclusion of Haplo-PT-Cy in the treatment strategy of patients with PGF. Figure 1. Figure 1. Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria. Peffault De Latour:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Background We previously demonstrated that the combination of Nilotinib (NIL) + Pegylated IFN-a2a (Peg-IFN) is able to induce high deep molecular response rates in chronic phase CML (CP CML) patients, as first-line therapy (Nicolini FE et al., Lancet Haematol. 2015). Aims Assessment of the molecular responses obtained with the same combination vs NIL alone prospectively, in newly diagnosed CP-CML. (EudraCT 2013-004974-82). Methods Patients (pts) ≤65 years with no history of arterial damage were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone (± HU) for 30 days (M-1 to M0) 30 mg/wk as a priming, prior to a combination of NIL 300 mg BID + Peg-IFN 30 mg/wk 2 weeks, upgraded to 45 mg/wk thereafter if proper tolerance for up to 2 years (M0 to M24, arm B) followed by NIL alone for 2 more years. The primary endpoint was the rate of molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised, quantifications were expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Results Two hundred and one pts were randomized (100 in arm A, 101 in arm B), 65 males in both arms, 35 females in arm A, 36 in arm B. The median follow-up is 20.6 (9.1-34.7) months. Results are analysed in intention-to-treat. Sokal scores were high in 25%, intermediate in 36% and low in 39% of pts; Euro scores were high in 13%, intermediate in 44% and low in 43% of pts; Eutos LTS scores were high in 2%, intermediate in 17%, and 81% low; equally balanced in the 2 arms The median age was 46 (18-66) years, equally balanced. Eight (4%) pts had a cryptic Philadelphia chromosome, 12 (6%) a variant form, and 15 (7.5%) had ACAs, all pts had a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (arm B) and in 88% of pts in arm A and 90.4% of pts in arm B at M1. The rates of CCyR at M3 were 63% vs 65% in arms A and B, and BCR-ABL1≤1% at M6 were 83% in arm A vs 86% and arm B, on evaluable samples. The incidence of molecular responses are shown in Fig. 1. Of note, 90% of the pts had a BCR-ABL1 ≤10% at M3 in arm A vs 84% in arm B (p=ns). By M12, the rates of MMR were 69.9% vs 72.4% (p=0.079), MR4 were 34.65% vs 47.9% (p=0.094), MR4.5 were 17.9% vs 24.11% (p=0.272), MR5 12.1% vs 22.31% (p=0.075), in arm A and arm B respectively. Data from 11 pts in arm A and 16 in arm B at M12 are still pending. Definitive results at 1 year will be presented. One pt progressed toward accelerated phase in arm A with a Y253H mutation. Fifteen pts were withdrawn from study in arm A (toxicity 5, other cancer 2, failure 8) and 12 patients from arm B (toxicity 6, failure 6), no pt died. Interestingly, 5 mutated (ie. failure) pts were found in arm A (3 Y253H, 1 E225K, 1 F317L), vs only 1 pt (T315I) in arm B. The median dose of Peg-IFN delivered in arm B during the first month is 30 (0-30) mg/wk, 30 (0-45) mg/wk at M2, 45 (0-45) mg/wk at M3, 37.5 (0-45) mg/wk at M6, 30 (0-45) mg/wk at M9 and 12. The median doses of NIL delivered were 600 mg daily at M2, 3, 6, 9, 12 as initially planned in both arms. The rate of grade 4 hematologic toxicities overall was 15%, with no anemias, 1% and 4% thrombocytopenias, 3% and 4% neutropenias, 0% and 1% leucopenias, and 0 and 1% pancytopenias in arms A and B respectively. Grade ¾ non-hematologic toxicities consisted in 4% of cardiac disorders in arm A (1 coronaropathy, 2 thoracic pains and 1 atrial fibrillation) vs 1% in arm B (palpitation), 2% vascular disorders in arm A (1 pulmonary embolism, 1 transient ischemic attack) and 1% in arm B (PAOD). Three % of gastro-intestinal disorders in arm A (resolutive pancreatitis) vs 1% in arm B (anal fissure); 1% of skin disorders in arm A; 2% auto-immune disorders in arm B (1 recurrent pericarditis, 1 hemolytic anemia); 2 and 5 pregnancies (of the partner except 1) were observed in arm A and B respectively, despite recommended contraceptive methods. We observed 10% lipase elevations in arm A, 3 in arm B, 2% cholestatic episodes in arm A, 1% in arm B; 1% of transaminase elevations in each arm. There were 2% depressive episodes in arm B, 1% in arm A; infections were detected in 1% arm 1 and 3% in arm B. Finally 3 intercurrent cancers were detected in arm A (cervix, breast, thyroid). Conclusion The combination of NIL + Peg-IFN seems to provide slightly deeper molecular responses rates (especially MR5) by M12, but so far not significantly, in newly diagnosed CP CML pts without increasing the rate of more frequent early SAEs in such a setting. Definitive results at M12 will be updated for the meeting. Disclosures Nicolini: BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Etienne: Incyte: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Research Funding. Guerci-Bresler: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Charbonnier: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Legros: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Coiteux: Incyte: Speakers Bureau; BMS: Speakers Bureau. Cony-Makhoul: BMS: Speakers Bureau. Rousselot: Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding. Guyotat: BMS: Speakers Bureau. Ianotto: Novartis: Other: Grant. Rea: BMS: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Mahon: Pfizer: Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin's lymphoma (HL), in particular those having failed a previous autologous SCT (ASCT). When an HLA-matched donor is lacking, a graft from a haploidentical donor (HAPLO), a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective, registry-based study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from a HAPLO, MMUD or CB graft. After detailed review of our database, we found 98 consecutive patients with HL who underwent a NMA/RIC allo-SCT from an alternative HLA-mismatched donor at 24 French and Belgian centers between January 2009 and December 2014. Probabilities of overall survival (OS), event-free survival (EFS) and graft-versus-host disease (GVHD)-free Relapse-free Survival (GRFS) were determined using the Kaplan-Meier method. The cumulative incidences of relapse (CIR), non-relapse mortality (NRM) and cGVHD were studied using a competing risk methodology. We defined GRFS as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD (all grades included). Regarding conditioning regimens and intensity, patients in the HAPLO group (n = 34) received a T-cell replete allo-SCT after a NMA (as described by the Baltimore group in Luznik et al, Biology of Blood and Bone Marrow Transplantation, 2008, n = 31, 91%) or a RIC (n = 3, 9%) followed by post-transplant cyclophosphamide (PT CY). Patients in the MMUD group (n = 27) received a variety of NMA (n = 7, 26%) and RIC (n = 20, 74%). All patients in the CB group received a RIC (n = 37, 37%). All but one patient (n = 33) in the HAPLO group received the following GVHD prophylaxis: Cy 50 mg/kg on day +3 and day +4, tacrolimus or CsA and mycophenolate mofetil started on day +5. One patient received only one day of PT CY 50mg/kg at day +3 and also received ATG on day -2 and day -1 for a total dose of 5mg/kg. GVHD prophylaxis for MMUD consisted of CsA or tacrolimus, started on day -3 or day -1 in all patients according to local practice with either mycophenolate mofetil (n = 25, 89%) or methotrexate 15 mg/m2 at day +1, 10 mg/m2 at day+3 and day +6 (n = 3, 11%). GVHD prophylaxis consisted of CsA and mycophenolate mofetil starting on day -3 for all CB patients. Median age at allo-SCT was 28 (range: 16-68). The median number of treatments before allo-SCT was 4 (range: 3-6). An ASCT had been performed prior to allo-SCT in 77% (n = 26), 100% (n = 28%) and 100% (n = 37) of cases in the HAPLO, MMUD and CB group, respectively. Disease status at allo-SCT per Cheson 1999 criteria was complete remission in 51% (n = 51), partial response in 32% (n = 31), stable or progressive disease in 11% (n = 11), while no data was available in 5% (n = 5). Positron emission tomography was positive at allo-SCT in 45% (n = 44), negative in 43% (n = 43) while no data was available in 12% (n = 12). Median follow-up was 31 months (range: 3 - 79). In univariate analysis we observed a significantly higher probability of GRFS in patients who received a HAPLO allo-SCT (52% versus 22% and 31% at three years in the HAPLO, CB and MMUD groups, respectively, p = 0.02, Logrank test). Higher GRFS was also observed in patients receiving a NMA conditioning compared to a RIC (50% versus 27% at three years, p = 0.009, Logrank test). We did not observe significant differences in OS, EFS or NRM, according to donor type. Disease status at allo-SCT significantly impacted OS (p In conclusion, significantly higher GRFS was observed in HL patients receiving a haploidentical NMA/RIC T-cell replete allo-SCT with PT CY. How this separation of the GVH from the graft-versus-lymphoma effect occurs requires further investigations. Haploidentical NMA/RIC T-cell replete allo-SCT with PT CY for advanced HL should now be compared with NMA/RIC allo-SCT from related and unrelated HLA-compatible donors, ideally within prospective trials. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Peffault De La Tour:ALEXION: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding.

Background Many patients with relapsed or refractory Hodgkin's lymphoma (HL) undergo high-dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT). However, most large reports include patients treated in the 90's. We aimed to analyze the outcome of a HL patients treated in the last decade with HDC and auto-SCT in a large cohort study. Patients and methods In the setting of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, we retrospectively analyzed 1987 consecutive adult patients (age < 65 years) with biopsy-proven HL who received a first auto-SCT between 2003 and 2014. Results Median age at auto-SCT was 33.7 years (range, 18-65) and 60% patients were male. Disease status at transplant was complete remission in 1040 patients (52%), partial response in 727 (37%) and progressive disease in 220 (11%). The main conditioning regimen was BEAM (Carmustine-Etoposide-Cytarabine-Melphalan, n=1497). At one month, cumulative incidence of neutrophil engraftment was 97.6% (95% CI 96.8-98.2), whereas cumulative incidence of death without engraftment was 0.2% (95% CI 0.07-0.5). After a median follow-up of 16.4 months (IQR, 4.4-47.2), 3-year overall survival (OS), disease-free survival (DFS), cumulative incidences of relapse (IR) and non-relapse mortality (NRM) were 80.4% (95% CI 78.1-82.9), 59% (95% CI 56.1-62), 35.9% (95% CI 33.1-38.7) and 5% (95% CI 3.9-6.4), respectively. There was no significant difference in terms of outcome between patients treated during the time period 2003-2008 and 2009-2014. 3-year OS and DFS were 70.5% and 43.7% in patients with progressive disease at transplant, 75% and 52.1% in patients in partial response, 87.2% and 67.8% in patients in complete remission (p Conclusion In conclusion, HDC followed by auto-SCT is highly efficient in relapsed HL patients. However, relapse occurs in over 40% of patients < 35 years old or with partial response at transplant and in over 50% of patients with progressive disease at transplant or ≥ 3 previous treatment lines. Additional data are being collected to better identify which high-risk patients could benefit from post-transplant immunotherapy or tandem auto-allo transplant. Disclosures Brice: Roche: Honoraria; Bristol Myers-Squibb: Honoraria; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Seattle Genetics: Research Funding; Gilead: Honoraria. Salles:Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria. Peffault De Latour:PFIZER: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding.

Purpose: The FB2A2 (fludarabine, intermediate doses of busulfan and ATG) reduced-intensity conditioning (RIC) regimen is considered as a standard RIC regimen in many centers worldwide. Recently, we have reported the prospective good results of a clofarabine-busulfan containing RIC regimen (CloB2A2) in adults with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in complete remission (CR) at time of transplant (Chevallier et al, Haematologica, 2014). Thus, this regimen may prove to be superior to the FB2A2 regimen in patients with AML/MDS. Patients and Methods: The aim of this study was to compare outcomes between adult AML/MDS patients who have received, between 2009 and 2015, in 26 French centers, either a FB2A2 RIC regimen (n=170, male 61%, median age: 58 years, AML 86%, CR1 79%) or the CloB2A2 RIC regimen (n=39, including the 16 cases treated within the prospective trial mentioned above, male 62%, median age: 61 years, AML 62%, CR1 64%). The FB2A2 and CloB2A2 regimens consisted of either 30 mg/m²/day Fludarabine for 5 days or 30mg/m²/day Clofarabine for 4 or 5 days, each combined with 3.2 mg/kg/day Busulfan for 2 days and 2.5 mg/kg/day Anti-thymocyte globulin (ATG, Thymoglobuline) for 2 days. As GVHD prophylaxis, cyclosporine (CsA) alone was used in case of related donor in both groups, and for the 16 CloB2A2 patients treated within the prospective trial, while CsA+ MMF were used in case of unrelated donors. The two groups were not statistically different in term of gender, median age and performans status at transplant, median white blood count at diagnosis, median time between diagnosis and transplant, type of donors or cytogenetics for AML patients. Conversely, there were more AML patients (86% vs 62%, p=0.0004) and more patients in CR1 (79% vs 64%, p=0.04) in the FB2A2 group. Also, CloB2A2 patients were transplanted more recently (median year of transplant: 2014 vs 2011, p Results: All patients engrafted, except one in the FB2A2 group. Median time of neutrophils recovery was similar between both groups (FB2A2: 17 days vs CloB2A2: 18 days, p=0.10). With a median follow-up of 28 and 14 months in the FB2A2 and the CloB2A2 groups, respectively, 2-year overall survival (OS) were 59% (51.4-66.7) for the former vs 77% (62.8-91.1) for the latter, p=0.07, 2-year leukemia-free survival (LFS) were 52.7% (44.9-60.4) vs 64% (48.1-79.9), p=0.23, 2-year relapse incidence were 31.1% (24.2-38.4) vs 27.5% (14-42.9), p=0.58, 2-year non relapse mortality were 16.2% (5.8-31.3) vs 8.5% (2.1-20.7), p=0.26 and 2-year chronic GVHD were 13.8% (8.3-20.5) vs 23.9% (8.1-44.2), p=0.12. Incidences of grade 2-4 or grade 3-4 acute GVHD were similar between both groups: FB2A2 22% vs CloB2A2 23%, p=0.86,and 8% vs 3%, p= 0.31. In multivariate analysis, FB2A2 RIC regimen was significantly associated with lower OS and LFS (HR: 2.45; 95%CI: 1.08-5.55, p=0.03; and HR: 2.32; 95%CI: 1.12-4.79, p=0.02) contrary to CR1 status which was associated with significant higher survivals (HR: 0.48; 95%CI: 0.28-0.83, p=0.008 and HR: 0.42; 95%CI: 0.25-0.70, p=0.001). MDS (HR: 1.88; 95%CI: 1.03-3.43, p=0.03) and higher WBC at diagnosis (>median) (HR: 1.76; 95%CI: 1.10-2.82, p=0.01) were also significantly associated with lower LFS. However, when considering AML and MDS patients separately, benefit of CLOB2A2 RIC regimen appears to be restricted to AML patients (2-year OS FB2A2: 58.1% vs CloB2A2: 80.2%; HR: 2.45; 95%CI: 1.08-5.55, p=0.03; and 2-year LFS FB2A2: 53.6%, vs CloB2A2: 76.9%; HR: 2.32; 95%CI: 1.12-4.79, p=0.02). Conclusion: Thisretrospective comparison suggests thattheCloB2A2 RIC regimen can likely provide a higher survival compared to the use of a FB2A2 RIC regimen for AML patients. A prospective phase 3 randomized study is warranted. Disclosures Deconinck: JANSSEN: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; ALEXION: Other: Travel for international congress; ROCHE: Research Funding; PFIZER: Research Funding; CHUGAI: Other: Travel for international congress; LFB loboratory: Consultancy. Mohty:Janssen: Honoraria; Celgene: Honoraria.

Introduction: 60-70% of AML patients have an indication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) during their treatment. Among those who undergo allo-HSCT, prognosis and quality of life depended on presence or absence of graft versus host disease (GvHD). Immune stimulation supports the principle of GvHD and graft versus leukemia (GvL) after allo-HSCT. The impact of immune activation prior to allo-HSCT on the pathogenesis of GvHD has never been evaluated. The aim of this study was to determine whether immune stimulation induced by infection or drug toxicity before transplantation increased the incidence of acute GvHD (aGvHD) in AML patients. Materials and methods: 345 AML patients were transplanted in first complete remission (CR) in 21 French centers from 2009 to 2013 after prospectively enrollment in the ALFA-0702 trial (patients aged 18-60y, de novo AML, favorable-risk AML excluded). Clinical data (skin, gut and liver infections or drug toxicities) before allo-HSCT were collected from the ALFA database and clinical data (skin, gut and liver aGvHD) after allo-HSCT were collected from the SFGM-TC database (ProMise). GvHD grading was defined according to Glucksberg criteria. Infection and drug toxicity grading was defined according to CTCAE v4.0. Mann-Withney and Kruskall-Wallis tests were used for continuous variables. Chi-square test was used for non-continuous variables. Overall survival (OS) and progression free survival (PFS) were assessed by Kaplan Meier method. Results: Median age at transplant and M/F sex ratio were 45 years (range, 19-61) and 195/150, respectively. Cytogenetics was intermediate-1, intermediate-2 and unfavorable in 24, 164, 144 patients according to ELN classification, respectively. 82.5% of the patients had reached CR after one cycle of induction. 193 (53%) patients presented infections during induction and 46 (17%) during consolidations. Moreover, 110 (30%) patients suffered from drug toxicity during induction and 36 (10%) during consolidations. Allo-HSCT was performed in all patients after one to three cycles of consolidation. 132 (36%) patients received reduced intensity conditioning. Sex matching was female in male for 74 (21%) patients. ABO matching was matched for 187 and mismatched for 158 patients. HLA matching was related for 138 and unrelated for 198 patients. Source of graft was bone marrow, peripheral stem cell and cord blood in 108, 217 and 12 patients, respectively. 181 (47%) patients underwent aGvHD, most frequently skin aGvHD (stage 1-2: 27.5%; stage 3-4: 9.5%). First, we observed a significant increase of incidence of aGvHD (all grades) if skin toxicities occurred during induction (45/57% for no toxicity and toxicities all grades, respectively p=0.07) or consolidations (46/70% for no toxicity and toxicities all grades, respectively p=0.04). Secondly, we observed a significant increase of skin aGvHD in cases of skin toxicities during induction [stage 0/1-2/3-4 skin aGvHD: 66/27/7% and 47/32/21% for no toxicity and toxicities all grades, respectively (p=0.001)] or consolidations [stage 0/1-2/3-4 skin aGvHD: 64/28/8% and 35/35/30% for no toxicity and toxicities all grades, respectively (p Conclusion: Skin immune stimulation induced either by infections during consolidations or by drug toxicity during induction and/or consolidations significantly increased the incidence of skin aGvHD. Nevertheless, we found no impact on OS and PFS in our cohort. Our results confirm the participation of inflammatory process in the physiopathology of GvHD. These data should be confirmed in a larger study to determine whether patients with prior infection and/or drug toxicity to allo-HSCT should receive different GvHD prophylaxis strategies. Disclosures Deconinck: PFIZER: Research Funding; ALEXION: Other: Travel for international congress; JANSSEN: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; LFB loboratory: Consultancy; ROCHE: Research Funding; CHUGAI: Other: Travel for international congress.

Introduction Reduced intensity conditioning (RIC) allogeneic stem cell transplantation (ASCT) remains a valuable and potentially curative strategy in high-risk CLL. Post-ASCT relapse remains an important (30-40%) cause of failure, predicted by persisting positive minimal residual disease (MRD) at 12m post-ASCT. ASCT is also associated with a toxic mortality and with the burden of chronic graft versus host disease (cGVHD). We evaluated the efficacy and safety of a preemptive immunointervention (PrIm) based on serial MRD assessment in high-risk CLL. (NCT01849939) Methods Main inclusion criteria were (1) EBMT criteria for ASCT, (2) CLL in PR/CR, (3) mass ≤5cm, (4) age ≤70, (5) SORROR score ≤2 and (6) HLA donor (10/10). RIC regimen included fludarabine 120 mg/m2, IV busulfan 6.4 mg/kg, rabbit ATG 5mg/kg and CsA prophylaxy. Centralized 10-color flow cytometry blood MRD was assessed before and at M1, M2, M3, M4, M5, M6, M9 and M12 post-ASCT. MRD[-] was defined by blood detection Results As of 2015, August the 1st, the 43 planned inclusions have been done. Before their last line prior to ASCT, pts had: (a) presence of a del(17p) in 1st line (n=24) or in relapse (n=3), (b) absence of del(17p) but relapse ≤2y post fludarabine-based combination (n=14) or post-autologous transplantation (n=1). At time of transplantation, 11/43 (26%) had achieved CR, 28/43 (65%) had achieved PR, 2/43 (5%) had SD with 2 unknown status. Six patients had undetectable MRD (limit of detection: 5x10-6). For the 37 other patients, the median pre-ASCT MRD level was 2.35%(0.014 to 70%). The results of these 43 pts will be available in December 2015. This abstract describes the outcome of the 30 first consecutive pts including 26 pts evaluable [alive with ≥12m post-ASCT follow-up] and 4 pts non evaluable [death at M10 (n=1; sepsis) and at M8 (n=1 GVHD), EBV induced lymphoproliferation (n=1) and immediate graft rejection (n=1)], all included in the ITT analysis. In the 29 pts with full engraftment, the full blood chimerism at 3m and 12m was 99.1[62.1 ;99.8] and 99.5[59.4 ;99.9], and the T-cell specific chimerism was 99.2[5.2;99.8] and 99.6[21.1;99.8], with 30% and 25% >95% donor derived CD3+ cells respectively. MRD evolution followed different patterns (Table 1). At the M3 checkpoint, among evaluable patients, 10 were already MRD[-], and 16 were still MRD[+]. Then 10 pts became MRD[-] and 6 remained MRD[+]. This approach achieved 67% blood MRD[-] at M12 (ITT). When early CSA T&D had failed DLI done in 6 pts did not achieve MRD negativity. Finally, 6 pts (20%) remained MRD[+] at 12m. At 12m FU, the rate of Gr≥2 aGVHD was (11/30) 37% (consecutive to early CsA T&D in 2 pts and to early CsA T&D followed by DLI in 1 pt) and the rate of extensive cGVHD was (5/29) 17% (consecutive to CsA T&D in 1 pt). Hence we observed the occurrence of Gr≥2 aGVHD and extensive cGVHD in 2/8 and 1/8 pts after early CsA T&D. We also observed one case of Gr≥2 aGVHD among the 6 pts who had early CsA T&D followed by DLI. Eighteen severe adverse events were reported, including the 2 aforementioned deaths. These events were not related to the study procedure (PrIm). Discussion These preliminary data highlight the feasibility, safety and efficacy of a standardized PrIm strategy in high-risk CLL. As DLI appears to have limited impact when CsA T&D fails, the preemptive use of new agents should be considered at this point for persistent MRD[+] after 3-6m post-ASCT. Table 1. Table 1 M12 MRD N % MRD[-] pre-ASCT remaining MRD[-] [-] 2 7 MRD[+] (M1-2) spontaneously translating to MRD[-] within 3m [-] 8 27 MRD[+] (M1-3) translating to MRD[-] after early CsA T&Dconcomitant of severe GVHD (≥G2 aGVHD and/or ext cGVHD) [-] 10 8 2 33 MRD[+] (M1-3) remaining MRD[+] despite early CsA T&D followed by DLIdespite early CsA T&D, transient MRD[-], relapse and DLI [+] 6 5 1 20 Non evaluable: toxic deaths (2), EBV LPD (1), graft rejection (1) NE 4 13 Disclosures Tournilhac: GSK: Other: Travel Support, Research Funding; Mundiphrama: Honoraria, Other: Travel Support, Research Funding; Celgene: Other: Travel support; Roche: Other: Travel support, Research Funding; Janssen Cilag: Honoraria, Other: Travel support; Gilead: Other: Travel Funding.

Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for malignant and non-malignant diseases. The late complications in the myeloablative setting, including secondary malignancies (SM), have been reported in several studies. For example, the CIBMTR reported a 10-years cumulative incidence (CI) of 1%. The recent development of reduced intensity conditioning (RIC) for older patients has dramatically increased the number of HCT. Because they are typically performed in older patients, the analysis of post-transplant SM in this population is of particular interest. However, reported data are scarce in this specific population in the RIC setting. As a consequence, we performed a single center retrospective study to assess the risk of SM with extended follow-up in patients transplanted after a RIC regimen. Patients transplanted at our center for a hematological malignancy after a RIC regimen between 01/01/2000 and 12/31/2012 were screened. The analysis was performed in the subgroup of patients alive and disease-free 2 years after transplant. Probabilities of overall survival (OS) were calculated from using the Kaplan-Meier estimate. Non-relapse mortality (NRM) included all causes of death without prior relapse, occurring at any time after transplant. All probabilities were calculated from the date of transplantation. CI curves were used for NRM and SM in a competing risk setting with relapse as a competing event for NRM and death for SM. The analysis of risk factors for SM was performed using the Fine and Gray model. Five hundred and six patients were transplanted after a RIC regimen during the period of study. Among them, 223 were alive and disease-free at 2 years and thus included in the study. The median follow up was 73 months (24.3; 173). The median age was 55 years (18; 67). The characteristics of patients, diseases and transplants are summarized in Table 1. The 5-year OS was 85.3 % (CI 95%: 80.3 - 90.6) (Figure1). The 5-year OS in the no SM vs SM groups were 85% vs 83.5% while the 10-year OS in the same groups were 79.4% vs 33.3%, respectively, (p=0.0052). Thirty-eight patients died: 11 of relapse, 7 of SM, 15 of chronic GVHD or infection, 2 of vascular complications, 2 of unknown causes and one of suicide. Twenty-five patients developed a SM (excluding non-melanoma skin cancer) at a median time of 63.7 months (13.57; 172) after transplant. The 5 and 10-year CI of SM were 6.4%±1.7% and 18,7%±3.9%, respectively (Figure 2). The SM were distributed as follow: lung cancer (n=5), squamous cell carcinoma (1 throat, 1 tongue and 1 sinus), oesophageal cancer (n=3), colon cancer (n=2), Hodgkin lymphoma (n=2), bladder cancer (n=2), prostate cancer (n=2), melanoma (n=1), ovarian cancer (n=1), endometrial cancer (n=1), sarcoma (n=1), glioblastoma (n=1) and an unknown primary cancer (n=1). Multivariate analysis identified CMV seropositivity of donor and/or recipient (HR 4,4, p=0,016), non-sibling donor (HR 2,7, p=0,01) and a female donor for a male recipient (HR 2,7, p=0,012) as risk factors for SM. In conclusion, we report a high incidence of SM as a late complication of HCT in patients with a median age of 55 years after an extended follow-up. This result strongly suggest that older patients should be carefully followed for a prolonged period after HCT and that attention must be paid to usual recommended screening tests and classical risk factors like tobacco and alcohol. Table 1 . Characteristics of patients, diseases and transplants (n=223) Value Median age (years) (range) 55 (18; 67) Gender Male Female 133 (60%) 90 (40%) Diseases AML ALL MDS CML MPD NHL HL CLL MM SAA 89 (40%) 12 (5%) 18 (8%) 2 (1%) 2 (1%) 38 (17%) 9 (4%) 11 (5%) 29 (13%) 13 (6%) Status at transplant Early stage Advance stage 106 (48%) 117 (52%) Prior autologous transplantation 85 (38%) Conditioning regimen Fluda + Bu 2 days TBI 2Gy + Fluda Fluda + Cy + TBI 2 Gy Cy + TBI 2Gy Other 133 (60%) 33 (15%) 24 (11%) 12 (5%) 19 (9%) Source of stem cell BM PBSC CB 20 (9%) 179 (80%) 24 (11%) Rabbit ATG ATG No ATG 156 (70%) 67 (30%) Donor HLA-identical sibling Matched related donor Matched unrelated donor Cord blood 105 (47%) 69 (31%) 25 (11%) 24 (11%) Prophylaxis of GVHD CsA CsA + MTX CsA + MMF 70 (31%) 82 (37%) 71 (32%) Period of transplant 2000-06 2007-12 87 (39%) 136 (61%) Download : Download high-res image (59KB) Download : Download full-size image Download : Download high-res image (45KB) Download : Download full-size image Disclosures Milpied: Celgene: Honoraria, Research Funding.

Introduction Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare form of acute leukemia associated with an overall bad prognosis. Only very few cases have been reported to reach durable remissions thanks to chemotherapy alone. Allogeneic hematopoietic stem cell transplantation (HSCT) using a myelo-ablative conditioning regimen (MAC) has been reported to be the gold standard treatment for BPDCN (Roos-Weil et al, 2013). However, little is known about the place of reduced-intensity/non-myelo-ablative conditioning regimens (RIC/NMA) in this setting. Methods We retrospectively collected from the database of the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) all cases of BPDCN treated with allogeneic HSCT. Immunophenotypes at diagnosis were centrally reviewed in order to confirm diagnosis according to the Garnache-Ottou diagnostic criteria (Garnache-Ottou et al, 2009). Twenty-eight patients had a diagnostic score of 2 or more. The remaining 15 patients all had CD4+ CD56+ disease, but as they were mostly diagnosed before publication of this score, other markers (such as CD123, BDCA-2 and BDCA-4) were not performed routinely at that time, precluding calculation of a score at least equal to 2. Results From February 2003 to January 2014, 43 patients with BPDCN received an allogeneic HSCT in 21 French centers. PatientsO characteristics are summarized in table 1. Median age was 57 (range: 20-72), sex ratio (M/F) was 2.1/1 and most patients were in CR1 at time of transplant. Sibling transplantation was performed in 42% of cases. Peripheral blood was the main source of stem cell used in this study (70% of cases). Conditioning regimens were MAC in 18 cases (42%) and RIC/NMA in 25 cases (58%, table 2). Four patients (9%) had engraftment failure or secondary graft rejection, 3 of whom having received cord blood units. All these 4 patients were transplanted again 2 to 17 weeks after the first transplant. After a mean follow-up of 668 days for the entire cohort (1050 days for alive patients), 22 patients (51.2%) were alive, 19 of whom being disease-free (44.2%). Eleven patients had relapsed, at a median of 225 days post-HSCT (range: 74-821 days). Two-year cumulative incidences of relapse (CIR) and non-relapse mortality (NRM) were 25.5% (95% CI = [0.13-0.40]) and 32.8% (95% CI = [0.186-0.479]) respectively (figure 1). At 2 years post-transplant, disease-free survival (DFS) and overall survival (OS) were 44.9% (95% CI = [0.291-0.595]) and 52.2% (95% CI = [0.357-0.664]), respectively. Even though not statistically significant, patients receiving a MAC (n = 18) were less likely to relapse than patients receiving RIC/NMA (2-year CIR = 7.1% and 36% respectively, P = 0.137), but had a higher NRM rate (43.9% versus 26% at 2 years, P = 0.419), resulting in similar 2-year DFS and OS (57.1% versus 38%, P = 0.511 and 57.1% versus 49.7%, P = 0.91). There was a trend for a lower incidence of NRM at 2 years in patients transplanted from a sibling donor versus others (16.7% and 39.9% respectively, P = 0.0505, figure 2), but donor source had no effect on CIR ( P = 0.826), DFS ( P = 0.194) and OS ( P = 0.188). Conclusion In this series of 43 patients with BPDCN, allogeneic HSCT was associated with a good disease control, but NRM was high. In this regard, transplantation from a sibling donor appears to be the best option. RIC/NMA are feasible and may also reduce the incidence of NRM, but at the expense of a higher incidence of relapse. | N | 43 | | -------------------------- | -------------- | -------- | | Age | 57 (20-72) | | Sex (M/F) | 29/14 | | Time from diagnosis (days) | 170 (107-1050) | | Disease status at HSCT | | | CR1 | | 34 (79%) | | CR2 | | 5 (12%) | | No CR | | 2 (5%) | | Unknown | | 2 (5%) | | Donor | | | Sibling | | 18 (42%) | | Unrelated | | 23 (53%) | | Mismatch relative | | 2 (5%) | | Cell source | | | Bone Marrow | | 7 (16%) | | Peripheral Blood | | 30 (70%) | | Cord Blood | | 6 (14%) | | Conditioning regimen | | | MAC | | 18 (42%) | | RIC/NMA | | 25 (58%) | | CMV status (D/R) | | | -/- | | 18 (42%) | | -/+ | | 9 (21%) | | +/- | | 4 (9%) | | +/+ | | 12 (28%) | | GVHD prophylaxis | | | Ciclo/MTX | | 15 (35%) | | Ciclo/MMF | | 19 (44%) | | Ciclo alone | | 5 (12%) | | Other | | 2 (5%) | | Unknown | | 2 (5%) | Table 1. Patients' characteristics | MAC | 14 | || | Cy/TBI | 11 | | Cy/TBI 12 Gy | | 9 | | Cy/TBI 10 Gy | | 1 | | Cy/Flu/TBI 12 Gy | | 1 | | Bu/Cy | 3 | | RIC/NMA | 29 | | Flu/Bu/ALG | 10 | | Flu/TBI 2 Gy | 10 | | Flu/TBI 2 Gy | | 5 | | Cy/Flu/TBI 2 Gy | | 4 | | AraC/Flu/TBI 2 Gy | | 1 | | Sequential | 5 | | Amsa/AraC/Flu/Cy/Bu/ALG | | 3 | | Amsa/AraC/Flu/Cy/TBI 2 Gy/ALG | | 1 | | Amsa/AraC/Flu/Bu/ALG | | 1 | | Flu/Bu/Thiotepa/ALG | 1 | | Flu/Mel | 1 | | Cy/TBI 8 Gy | 1 | | TLI/ALG | 1 | Table 2. Conditioning regimens ![Figure 1.][1] Figure 1. Cumulative incidences of relapse and non-relapse mortality ![Figure 2.][1] Figure 2. Non-relapse mortality according to donor type Disclosures No relevant conflicts of interest to declare. [1]: pending:yes

Blastic plasmacytoid dendritic cell neoplasm is a rare and aggressive neoplasm for which there is still no current consensus on the best therapeutic approach. Most patients respond to intensive chemotherapy, but relapses are almost inevitable with median overall survival (OS) in the largest patient series ranging from 8 to 12 months except for patients who could benefit from allogenic hematopoietic stem cell transplantation (allo-HSCT). We present results of the first line treatments used in France between 2000 and 2013 for 86 patients recruited in the French network of BPDCN (abstract ASH 2015 N°78460). Seventeen patients were treated with acute lymphoid leukemia (ALL)-like therapy (median age : 63 yo) , 19 with acute myeloid leukemia (AML)-like therapy (median age : 40 yo), 16 patients with CHOP-like therapy (median age : 72 yo), 16 patients with NK/T-like therapy (based on high-dose methotrexate and L-asparaginase, ± dexamethasone, median age: 59 yo), and 12 patients received "other treatments" (OT, means variable drugs, median age : 82 yo). Thirty four patients obtained a complete remission (CR) and received HSCT (autologous n=4, or allogeneic n=30). The response rates for CHOP-like and OT groups were 31.3% and 25.0% respectively. For ALL-like, AML-like, and NK/T-like groups, response rates reached 70.6%, 78.9%, and 62.5% respectively (no statistic difference). Relapse rates among responders for CHOP-like and OT groups were 60% and 33.3% whereas there were only 25%, 26.7%, and 20% in ALL-like, AML-like, and NK/T-like groups respectively. For patients who obtained remission, the median of remission duration was 8.0 and 14.0 months for patients who received CHOP-like treatments (n=5) and OT (n=3) respectively and 10.0, 10.0, and 9.0 months for ALL-like (n=11), AML-like (n=14), and NK/T-like groups (n=9) respectively (p = 0.6339). In preclinical studies, we have shown that BPDCN cells are sensitive in vitro to idarubicine (Angelot Delettre F et al, 2015) so we studied patients receiving idarubicine in first line therapy in our series (n=9). From these 9 patients, 7 obtained CR and only one relapsed after 10 months. The 6 patients in continuous CR without any relapse have received HSCT (allo, n=5 or auto, n=1). Two out of those 6 patients are alive at the time of data collection with a follow-up of 40 and 87 months; the other 4 patients died after the graft, one relapsed after auto-HSCT, and 3 died of infectious complications after allo-HSCT. The median OS for patients who received HSCT, auto or allo (n=34) and other patients (n = 52) is respectively 49 and 8 months (p < 0.0001, Figure 1). The beneficial effect of HSCT persists independently of age in multivariate analysis. These results suggest that NK/T-like, AML-like, and ALL-like groups give better results than CHOP-like and OT groups. However, there is no significant statistical difference between AML-like, ALL-like, and NK/T-like groups. Thus it seems to be wise to combine "lymphoid" drugs like methotrexate, L-asparaginase and dexamethasone with "myeloid" drug such as idarubicine. The importance of allogenic stem cell transplantation to sustain remission is clear in this study and other one (Roos-Weil et al, 2013). We also observed a prolonged CR in one patient after auto-HSCT. Based on our results, we will propose the first prospective, multicentric, phase II trial in BPDCN, testing a combination of 3 cycles of methotrexate, L-asparaginase, idarubicine and dexamethasone followed by an allo-HSCT in first clinical remission for all eligible patients or repeated cycle of these drugs for unfit patients with auto-HSCT if possible. Kaplan-Meier overall survival curves compared by the Log-Rank test in the cohort of 34 HSCT patients (auto and allo, blue line) and 52 non HSCT patients (red line) (p Figure 1. Overall survival of HSCT patients and non HSCT patients. Figure 1. Overall survival of HSCT patients and non HSCT patients. Disclosures Recher: Celgene; Amgen; Chugai: Research Funding; Janssen; Novartis; Amgen: Other: Travel, accommodations, expenses; Sunesis; Celgene: Consultancy. Deconinck:CHUGAI: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; ALEXION: Other: Travel for international congress; LFB loboratory: Consultancy; JANSSEN: Other: Travel for international congress; PFIZER: Research Funding; ROCHE: Research Funding.

Introduction: Peripheral T-cell lymphomas (PTCL) are heterogeneous diseases, lightly sensitive to chemotherapy, with an adverse outcome and a 5-year survival rate of about 30%. Allogeneic hematopoietic stem cell transplant (allo-SCT) can lead to durable remission even for patients (pts) who show poor response to chemotherapy. Several observations argue for a Graft Versus Lymphoma (GVL) effect in PTCL. However, allo-SCT is not consensually recommended, at least in first line therapy. The aim of the current study is to highlight GVL effect in PTCL. To do so, we evaluated the benefits of immune modulation on disease control (donor lymphocyte infusions (DLI) and immunosuppressive therapy tapering) with analysis of outcome in pts who relapsed after allo-SCT. Patient selection and methods: Between 1988 and 2012, 373 pts received an allo-SCT for treatment of PTCL. 80 pts in relapse after allo-SCT were identified in 27 SFGM-TC(French Society of Bone Marrow Transplantation and Cell Therapies) transplant centers. Exhaustive data were collected for 63 pts. Median age at transplant was 45 years; 67% were male. The main histopathologic subtypes were T-nos (20, 32%), primary cutaneous TCL (13, 21%) and anaplastic large TCL (11, 17%). Others were angioimmunoblastic TCL (8), T/NK lymphomas (5), HTLV1 lymphomas (5) and EIATL (1). At transplant, 38% were in complete remission (CR), 43% in partial remission (PR) and 19% had progressive disease. Median number of previous lines of treatment was 2 and 25% of the pts had previously received an autologous SCT. Conditioning regimen was myeloablative for 23 pts and non-myeloablative for 40. At relapse, pts were treated with either non-immunologic-based strategy (chemotherapy, radiotherapy) or immune modulation (DLI and/or discontinuation of immunosuppressive therapy), or both (Figure 1). We analyzed their outcomes according to the treatment they received at relapse. Results: Relapse occurred at a median time of 204 days after transplant (interquartile range: 49-190 days); seventeen pts had a localized cutaneous relapse (7 Mycosis fungoides, 2 angioimmunoblastic TCL, 3 T-nos, 3 anaplastic TCL and 2 NK/TCL). Among the 14 pts (22%) who received DLI (DLI alone: 5, DLI + radiation and/or chemotherapy: 9), 9 obtained a response (7CR, 2 PR) and 2 had a stable disease (SD) status (overall response rate: 78%). Six of these 14 pts remained alive at last follow up. Median overall survival (OS) of these 14 pts was 23.6 months. Among the 49 pts who did not receive DLI, immunosuppressive therapy was tapered or stopped for 23. Sustained CR after tapering immunosuppressive drugs was observed in2 pts along with extensive chronic graft versus host disease (cGVHD). In the non-DLI group, 30 out of 49 pts received a radio/chemotherapy treatment with a response rate of 50% and a 1-year survival rate of 25% after relapse. Among the 13/49 pts who experienced a response in this group, six developed a cGVHD after relapse. Median OS of these 49 pts was 3.6 months. Median follow up was 40 months for the whole population. Conclusion: DLI alone or in association with other therapies, when possible, seems to be an efficient salvage option. This study suggests the benefit of DLI in cases of post transplant relapse for PTCL and supports the existence of a GVL effect in these diseases. These findings could potentially lead to the set up of a proactive immune modulation strategy after transplant for pts with high-risk disease. However, the short time frame from transplant to relapse currently observed, might limit the feasibility of this therapeutic option. Figure 1: Combination treatments at relapse and response: Figure 1:. Combination treatments at relapse and response: Figure 2: Overall survival in non- DLI group (n=49) Figure 2:. Overall survival in non- DLI group (n=49) Figure 3: Overall survival in DLI group (n=14): Figure 3:. Overall survival in DLI group (n=14): Disclosures No relevant conflicts of interest to declare.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is performed in patients (pts) with high-risk features at diagnosis (del17p/p53 mutations) or advanced disease. Although approximately 30% of pts have matched siblings, alternative stem cell sources such as umbilical cord blood, extend the use of HSCT to pts lacking a conventional donor. However, little is known about outcomes after umbilical cord blood transplantation (UCBT) for CLL/SLL. We analyzed 68 pts (50 males) who underwent a single (n=16) or double (n=52) HLA-mismatched UCBT between 2004 and 2012 in 34 EBMT centers. Median age at UCBT was 57 years (yrs) (range, 27-68). At diagnosis, 56 pts had CLL/SLL, 8 prolymphocytic leukemia (4 B-cell and 4 T-cell) and 4 Richter transformations. Cytogenetic was available in 70% (48/68) of pts. Seventy-three percent had abnormal karyotype (36% del17p/p53, 17% del13q, 8% del11q and 12% others) and 27% normal. Median time from diagnosis to UCBT was 54 months (range, 3-358). Thirty-seven pts were in partial remission (PR) at UCBT, 23 in complete remission (CR) and 8 had refractory disease (RD). The hematopoietic stem cell comordibity index (HCT-CI) at UCBT was 0 in 60% of pts, 1-2 in 25% and 3-4 in 15%. Sixty-five percent of pts received ≥3 chemotherapy lines prior to UCBT, 28% were refractory to purine analogues and 16% underwent previous autologous stem cell transplantation (ASCT). Sixty patients received low-dose TBI (2-4 Gy) from which the Minnesota RIC regimen (TBI-Cyclophosphamide-Fludarabine: TCF) was given to 57 pts; 15 pts received ATG and GVHD prophylaxis was CsA+MMF in 61 pts. Median TNC collected was 3.7x107/Kg (1.8-7.1) for single and 5x107/Kg (2.0-9.7) for double UCBT. Units were HLA matched to the recipient at 5-6 loci in 30% of pts and at ≤4 in 70%. Median follow-up was 37 months (range, 3-98). OS and PFS at 3 yrs were, respectively, 53±7% and 45±7%. The cumulative incidences (CI) of neutrophils and platelets engraftment were 84±5% and 72±6%, respectively with a median time for engraftment of 21(range, 5-67) and 43 (range, 1-189) days, respectively. CI of acute graft-versus-host disease (aGVHD) at 100 days was 43%±6 for grade II-IV and 19±5% for grade III-IV with a median time of onset of 23 days (9-95). Three yrs CI of chronic GVHD (cGVHD) was 32±6% (12 limited and 6 extensive) with a median time of onset of 130 (range, 101-393) days. CI of relapse and NRM at 3 yrs were,16±5% and 39±6%, respectively. In a univariate analysis the use of TCF conditioning was associated with improved OS (62% vs 15%, p The use of TCF (HR: 0.34 (0.14-0.82), p=0.02), fludarabine sensitive disease at transplantation (HR: 0.41 (0.20-0.81), p=0.01) and HCT-CI ≤2 (HR: 0.38 (0.17-0.87), p=0.02) were associated with improved PFS in multivariate analysis. Acute GVHD grade III-IV was associated with lower OS (HR: 3.4 (1.6-7.4), p=0.002) and PFS (HR: 2.8 (1.4-5.8), p=0.005) in a time-dependent model. Overall, 32 patients died; 7 died of relapse and 25 of transplant related causes (10 infections, 4 post-transplant lymphoprolypherative diseases, 3 aGVHD, 3 toxicities, 1 secondary lung cancer and 4 other causes). In conclusion, RIC-UCBT appears to be a valid option for CLL/SLL patients. Strategies to optimize infection prophylaxis, use of low-dose TBI RIC conditionings and to perform the UCBT before development of fludarabine resistance may improve overall outcome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Purpose: Pediatric-like protocols have yielded significant advances in younger adults with Ph-negative ALL. Nonetheless, the 5-year cumulative incidence of relapse was still estimated at 32% in the GRAALL-2003/2005 trials, approximately 25% of the relapses occurring after allogeneic stem cell transplantation (SCT). We report here on the outcome of these relapsing patients. Patients and Methods: Among 880 GRAALL-2003/2005 patients(18-60 years) with Ph-negative ALL in first complete remission (CR1), 264 relapsed. Data were available for 229 of them (151 B-cell precursor [BCP] ALL, 78 T-ALL; 45 standard-risk, 165 high-risk, and 19 unclassified ALL according to the risk classification used in these trials). Relapse site was bone marrow (BM), isolated CNS, combined BM/CNS and other in 181, 20, 17 and 11 patients, respectively. At relapse, median age was 35.7 years (range, 17-63). Median CR1 duration was 10 months (range, 0.5-74), 50 patients (22%) having CR1 > 18 months. Fifty-four patients (24%) had received allogeneic SCT during CR1. First salvage treatments were classified as follows: standard curative therapy, 194 (85%); low-intensity therapy, 21 (9%); allogeneic SCT, 6 (2.5%); and best supportive care (BSC), 8 (3.5%). Post-relapse allogeneic SCT was analyzed as a time-dependent event using Mantel-Byar estimations. Results: A total of 121 patients (53%) achieved CR2, including 100/194 patients after standard salvage, 7/21 patients after low-intensity salvage, and 14 patients after SCT (6 as first salvage, 8 as subsequent salvage after standard salvage failure). Thus, 107/215 patients (50%) treated with standard or low-intensity first salvage achieved CR2 and in multivariable analysis (including age, ALL lineage, ALL risk classification, CR1 duration, prior SCT, relapse site and salvage type), a younger age and a longer CR1 duration were associated with CR2 achievement in these patients. Of note, few patients with t(4;11) BCP-ALL reached CR2 (19%). A total of 77 patients received allogeneic SCT after relapse, including 55 patients in CR2 after standard salvage (52 in CR2 at SCT time), 4 patients in CR2 after low-intensity salvage (all in CR2 at SCT time), the 6 patients transplanted as first salvage (all reaching CR2), and 12 patients transplanted as subsequent salvage (8 reaching CR2). The median time between relapse and SCT was 111 days (range, 5-311). With a median post-relapse follow-up of 3.1 years, post-relapse overall survival (OS) was 19.3% (14-25%) at 2 years and 13.3% (9-19%) at 5 years (median OS, 6.7 months). In landmark analysis, OS was significantly longer in patients who achieved CR2 (HR, 0.19; p 18 months (HR, 0.43; p 18 months and SCT after relapse were associated with longer OS (HR, 0.49 and 0.39; p=0.001 and 18 months and SCT after relapse were the two factors that independently predicted longer DFS (HR, 0.36 and 0.44; p=0.001 and 0.003) and OS (HR, 0.39 and 0.57; p=0.004 and 0.043, respectively) in these patients. Conclusion: Adult patients relapsing after current ALL therapies still retain apoor outcome. Although a minority of them may be cured, especially if CR1 duration exceeds 18 months and if they may receive allogeneic SCT in CR2, new therapies are definitely needed for these patients. Disclosures No relevant conflicts of interest to declare.

Background: Twenty percent of classical Hodgkin Lymphoma (cHL) patients are aged 60 years or older. Their survival rate is inferior to that of younger patients for several reasons including lower delivery of standard chemotherapy and toxicity excess. For relapsed or refractory (R/R) cHL young patients, autologous stem cell transplantation (ASCT) is a standard of care after salvage chemotherapy. However, little is known regarding the outcome of R/R cHL in elderly patients (≥60 years) receiving ASCT. Method: The current report retrospectively analyzed the outcome of all consecutive patients aged 60 years or older with the diagnosis of R/R cHL who were transplanted between 1992 and 2013 and who were reported to the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) registry. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all SFGM-TC centers. This study was approved by the scientific committee of the SFGM-TC and is in accordance with Helsinki declaration for clinical research. Of note, specific study questionnaires were sent to transplant centers to obtain comprehensive, updated data. Results: One hundred and twenty patients met these criteria. Ninety-one patients (63M/28F) with documented data from 28 transplant centers were analyzed. Median age was 63 years at transplant (range 60-75). At diagnosis, 64 patients had advanced stage cHL, 46 had B symptoms and 6 had poor performance status (ECOG 2). Thirty-four patients had primary refractory disease, and 22 patients relapsed within the first year after first CR. The median number of salvage chemotherapy regimens was 2 (range 1-4). Most of the patients showed disease sensitivity to salvage treatment with 52 patients transplanted in CR, 5 patients in CRu, 30 patients in PR and 1 patient transplanted with progressive disease. The most frequently used conditioning regimen consisted of BEAM chemotherapy (93%) (Carmustine 300 mg/m2 d-6, Etoposide 100 mg/m2 Q12H d -5 to -2, Cytarabine 200 mg/m2 IV Q12H d-5 to -2, Melphalan 140 mg/m2 d -1). The median number of CD34 peripheral blood stem cells was 4.2 106 cells/kg (range 0.9-17.8). The median duration of hospitalization was 22 days (8-49). The median time to achieve neutrophil count >1x109/L and platelet count > 20x109/L were 11 days (range 8-104) and 13 days (range 7-115), respectively. Grade 3-4 toxicities occurred in 24 patients (mucositis: 13, sepsis: 3, interstitial pneumonia: 2, diarrhea: 2, heart failure: 2, multiorgan failure (MOF): 1, unspecified case: 1. With a median follow-up of 32 months (range 1-185), the 6-year estimate of OS was 64% (95% CI 51-75). In univariate analysis, none of the usual prognostic factors (gender, age ≥ 65, disease status before transplant, CD34+ cells count, time to relapse < 1 year, disease stage at relapse, Hb level) significantly influenced OS. At last follow-up, 13 patients died: 5 from toxicity (1 MOF, 2 interstitial pneumonia, 1 heart failure and 1 invasive pulmonary aspergillosis), 4 from disease progression, and 4 from unspecified causes. Conclusion: This retrospective study with long term follow-up, despite its limitations, suggests that in selected elderly patients ASCT is a valid treatment option for chemosensitive R/R cHL patients, with an acceptable rate of toxicity warranting further investigations in the era of novel agents such as brentuximab. Disclosures Brice: Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria.

Abstract 411 Background: LDAC is an established treatment option for patients (pts) with AML considered ineligible for intensive remission induction treatment. However, the outlook for pts who receive LDAC remains unsatisfactory, and novel therapeutic strategies are needed to improve clinical outcome in these pts. Plk1 plays a key role in mitosis and cell cycle progression and is an attractive target for novel therapeutic approaches in cancer. Volasertib (V) is a first-in-class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plks. The phase I part of this trial determined the maximum tolerated dose of V in combination with LDAC (V + LDAC) to be 350 mg and demonstrated antileukemic activity of V and V + LDAC in pts with relapsed/refractory AML ineligible for intensive therapy (Bug et al, ASH 2010 and 2011). Here we present preliminary phase II data for the randomized comparison of V + LDAC vs LDAC in pts with newly diagnosed AML ineligible for intensive treatment. Methods: In the phase II part of this open-label study, eligible pts were randomized to receive V (350 mg 1-hr intravenously, days 1, 15 Q4W) + LDAC (20 mg bid subcutaneously, days 1–10 Q4W), or LDAC alone until progression/relapse or intolerance. The primary endpoint was objective response (complete remission [CR] or CR with incomplete blood count recovery [CRi]); secondary endpoints included event-free survival (EFS), overall survival (OS), safety and pharmacokinetics (PK). Results: 87 pts were treated with V + LDAC (n=42) or LDAC (n=45). Pt characteristics (V + LDAC/LDAC) were largely balanced: median age, 75/76 yrs; secondary AML, 40.5%/64.4%; adverse cytogenetic group, 35.7%/33.3%. At time of analysis (February 22 2012) 15 pts were still on treatment (12 with V + LDAC). Pts received a median (range) of 2 (1–12) cycles of V + LDAC and 2 (1–11) cycles with LDAC. A significantly greater proportion of pts who received V + LDAC achieved a CR or CRi compared with pts who received LDAC (31.0% vs 11.1%; odds ratio 3.59 [95% CI: 1.15, 11.18]; P = 0.0277), with a median (range) time to remission of 71 (29–158) days and 69 (34–125) days, respectively. Remissions with V + LDAC were observed across genetic groups, including pts with adverse cytogenetics. A trend for longer median EFS was observed for pts who received V + LDAC compared with those who received LDAC (HR 0.61 [95% CI: 0.35, 1.05]; P = 0.0725; Figure). Follow-up for OS was ongoing at the time of this analysis. Among pts achieving CR/CRi, only 2 had experienced recurrence or death at the time of analysis (1 in each arm after a remission duration of 57 [V + LDAC] or 67 [LDAC] days). For all other pts ongoing in remission, the remission duration was censored after 53–407 days (LDAC + V) or 32–282 days (LDAC), consistent with prolonged duration of remission in some pts. The most frequent all grade adverse events (AEs) in the V + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%) and anemia (40.5%). In the LDAC arm, the most common all grade AEs were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), and constipation, asthenia and diarrhea (26.7% each). More pts who received V + LDAC experienced ≥ grade 3 AEs than those who received LDAC (95.2% vs 68.9%), particularly for blood and lymphatic system disorders (81.0% vs 44.4%), gastrointestinal disorders (21.4% vs 6.7%), and infections and infestations (45.2% vs 22.2%). The early death rates (V + LDAC/LDAC) at 30, 60 and 90 days were comparable between the two treatment arms: 30 days, 9.5%/8.9%; 60 days, 21.5%/17.8%; 90 days, 28.9%/33.4% (rates calculated using Kaplan-Meier method). PK analyses demonstrated that V is a moderate clearance drug with multi-compartmental PK behavior, a large volume of distribution and a long terminal half-life. Preliminary data suggest no drug-drug interactions following combination of V with LDAC. Conclusions: These preliminary phase II data demonstrate a significantly improved CR/CRi rate and a trend for EFS benefit with V + LDAC compared with LDAC alone in pts with newly diagnosed AML ineligible for intensive treatment. An increased frequency of AEs was observed with the addition of V, which was expected given its myelosuppressive mechanism of action; available data do not suggest increased early mortality for V + LDAC vs LDAC. A confirmatory phase III trial is needed to determine the clinical benefit of V + LDAC in pts with AML ineligible for intensive treatment. Disclosures: Off Label Use: Volasertib is an investigational agent. Fiedler:Pfizer, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bug:Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Tidow:Boehringer Ingelheim: Research Funding. Voss:Boehringer Ingelheim: Employment. Taube:Boehringer Ingelheim: Employment. Fritsch:Boehringer-Ingelheim: Employment. Döhner:Celgene, Amgen, Ambit, Astellas, Lilly: Consultancy.

Abstract 3561 Background: Adolescents (15–19y) with acute lymphoblastic leukemia (ALL) markedly benefit from pediatric rather than adult chemotherapy regimens, as highlighted by many retrospective studies (Boissel et al., JCO 2001). In young adults with ALL, there are now strong evidences that pediatric or pediatric-inspired protocols may also improve long-term outcome (Huguet et al., JCO 2009). However, whether care environment (adult vs pediatric unit) may impact this outcome remains an open issue. To address this question, we explored the outcome of adolescents and young adults (AYA, 15–29y) treated in adult hematology departments by the pediatric FRALLE 2000-BT protocol. Methods: From February 2001 to June 2011, 89 AYAs with Ph-negative ALL including 60 adolescents (15–19y) and 29 YAs (20–29y) were treated according to the pediatric FRALLE 2000-BT protocol in 13 French and Belgian adult hematology units (median follow-up, 5 years). After a prednisone prephase and a four-drug induction (prednisone, daunorubicin, vincristine and L-asparaginase), patients achieving CR received four 8-week phases of treatment: consolidation, 1st delayed intensification (DI), interphase, 2nd DI, and maintenance. According to FRALLE protocol recommendations, each phase should begin after hematological recovery of previous phase (ANC>1 G/L, Platelets>100 G/L). Twenty-five patients (18 adolescents and 7 YAs) underwent allogeneic transplantation after consolidation phase or 1stDI. Results: Apart age (median age, 18 vs 23y; p Conclusion: The outcome of AYAs treated in adult units with the pediatric FRALLE 2000 protocol is encouraging, particularly in YAs. The poorer outcome observed in adolescents may be related to increasing intervals from initial induction to the different phases of treatment. Prospective trials are required to register individual reasons that lead physicians and patients to progressively delay therapy. This study suggests that trial itself is not sufficient to improve the outcome in adolescents with cancer and that AYA programs are needed to explore the difficulties encountered by patients and care teams to adhere to therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 422 Background: The IPSS published in 1997, based on cytogenetics, marrow blast % and the number of cytopenias, has played a major role in prognosis assessment in MDS. A provisional revised IPSS had been presented in 2011, which in our experience brought limited additional prognostic value for outcome of AZA treatment (Lamarque, ASH 2011). A final IPSS-R has now been published (Greenberg, Blood 2012), using the same parameters but 5 rather than 3 cytogenetic subgroups (Schanz et al, JCO, 2011), new cut off values for cytopenias and bone marrow blast % and different weighing of parameters. It appears to refine IPSS prognostic value but, like the original IPSS, was established in pts who had received no disease modifying drugs. We assessed the prognostic value of IPSS-R in 264 higher risk MDS treated with AZA, a drug with a survival impact in those pts. Methods: Between Sept 2004 and Jan 2009, before drug approval in EU, we enrolled 282 IPSS high and int 2 (higher) risk MDS in a compassionate patient named program of AZA and established in this cohort a prognostic scoring system (“AZA predictive score” based on Performance status (PS), cytogenetics, presence of circulating blasts, and RBC transfusion dependency) (Itzykson, Blood, 2011). We took advantage of this cohort to evaluate the prognostic impact of IPSS-R in higher risk MDS treated with AZA. Results: Median age was 71 years. WHO diagnosis: 4% RA, RARS or RCMD, 20% RAEB-1, 54%RAEB-2, 22% RAEB-t/AML. Cytogenetics could be reclassified using IPSS-R cytogenetic groups (Shanz, JCO 2011) in 265 pts, in: 1% very good, 37% good, 18% int, 12% poor and 32% very poor. 18%, 48% and 34% pts had Hb10 g/dl, respectively. 43%, 32% and 25% had baseline platelet count 100 G/L, respectively. ANC was 10 % in 2%, 3%, 18% and 77% pts. Overall IPSS-R could be calculated in 259 patients and was low (1 pt), Intermediate (28 pts, 11%), high (87 pt, 34%) and very high (143 pt, 55% pts). The only pt in the low group was excluded from further analysis. Using the “classical” IPSS, high and Int-2 patients treated with AZA had significantly different Response (37% vs 49%, p=0.05) and OS (median 9.4 vs 16 mo, respectively, p=0.004). Using the IPSS-R, 46%, 47% and 39% responded (CR, PR, or Hematological improvement- HI) to AZA in the int, poor and very poor groups, respectively (p=0.463). Individual IPSS-R parameters, including IPSS-R cytogenetic classification (p= 0.646), Hb level (p= 0.948), platelet count (p=0.10), ANC (p= 0.465) and marrow blast % stratified according to R-IPSS (p=0.287) had no significant impact on AZA response. According to IPSS-R cytogenetic classification, median OS was 21.8 mo, 12.3 mo, 15.1 mo and 7.1 mo in the good, int, poor and very poor risk groups respectively (overall p The 55% patients with very high risk according to IPSS-R could be further subdivided by our AZA scoring system (Itzykson et al, Blood, 2011) in 3%, 67% and 30% low, int or high risk with a significant different OS across those groups (median not reached (NR), 12.7 and 5.9 mo, p Conclusion: Contrary to the provisional IPSS-R presented in 2011, the final IPSS-R (Greenberg, Blood 2012) has strong prognostic value for survival in MDS pts treated with AZA.Its prognosic value can be further improved by specific scoring systems established for AZA treatment, like the one published by our group (Itzykson, Blood, 2011). Disclosures: No relevant conflicts of interest to declare.

Abstract 2008 T prolymphocytic (T-PLL) is a rare aggressive mature T cell disorder with distinctive clinical, morphologic, immunophenotypic and cytogenetic characteristics. The median overall survival (OS) is approximately 7 months with conventional chemotherapy. The introduction of the anti-CD52 monoclonal antibody, alemtuzumab, allowed for an improved overall response rate around 75% with a CR rate of 60% and a median OS of 10 months. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only potentially active option to consolidate response to initial chemo-immunotherapy in those eligible patients. We retrospectively studied all patients fulfilling the requirements for P-TLL diagnosis and who underwent allo-HSCT reported to the “Société Française de Greffe de Moelle et de Thérapie Cellulaire” (SFGM-TC) registry. Twenty patients were identified from 14 SFGM-TC centers from 2000 to 2010 (median year, 2009). Prior to allo-HSCT, 9 patients were in CR, 8 in PR, 3 refractory or in progression. Alemtuzumab was used in 17 patients prior to transplant. Following transplantation, as best response, 17 patients were in CR while 1 progressive patient became partial responder. For two patients, response could not be determined due to early transplant-related mortality (TRM). Engraftment was achieved in 96% of the patients. Eleven patients developed acute GVHD (grade I, n=1; grade II, n=2; grade III, n=2; and grade IV, n=1). The cumulative incidence of grade II to IV GVHD was 52% (95%CI: 29–70%). Chronic GVHD was observed in 45% of the patients, with 4 having a limited form and 5 an extensive form. With a median follow-up of 28.8 months (range 6.8–103) for surviving patients, 10 patients are alive with 7 of them being in CR. The KM estimates of OS and progression-free survival (PFS) at 3 years were 41.7 (95%CI: 18–62%) and 29% (95%CI: 14–50%), respectively. The cause of death among the 10 patients was transplant related in 6 and due to disease progression in 4. The relapse incidence was 51%. Relapse was observed at a median of 14 months (range, 2–24) after allo-HSCT. Among the eight relapses, four occurred during the second year. TRM incidence was 38 % at 3 years. Though not statistically significant due to the relatively low number of patients, the use of TBI in the conditioning regimen was associated with a better PFS. We conclude that allo-HSCT may allow long term survival in some patients with T-PLL following induction treatment. Given the rarity of this disease, national and international collaborations (e.g. registry) are needed to further clarify the role of allo-HSCT and natural history of this rare and fatal disease. Disclosures: No relevant conflicts of interest to declare.

Abstract 1473 Introduction: L-asparaginase-loaded red blood cells (GRASPA®) has been shown to be a new available option for combining L-asparaginase with standard chemotherapy in different ALL population, including older patients with the disease. Tolerability and preliminary results of efficacy of GRASPA® in GRASPALL/GRAALL-SA2–2008 study have already been presented. We report below the 2-year follow-up efficacy results of this study. Methods: GRASPALL/GRAALL-SA2–2008 study aimed at determining optimal dose of GRASPA® that could be combined with standard EWALL chemotherapy backbone in patients aged >55y with newly diagnosed Ph-ALL. It was an open label Phase II dose escalation study. Primary endpoint combined tolerance and efficacy (asparagine depletion ≥7 days). Three doses of L-Asparaginase-Loaded Red Blood Cells (50, 100 and 150 IU/kg), infused twice during induction cycles, were investigated. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone d1–2/8–11, vincristine d1,8, and idarubicine d1–2/8–9) and induction-2 (cyclophosphamide d15–17 and cytarabine d16–19/23–26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (d1) / E.coli asparaginase (d2) and high-dose cytarabine (d1, 3, 5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for 2 years. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival were secondary endpoints. Results: Between March 2009 and October 2010, 30 patients were recruited in 20 centres in France by the GRAALL network. The 50, 100 and 150 dose levels included 3, 13 and 14 patients, respectively. Median age was 67 years (range 59–77). No differences in baseline characteristics were observed across the 3 dose level groups. The tolerability with L-Asparaginase-related side effects is reported below: GRASPA Dose (IU/kg) 50 100 150 Number patients/group 3 13 14 Allergic reaction 0 0 0 Clinical thrombosis 1 (33%) 1 (8%) 2 (14%) Antithrombin III decrease 2 (67%) 7 (54%) 12 (86%) Other Coagulation disorder 2 (67%) 3 (23%) 11 (79%) Clinical pancreatitis 0 0 0 Pancreatic enzymes increased >2N 1 (33%) 5 (38%) 5 (36%) Protein synthesis dicrease (hypoalbuminemia 1 (33%) 1 (8%) 6 (43%) Transaminases increase >5N 2 (67%) 4 (31%) 6 (43%) Overall L-asp expected adverse events tended to be lower in the 100 UI/kg group. Regarding the efficacy and benefit/risk, asparagines depletion, remission rate, EFS and OS are reported below: Dose level N Pts with at least 7 days depletion N (%) Patients with DLT N (%) Pts with at least 7 days depletion and no DLT N (%) Remission After Induction CR EFS OS Median 1 year 2 years Median 1 year 2 years 100 IU/Kg 13 11 (85%) 2 (15%) 9 (69%) 10 (77%) 11.8 mo 46% 23% 15.6 mo 62% 23% 150 IU/Kg 14 10 (71%) 5 (36%) 7 (50%) 9 (64%) 4.0 mo 33% – 9.5 mo 43% – Three patients received the dose of 50 UI/kg but this dose was insufficient to reach a 7-day asparagine depletion. Survival analysis showed that the dose of 100IU/kg was associated with median OS of 15.6 months an absolute value that compared favorably with historical controls: 8,8 mo (Rousselot et al. Drugs Aging,2011) and 10,5 mo (Hunault et al. Haematologica,2011) Conclusion: GRASPA® at a dose of 100 UI/kg appears to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older patients with Ph- ALL with a sustained asparagine depletion and a good efficacy/safety profile. Disclosures: Godfrin: ERYTECH Pharma: COO Other.

Abstract 2586 Even when intensively treated within pediatric-inspired protocols, about 25 to 30% of adults with ALL eventually relapse. With standard 4-drug or Hyper-CVAD salvages, post-relapse outcome remains very poor. Clofarabine is one of the new agents approved in US and EU to treat relapsing B-cell precursor (BCP) and T-cell ALL in children and young adults (up to 21 at initial diagnosis). In these patients, clofarabine is associated with a salvage rate around 30% when used as single agent. Combining clofarabine with conventional drugs in an intensive schedule may provide a chance to improve results in this difficult to treat population. Methods: Fifty-five patients were treated between March 2008 and February 2011. Thirty-seven patients received the VANDEVOL chemotherapy combining dexamethasone 10 mg/m2/12h day 1–5, mitoxantrone 8 mg/m2/d day 3–4, etoposide 150 mg/m2/d day 3–5, Peg-asparaginase 2.500 UI/m2 day 7, and Clofarabine 30 mg/m2/day day 1–5 and eighteen patients received the ENDEVOL chemotherapy combining cyclophosphamide 300 mg/m2/d day 1–3 and clofarabine 30 mg/m2/d day 1–5. Median age was 34 (19–67) and 53 (18–78) years in the VANDEVOL and ENDEVOL cohort, respectively. The proportion of first relapsing patients was 68% in the VANDEVOL cohort and 39% in the ENDEVOL cohort. Fifty patients had BCP-ALL (including 8 Ph+ ALL) and 5 patient had T-ALL. Results: Complete remission was achieved in 15/37 (41%) VANDEVOL patients and in 9/18 (50%) ENDEVOL patients. Early death rate was 5/37 (14%) in patients treated with VANDEVOL and 1/18 (6%) in patients treated by ENDEVOL. Grade 3–4 infectious, neurological, GI, and liver toxicities were observed in 22, 5, 5, and 11 VANDEVOL patients and in 10, 0, 0, and 2 ENDEVOL patients, respectively. Thirteen patients in the VANDEVOL group and three in the ENDEVOL group received subsequent allogeneic stem cell transplantation (overall transplant rate, 29%). After a median follow-up of 6 months, the median OS was 6.5 months. Conclusion: Combination of clofarabine with standard chemotherapy seems to be a promising and relatively safe approach to treat adult patients with refractory/relapsing ALL. This approach may be considered as a bridge to transplant in patients eligible for subsequent allogeneic stem cell transplantation. Updated data will be presented. The GRAALL will soon initiate a large multicenter prospective Phase II study using the VANDEVOL regimen. Disclosures: No relevant conflicts of interest to declare.

Abstract 972 Background: The IPSS published in 1997, based on cytogenetics, marrow blast % and the number of cytopenias, has played a major role in prognosis assessment in MDS. A recently presented (Greenberg, International MDS Workshop, Edinburgh 2011) IPSS provisional update (IPSS-R), using the same parameters but 5 rather than 3 cytogenetic subgroups (Schanz et al, EHA 2010), a new cut off for ANC (0.8 G/L) and different weighing of parameters, appears to refine IPSS prognostic value but, like the original IPSS, was established in pts who had received no disease modifying drugs. We assessed the prognostic value of IPSS-R in 265 higher risk MDS treated with AZA, a drug with a survival impact in those pts (Lancet Oncol, 2009). Methods: Between Sept 2004 and Jan 2009, before drug approval in EU, we enrolled 282 IPSS high and int 2 (higher) risk MDS in a compassionate patient named program of AZA and established in this cohort a prognostic scoring system (“AZA predictive score” based on Performance status (PS), cytogenetics, presence of circulating blasts, and RBC transfusion dependency) (Itzykson, Blood, 2011). We analyzed in this cohort the prognostic impact of IPSS-R in higher risk MDS treated with AZA. Results: Median age was 71 years. WHO diagnosis: 4% RA, RA RARS or RCMD, 20% RAEB-1, 54%RAEB-2, 22% RAEB-t (AML 20–30% blasts). Cytogenetics could be reclassified using new IPSS-R cytogenetic groups in 265 pts, in: 1% very good, 37% good, 18% int, 12% poor and 32% very poor. 66% pts had Hb 56%, 55% and 38% had a response (CR, PR, or Hematological improvement- HI) to AZA in the int, poor and very poor R-IPSS groups, respectively (p=0.029). However, individual IPSS-R parameters, including IPSS-R cytogenetic classification (p=0.39), Hb level (p=0.42), platelet count (p=0.10), ANC (p=0.25) and marrow blast % (p= 0.129) stratified according to R-IPSS had no significant impact on AZA response. According to IPSS-R cytogenetic classification, median OS was 22.6 mo, 12.3 mo, 15.1 mo and 7.1 mo in the good, int, poor and very poor risk groups respectively (overall p According to IPSS-R, median OS was 30.7 mo, 23.1 mo and 10 mo in the int, poor and very poor R-IPSS groups respectively (Int vs poor: p=0.7; poor vs very poor: p Using the “classical” IPSS, high and Int-2 patients treated with AZA had significantly different Response (37% vs 49%, p=0.05) and OS (median 9.4 vs 16 mo, respectively, p=0.004). Conclusion: In high and int 2 risk MDS (with current IPSS) treated with AZA, the R-IPSS could predict response to AZA but found no different OS between intermediate and Poor risk patients, who represented one third of the population. Thus, refined prognostic systems established in untreated patients may have to be complemented by more specific scores when using disease-modifying drugs, like our AZA predictive score in AZA treated patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 280 Background: Two phase 2 studies have recently shown promising results of peg-IFNα-2a therapy in PV and essential thrombocythemia, including major efficacy, satisfactory tolerance, and significant molecular responses, renewing the interest for IFNα therapy in patients (pts) with MPN. However, no prospective study has assessed the long-term safety and efficacy of IFN therapy in those pts. We analyzed the long-term results of the PVN1 trial (www.clinicaltrials.gov #NCT00241241), a phase 2 study of peg-IFNα-2a therapy in PV, after a median follow-up (FU) of 6.4 years. Patients and methods: 40 PV pts were enrolled in the study between Sept 04 and Sept 05. 4 pts were not evaluable (1 inclusion criteria violation, 2 withdraws of consent, 1 allergic reaction at first injection). Median age was 50 yrs (range 22–65). Median time since diagnosis was 6 months (range 1–65). 9 pts (25%) had previously received hydroxyurea. 6 pts (17%) had a history of thrombosis. 7 pts (20%) had splenomegaly. Long-term analyses were performed in 34 patients in June 11 (2 pts lost to FU). Hematological, molecular and histological responses were assessed according to the European LeukemiaNet (ELN) criteria. Results: Median FU was 77.4 months (mos) (Q1−Q3: 72 – 81 mos) and median duration of peg-IFNα-2a therapy was 47.4 mos (Q1-Q3: 28 – 77 mos). Clinical-hematological efficacy: At last evaluation, 32/34 pts (94%) were in hematological response including 28/34 complete responses (CR) (82%) and 4 partial responses (PR), and 2 pts had relapsed. 14 pts (41%) were still treated with peg-IFNα-2a for a median time of 70 mos. During FU, 20 pts stopped IFN after having received the drug for a median time of 42 mos. Among them, 10 pts (29% of the total cohort) had stopped because of sustained hematological CR, 8 (23%) because of toxicity, and 2 (6%) at investigator's discretion. 13 (38% of the total cohort) of the 20 pts who stopped therapy did not received any other cytoreductive treatment after peg-IFNα-2a discontinuation, and 10/13 were still in hematological CR off-therapy at last evaluation after a mean observation period of 28+ mos (range 3+ – 64+ mos). During FU, PV relapsed in 3/13 pts who had stopped cytoreductive therapy after a mean time of 25 mos (range 6 – 37 mos). Peg-IFNα-2a was restarted in 2 of them and a second hematological CR was achieved. None of the patients experienced any vascular event during FU, when about 10 events would have been expected in this series of 34 PV pts followed for 77 mos (5.5% pts/year in the ECLAP study). Molecular and histological responses: Molecular response was assessed by measuring JAK2V617F allele burden in granulocytes (%V617F) in 29 pts with serial samples: a molecular response was achieved in 24 pts (83%) including 8 molecular CR (28%), and only 5 pts (17%) had no decrease in their %V617F. Mean %V617F was 47% (range 10 – 100%) at baseline, and 10% (range 0 – 45%) at 72 mos. 4 pts had a TET2 mutation: in none of them the TET2 mutant allele burden decreased during therapy although median decrease in %V617F in the same samples was 100% (Q1 – Q3: 75% – 100%). Bone marrow biopsies performed in some pts in hematological CR after discontinuation of peg-IFNα-2a found a normalized BM morphology fulfilling the ELN criteria for histological CR, and excluded an evolution to myelofibrosis as a cause for “apparent” remission. Toxicity: Peg-IFNα-2a was stopped because of adverse event in 8 pts (23%): fatigue in 2, depression in 1, grade 2 neuropathy in 1, arthralgia in 1, thyroiditis in 1, auto-antibodies in 1, liver enzyme elevation in 1 pt, respectively. Importantly, no unexpected adverse event was observed in spite of the very long-term use of peg-IFNα-2a (median of 45.5 mos). Conclusion: In this prospective phase 2 study of PV pts treated with peg-IFNα-2a after 6.4 years median FU, we recognized that: 1) 94% of pts were still in hematological response, including 82% CR; 2) 29% of pts could stop peg-IFNα-2a and remained in hematological response without further cytoreductive therapy after a median observation time of 28+ mos (up to 64+ mos); 3) major and sustained molecular response in %V617F was confirmed in 83% of patients, including 28% who achieved complete molecular response, while TET2 mutated clones appeared resistant to peg-IFNα-2a; 4) histological CR was also achieved in selected patients; 5) no vascular event was observed after 6.4 years median FU; 6) no new safety concern arose with prolonged utilization of peg-IFN alpha-2a. Disclosures: Off Label Use: Phase 2 study of pegylated-Interferon alpha-2a in polycythemia vera (off-label).

Abstract 2579 Introduction: In adults with Ph- ALL, the clinical benefit of L-asparaginase is hampered by its toxicity. With its improved efficacy/tolerability potential, L-asparaginase-loaded red blood cells (GRASPA®) could be a suitable option for combining L-asparaginase with standard chemotherapy, especially in older patients with the disease. Methods: The GRASPALL/GRAALL-SA2-2008 was an open label Phase II dose escalation study conducted by the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) in patients aged >55y with newly diagnosed ALL Ph-. The aim was to determine the optimal dose of GRASPA® that could be combined with the standard EWALL chemotherapy backbone in these patients. The primary composite endpoint included tolerance and efficacy, the latter being defined as the achievement of target asparagine depletion for at least 7 days. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival and anti L-asparaginase antibody titer (Abs), were secondary endpoints. Three doses of Graspa® (50, 100 and 150 IU/kg), infused at d3 and d6 of two successive induction cycles, were investigated, using a Bayesian experimental plan. After each 3-pt cohort, an independent Data Safety Monitoring Board reviewed study drug tolerance before opening the next dose. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone 10 mg/m2 d1-2,/8-11, vincristine 1 mg d1,8, and idarubicine 10 mg d1-2/8-9) and induction-2 (cyclophosphamide 500 mg/m2 d15-17 and cytarabine 60 mg/m2 d16-19/23-26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (1 g/m2 d1), E.coli asparaginase (10,000 IU/m2 d2) and high-dose cytarabine (1 g/m2/q12 hrs d1,3,5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for a total duration of 2 years. Dose reductions were recommended for pts aged >70y. Results: Between March 2009 and October 2010, 30 pts were recruited in 20 GRAALL centers. The 50, 100 and 150 dose levels included 3, 13 and 14 pts, respectively. Median age was 67 years (range 59–77). Twenty-six pts had B-lineage ALL and 4 had T-ALL. No differences in baseline characteristics were observed across the 3 dose level groups. Overall, 0 (0%), 2 (15%) and 5 (36%) pts presented limiting toxicities in the 50, 100 and 150 dose level, respectively. Because of insufficient efficacy, only 3 pts received the lower 50 IU/kg dose. At the higher 100 and 150 dose levels, 85% and 71% pts reached target asparagine depletion at d7, respectively. In these two 100 and 150 IU/kg groups, grade 3/4 infections were observed in 69% and 71% pts and invasive fungal infection in 23% and 43% pts, respectively. Incidences of adverse events tended to be lower in the 100 IU/kg group: Dose levels 50 IU/kg n=3 100 IU/kg n=13 150 IU/kg n=14 Pancreatic enzyme elevation 1 (33%) 4 (31%) 4 (28%) Clinical Pancreatitis 0 0 0 Liver enzyme elevation 2 (66%) 9 (69%) 9 (64%) Antithrombin III decrease 2 (66%) 7 (54%) 12 (86%) Thrombosis 1 (33%) 1 (8%) 2 (14%) Protein synthesis disorders 2 (66%) 4 (30%) 7 (50%) Allergy 0 0 0 Anti L-asparaginase Abs were detected in 0/3, 2/13 and 1/14 pts after induction-1 and 1/2, 3/9 and 5/9 pts after induction-2, in the 50, 100 and 150 dose level group, respectively. Nevertheless, no clinical allergy was observed after the second drug infusion, but allergic reactions to native E-Coli L-asparaginase were observed in 5/19 pts after consolidation 1. Grade 3–4 infections and renal methotrexate toxicities were observed in 11% (11/99) and 10% (11/51) of consolidations courses. Responses to therapy were as follows: Dose levels 50 IU/kg n=3 100 IU/kg n=13 150 IU/kg n=14 All Induction failure 0/3 (0%) 1/13 (8%) 2/14 (14%) 3/30 (10%) Induction death 1/3 (33%) 1/13 (8%) 4/14 (28%) 6/30 (20%) Complete remission (CR) 2/3 (77%) 11/13 (84%) 8/14 (57%) 21/30 (70%) MRD clearance 1/2 (50%) 4/8 (50%) 1/5 (20%) 6/15 (40%) Pts alive at 6 months 2/3 (67%) 11/13 (85%) 9/14 (64%) 22/30 (73%) Pts alive in CR at 6 months 2/3 (67%) 11/13 (85%) 5/14 (36%) 19/30 (63%) Conclusion: Two infusions of 100 IU/kg GRASPA® appear to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older pts with Ph- ALL. Larger prospective evaluations of this new L-asparaginase formulation are warranted. Disclosures: Liens: ERYTECH Pharma: Employment, Equity Ownership. Godfrin: ERYTECH Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Abstract 6 Aim. GO is a potent antibody-directed chemotherapy against CD33 antigen. Two MRC and SWOG Phase 3 studies have compared standard CT alone or combined with one single GO infusion (at 3 and 6 mg/m2, respectively) in younger adults with AML with contradictory results (Burnett, JCO 2011; Petersdof, Blood 2009). We have shown in relapsed AML Phase 2 studies that fractionated infusion of GO 3 mg/m2 on day 1, 4 and 7 was effective and might be safely combined to standard 3+7 DNR/AraC induction (Taksin, Leukemia 2007; Farhat, AJH, accepted). Here, we report the results of the prospective open label randomized multicentric Phase 3 ALFA 0701 trial (ClinicalTrial.gov ID, NCT00927498) designed to evaluate the efficacy and safety of adding this fractionated GO schedule to standard front-line chemotherapy in older AML pts. Methods. Eligible patients (pts) were adults aged 50–70 years old with previously untreated de novo AML. Pts were randomized to receive induction with DNR 60 mg/m2/d on day 1–3 and AraC 200 mg/m2/d CI on day 1–7, without (DA arm) or with GO at 3 mg/m2/d on day 1, 4 and 7(DAGO arm). Pts with persistent marrow blasts at day 15 received additional DNR 35 mg/m2/d on day 1–2 and AraC 1g/m2/12h on day 1–3. Pts achieving CR/CRp received two consolidation courses with DNR 60 mg/m2/d on day 1 and AraC 1 g/m2/12h on day 1–4, ± GO at 3 mg/m2/d on day 1 according to the randomization arm. The primary study objective was event-free survival (EFS). The study was designed to detect a 25% to 40% EFS gain at 3 years, (two-sided test, power 80%, type I error 5%). Secondary objectives were response rate, disease-free survival (DFS), overall survival (OS), and safety. Results. From March 2008 to November 2010, the required sample of 280 pts (median age, 62 years) was enrolled. Nine pts did not satisfy for inclusion criteria and were excluded from analysis. Cytogenetics was favorable (N=9), intermediate (N=177), adverse (N= 57), not done/failure (N=28). Overall, 52 pts had a favorable NPM1+ w/o FLT3-ITD genotype. The two treatment arms were well matched for all pre-treatment characteristics including age, sex, ECOG-PS, WBC, cytogenetics and molecular characteristics. CR+CRp was achieved in 220/271 pts (77%): 100/134 (75%) in the control DA arm versus 110/137 (80%) in the DAGO arm (P=0.31). There were 5/134 (4%) induction deaths in DA arm and 9/137 (6%) in DAGO arm (P=0.41). Primary resistant AML rate was 29/134 (22%) after DA versus 18/137 (13%) after DAGO (P=0.08). At 2 years, EFS was estimated at 15.6% in DA arm versus 41.4% in the DAGO arm (P=0.0018), while DFS was 18.1% in DA arm and 48.5% in the DAGO arm (P=0.0009). This significant benefit in EFS (primary objective) was observed in pts aged Conclusion. The addition of fractionated doses of GO (3 mg/m2/d on day 1, 4, and 7) to standard CT significantly improves EFS and to a less degree OS in AML pts aged 50–70 years old. The main toxicity observed with GO was prolonged thrombocytopenia in 19 patients and 3 episodes of VOD. Disclosures: Castaigne: Pfizer/Wyeth: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Gemtuzumab Ozogamicin is available in Europe as a compassionate treatment for relapsed AML. In this study patients GO was used in front-line treatment.

Abstract 2911 Background: AZA gives 50–60% responses and improves OS in higher-risk MDS but its role in t MDS/AML, characterized by a high frequency of unfavorable karyotypes and poor response to available treatments, remains unknown. Methods: An AZA compassionate program (ATU) was opened in France between Dec 2004 and Jan 2009 for higher risk MDS, and for AML not candidates to or refractory to intensive chemotherapy (IC). We analyzed t MDS/AML included in this program and having received at least 1 cycle of AZA, excluding patients (pts) previously treated with chemotherapy (CT) for their tMDS/AML. Results: 60 tMDS/AML were included: M/F:24/36, median age 69 (range 20–87). Primary disease was Breast Carcinoma (n=17), CLL (n=6), Hodgkin's disease (n=4), NHL (n=7), ALL (n=2), ovarian (n=2), liver(n=2), prostate carcinoma (n=2), other cancers (n=16), immunosuppressive therapy for lupus or Lung transplant in the last 2 pts. Treatment of primary neoplasm consisted in C×T in 86% and R×T in 61%. Diagnosis (WHO) was RCMD+/− RS in 4 pts, RAEB-1 in 10 pts, RAEB-2 in 28 pts MDS with myelofibrosis in 1 pt, and AML in 17 pts (including 12 FAB RAEBt). IPSS cytogenetics were fav in 4 (6.7%), int in 11 (18.3%), and unfav in 45 (75%, including 71% Complex karyotypes). Patients received a median of 4 cycles (range 1–24) of AZA, at FDA/EMEA-approved schedule (75 mg/m2/d ×7d/4 week) in 73% patients and a less intensive schedule (5d/4w, or 4 cycles, ORR was 21/35 (60%). Age, WBC count, baseline platelet count, % marrow blasts, karyotype (whatever the categorization) and ECOG status had no impact on ORR. 1, 2 and 3 year survival was 35%, 15% and 7%. Female gender (p=0.02), achievement of response (p=0.003) and ECOG status (0-1 vs 2–4) (p=0.04) had significant impact on OS while karyotype and % marrow blasts had no impact. However, there was a trend for lower OS in patients with chrom 5 abn (2y 0S 7.7% vs 23 %, p=0.08). 9 (15%) patients, all females, median age 55 (range 35–66) were allografted after a median number of 6 AZA cycles (range 2–17), including 3 pts, 4 pts and 2 pts who had achieved CR, mCR and no response to AZA, respectively. 4 (44%) of them were alive after 5+,17+,32+ and 42+ months. By comparison to the 232 pts with de novo MDS/AML included in the same program, tMDS/AML had a higher frequency of complex karyotype (71 vs 29.5, p Conclusion: In this cohort of tMDS/AML, survival with AZA was shorter than in de novo MDS/AML, probably largely due to their more severe baseline characteristics. Only 15% of tMDS/AML could be allografted, half of them with so far a favorable outcome. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Abstract 13 Background: The combination of ATRA and anthracycline based chemotherapy (CT) is the reference induction and consolidation treatment of newly diagnosed APL. Whereas in high risk pts (ie with baseline WBC>10G/L), AraC is often considered useful in combination with an anthracycline to prevent relapse, CT with idarubicin alone appears sufficient to yield very low relapse rates in standard risk APL (with WBC< 10G/L) (Ades, Blood 2008, 111:1078-84). On the other hand our APL2000 trial, where standard risk pts were randomized between ATRA with DNR+AraC and ATRA with DNR without AraC, was prematurely terminated after the first interim analysis due to significantly more relapses and shorter survival in the arm without AraC (JCO 2006, 24:5703-10). We reevaluated those results, 6 years after the last patient inclusion. Methods In APL 2000 trial newly diagnosed APL patients < 60 years with WBC < 10G/L were randomized between the AraC+ group: induction with ATRA 45mg/m2/d until CR and DNR 60 mg/m2/d x3 + AraC 200mg/m2/d x7 started on day 3; first consolidation with the same CT course, second consolidation with DNR 45 mg/m2/d x3d and AraC 1g/m2/12h x4d; maintenance during two years with intermittent ATRA (15 d/ 3 months) and continuous 6 MP + MTX, and the AraC- group: same treatment, but without AraC. Pts < 60 years with WBC > 10 G/l (high WBC Group) were not randomized but received the AraC+ group treatment, but with higher AraC dose during the second consolidation (2 g/m2/12 hx 5 days). The current analysis was made at the reference date of 1 January 2010, 72 months after inclusion of the last pt. Results: Overall, 340 pts entered APL 2000 trial between July 2000 and Feb, 2004 (pts included in APL2000 trial after termination of inclusion in the AraC- group, until 2006 are not analyzed here). The AraC+ and AraC- groups (95 and 101 pts, resp) were well balanced for all pretreatment characteristics except WBC count that was higher in the AraC+ arm (mean 2.8 vs. 2.4 Giga/L). In the AraC+, group, 94 pts (99 %) achieved CR and one had early death (ED), as compared to 95 (94 %) CR in the AraC- group (p= 0.12), while there were 1 vs. 4 early deaths (ED), and 0 vs. 2 resistant leukemias in the two arms. The 5-year cumulative incidence of relapse, EFS and survival were 13.4 % vs. 29.0% (p = 0.013), 82.2% vs. 64.8% (p = 0.01), and 92.9% vs. 83.3% (p = 0.07) in the AraC + and AraC- group, respectively. Of the 23 relapses in the AraC- group, 20 were Hematological Relapses and 3 were Molecular Relapses, as compared to 10 and 2, respectively, for the 12 relapses in the AraC+ group. In the high WBC group (where there was no randomization and all pts received AraC), the CR rate, 5-year CIR, 5-year EFS and 5-year survival were 97%, 7.5%, 82.5%, and 89.8%, ie an outcome that appeared slightly superior to that of standard risk pts treated without AraC. Conclusion: With longer follow up, our findings suggest that, in standard risk APL(WBC < 10G/l), avoiding AraC for chemotherapy may lead to an increased risk of relapse when the anthracycline used is DNR. Our results caution against the use, in standard risk APL, of very effective treatment regimens without AraC like the PETHEMA 99 trial (Sanz, Blood 112:3130-34), but where idarubicin would be replaced by DNR. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Abstract 3996 Background: AZA significantly improves OS in higher-risk MDS (including RAEB-t/AML) compared to conventional treatments (AZA 001 trial, Lancet Onc, 2009), but prognostic factors of response and OS to AZA remain largely unknown. We designed a prognostic score for OS in a cohort of AZA treated higher-risk MDS in a patient-named compassionate program (French ATU), and validated it in patients from the AZA 001 trial. Methods: Between Sept 2004 and Jan 2009, prior to AZA approval in Europe, IPSS int-2/high risk MDS (including RAEB-t) not previously treated with intensive chemotherapy (IC), allo SCT, or a hypomethylating agent were included in a compassionate program (ATU), and received AZA (planned schedule 75 mg/m2/d ×7 d every 28 d for ≥4 cycles). Independent prognostic factors of OS were individualized in a Cox model. A prognostic score was then developed based on those factors. After validation of the score as a continuous variable, pts were grouped in three distinct risk categories. We subsequently tried to validate this score in the 175 higher risk MDS pts treated with AZA at the same schedule in AZA 001 trial (4 of the 179 pts randomized to AZA in that trial did not start AZA). Results: The ATU cohort included 282 pts with de novo (74%) or therapy related (t) (26%) higher-risk MDS (IPSS int-2 in 54% high in 43%, at least int-2 in 2%). ECOG PS ≥2, RBC transfusion dependence ≥4 units/8 weeks and circulating blasts were present in 21%, 46% and 46% of pts respectively (resp). Cytogenetic risk was good, int, and poor in 31%, 17% and 47% (unknown in 5%). 10% pts had previously been treated with LD araC for their MDS. Multivariate analysis of survival retained PS ≥2 (HR= 2.0 [95% CI: 1.4–2.9]), RBC transfusion dependence ≥4 units/8 weeks (HR=1.9 [1.4-2.6]), presence of circulating blasts (HR=2.0 [1.5-2.7]), and IPSS cytogenetic risk (intermediate: HR=1.4 [0.8-2.3], poor: HR=3.0 [2.0-4.3]) as independent prognostic factors (all p The validation cohort included 175 pts of the AZA-001 trial with higher-risk MDS. Apart from the presence of 5 (3%) int-1 pts in AZA-001 cohort (their removal did not affect conclusions), IPSS (int-2 in 42% high in 46%, at least int-2 in 9% vs 54%, 43%, 2% resp., p=0.15) was comparable to the ATU cohort, as well as RBC transfusion dependence ≥4 units/8 weeks (46 vs 45%, p=0.8), presence of circulating blasts (51 vs 45%, p=0.4), whereas all AZA-001 pts were de novo (vs 74% in the ATU cohort), had not been pretreated (vs 10% pretreated by LD AraC in the ATU cohort), had better PS (7% PS ≥2 vs 21% in the ATU cohort, p Conclusion: Our compassionate cohort scoring system based on conventional prognostic factors (ECOG PS, RBC transfusion requirement, circulating blasts and karyotype) was prognostic for survival. Additionally, it was successfully validated in a more selected cohort of higher-risk MDS from a prospective multicenter trial. Prognostic factors of outcome with AZA based on more refined biological studies (including gene methylation status) will probably emerge. In particular, we found in a more recent patient cohort (Itzykson, abstract also submitted to ASH 2010), that TET2 mutations may predict better response to AZA in higher risk MDS. Disclosures: Beach: Celgene: Employment. Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding.

Abstract 1084 Background: CNS relapse is rare in APL, and predominates in patients (pts) with increased WBC counts. (De Botton, Leukemia, 2006,20,35; Montesinos, Haematologica,2009,94,1242). We report the incidence, risk factors and outcome of CNS relapse in 2 multicenter clinical trials of the European APL group. Methods: Between 1993 and Feb 2004 (when randomization for AraC in APL 2000 trial ended), 916 APL patients (pts) were included in APL93 (n=576) and APL 2000 (n=340) trials, and 92.2% of them achieved CR (Ades L, Blood 2010, Ades L, JCO 2006). In both trials, induction treatment consisted of ATRA (45 mg/m2/d until CR) and DNR 60mg/m2/d x3 + AraC 200 mg/m2/dx7 followed by a first similar consolidation course and a second course with DNR 45 mg/m2/d x3 and AraC 1g/m2/12hx8 (except in one arm of APL 2000 trial where pts with WBC 10G/L. Median follow up was 10 and 5 years, respectively, in APL 93 and APL 2000 trial. Results: 6 first relapses involving the CNS were seen (3 in APL 93 and 3 in APL 2000 trial), after 6 to 37 months (median 15 months), representing 3% of the relapses (2% and 6% in APL 93 and 2000, respectively) and 0.7% of the pts who had achieved CR (0.56% and 0.9% in APL 93 and 2000, resp). Of the 6 CNS relapses, 1 was isolated and 5 accompanied by relapse in the bone marrow (haematological in 4 cases, and only molecular in 1 case). Median age was similar (46y) in pts who had or not CNS relapse. Median WBC count was 7.9 G/l in pts with CNS relapse vs 2.5G/l in pts without CNS relapse (p=0.07). 5 of the 6 pts with CNS relapses had WBC> 5G/L, but only 2 had WBC > 10G/l. Among pts who achieved CR, 3 of the 146 (2.05%) pts who received no Ara C had CNS relapse versus 3 of the 699. (0.4%) pts who received AraC (with HD araC in the last consolidation course) (p= 0.06). In pts with WBC > 10G/l, none of 72pts in APL 2000 (who received both HD araC and intrathecal CNS prophylaxis) had CNS relapse, compared 2 of the the 123 (1.6%) pts in APL 93 trial (who received HD araC and no intrathecal CNS prophylaxis). The 6 pts with CNS relapse were all salvaged by intrathecal CT, combined to ATRA and systemic CT in APL 93, and ATO in APL 2000 trial. 4 of them were durably salvaged, 3 after auto SCT and 1 after ATO and CT. Conclusion: CNS relapse was very rare in APL in our experience, and only 2 of 6 pts with CNS relapse had baseline WBC > 10G/l. CNS relapse was generally associated to concomitant marrow relapse (sometimes only molecular), and was seen in 0.4% and 2.05% pts treated with and without HD AraC, respectively (p=0.06), suggesting a possible preventive role of HD AraC, although numbers were small to conclude. Interestingly, by comparison, in the Spanish PETHEMA experience where pts received no AraC, 1.6% of the 667 pts who achieved CR had CNS relapse (Montesinos, Haematologica, 2009, 94, 1242). On the other hand, the role of intrathecal CNS prophylaxis was unclear in our experience. Finally, outcome of CNS relapses was better than in our previous report (De Botton, Leukemia, 2006,20,35), possibly due in part to the recent treatment of relapses by ATO, known to penetrate the blood brain barrier (Au et al, Blood, 2008,3587) and which could also play a role in CNS prophylaxis when administered during first line treatment. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Abstract 2125 Background: Over the last three decades, progress in the treatment of childhood acute lymphoblastic leukemia (ALL) has considerably improved the outcome of children, leading to 5-year OS of more than 80%. Numerous comparisons, including the French LALA/FRALLE (Boissel et al. JCO 2001), have reported a better outcome in teenagers treated with pediatric as compared to standard historical adult ALL protocols. Even if modern pediatric-inspired adult ALL protocols have recently reported impressive improvements, especially in younger patients (Huguet et al. JCO 2009), the issue of whether younger adults (YAs) should be treated according to pediatric or adult protocols remains an open one. The aim of this study was first to evaluate the feasibility and the results of a non-modified pediatric protocol (the French FRALLE 2000) in adolescents and younger adults (AYAs, aged 15–29 years) treated in adult departments. Methods: From February 2001 to June 2010, 72 AYAs with Ph-negative ALL were treated according to the pediatric FRALLE 2000-BT protocol in 12 adult hematology units in France and Belgium. After a prednisone prephase and a four-drug induction (prednisone, daunorubicin, vincristine and L-asparaginase), patients in CR received a consolidation, a 1st delayed intensification, an interphase, a 2nd delayed intensification, and a maintenance chemotherapy during two years. Results: The median age was 19 years (range, 15–29 years). The cohort was separated in 2 subgroups: 44 adolescents aged 15–19 years and 28 young adults (YAs) aged 20–29 years. There were no significant differences between the adolescent and the YA populations in term of sex ratio, white blood cell count (WBC), central nervous system involvement, and phenotype (BCP- vs T-ALL). As expected, few recurrent cytogenetical abnormalities were identified in this population and did not differed between both subgroups. In the adolescent group, we identified 2 patients with t(4;11), 1 patient with t(1;19), and 3 patients with hypodiploïdy and/or neartriploïdy, whereas this repartition was 2/2/1 in YAs. Rates of good early response to prednisone were in 68% in adolescents and 61% in YAs (p=.52), while rates of good early response to chemotherapy were 80% and 86%, respectively (p=.51). No patient died during induction. Complete remission (CR) rate did not differ between subgroups (98% vs 100%, p=.42). With a median follow up of 4.8 years, 5-year EFS was 57% (41% in adolescents vs 79% in YAs, p=.03) and 5-year OS was 67% (56% and 82% respectively, p=.09). In patients with BCP-ALL, 5-year EFS was 60% (43% in adolescents vs 91% in YAs, p=.02) and 55% in T-ALL (57% vs 50% respectively, p=.81). Twelve patients (17%) received an allogeneic stem cell transplantation (SCT) in first CR (5 adolescents and 7 YAs). Four patients died in first CR, all after SCT, (2 adolescents and 2 YAs). In univariate analysis, a high WBC (continuous variable, p=.02) and a poor early response to chemotherapy (33% vs 63%, p=.02), but not phenotype or poor early response to prednisone, were significantly associated with a shorter EFS. In multivariate analysis, age (adolescents vs YA, p=.04), WBC (continuous variable, p=.0005), and poor early response to chemotherapy (p=.006) had still an impact on EFS. The poor outcome of adolescents compared to YAs, also observed in the French adult GRAALL protocol (not published), was not explained by differences in ALL characteristics, early response to therapy, or treatment-related toxicity. Conclusion: The pediatric protocol FRALLE 2000 is effective and safe for the treatment of selected AYAs with Ph-negative ALL referred to adult departments. The results observed in the YA population are promising, warranting prospective comparisons with the more recent pediatric-inspired adult protocols. The unexpected poorer outcome of adolescents deserves further investigations to explore a potential impact of the quality of care delivered in an adult environment. Disclosures: No relevant conflicts of interest to declare.

Abstract 2183 Background: AZA has been shown to improve overall survival (OS) compared with conventional care regimens (p=0.005) in elderly pts with WHO-defined AML (20-30%) bone marrow [BM] blasts), despite a modest 18% CR rate (AZA 001 trial, JCO, 2010;10:223). AZA as frontline therapy also appears active in pts with AML with >30% blasts who are unfit for intensive chemotherapy (IC) (Thépot et al, Blood, 2009:A843). For AML pts receiving IC, CR is often considered a prerequisite to improved survival. In pts with higher-risk myelodysplastic syndromes (MDS) treated with AZA, an OS benefit has been observed in pts with a best response of partial remission (PR) or hematological improvement (HI), and most recently, stable disease (SD) (JCO, 2008;26:A7006; JCO, 2010;28:A6503). It is unknown whether OS benefits with AZA in the absence of CR will be obtained by pts with AML. We analyzed the best response to AZA obtained by pts with WHO AML (>20% blasts) from 2 independent pt cohorts who survived ≥2 years. Methods: AZA-001 included 55 pts with WHO-defined AML (20-30% BM blasts, none of them therapy related) randomized to AZA treatment, and the French AZA compassionate program (ATU) included 148 pts with WHO-defined AML treated with AZA as frontline therapy (median 33% marrow blasts), of whom 24% had therapy-related AML and 38% had AML post-MDS. Pts received AZA at the FDA/EMEA-approved schedule (75mg/m2/d × 7d/28d) for a minimum of 6 cycles in the AZA -001 trial, as did 48% of pts in the ATU for a minimum of 4 cycles (52% of pts in the ATU received AZA in a 5-day regimen, or less often, as a flat 100mg daily dose over 7 days). Responses to AZA in the ATU cohort reflect AML response criteria (JCO 2003;21:4642), or in the case of HI, IWG 2006 criteria for MDS (Blood 2006;108:419). Responses to AZA in the AZA-001 cohort reflect IWG 2000 criteria for MDS (Blood 2000;96:3671). Best responses were evaluated in pts who survived ≥2 years in both cohorts. Results: The 55 pts in the AZA-001 cohort had a median age of 70 years (52-80), 23% (20-34%) median BM blast count, and 26% and 69%, had IPSS unfavorable or intermediate cytogenetics, respectively. Pts received a median of 8 (1–39) AZA treatment cycles. With a median follow-up of 20.1 months, 11/55 (20%) pts in this cohort were alive ≥2 years after beginning AZA. None of the 11 pts had achieved CR or PR with AZA. According to IWG 2000 criteria, 4 pts had achieved HI and 7 pts had SD as best responses. In the ATU cohort, median follow-up was 15.6 months. Of 148 AML pts, 68 (46%) had entered the study ≥2 years before the reference date of analysis (Jan 2010). Of them, 29 pts had 20–30% BM blasts and 39 pts had >30% BM blasts. Of pts with 20–30% BM blasts, 7/29 (24%) were alive at 2 years. As best response to AZA, only 2 of the 7 pts (29%) had achieved CR, 2 achieved HI, and 3 had SD. Of pts with >30% BM blasts, 5/39 (13%) were alive at 2 years; best responses included CR (n=1), PR (n=1), morphologic CR with incomplete count recovery (CRi; n=2), and SD (n=1). Only 1 of the 12 AML pts who survived ′2 years had undergone allogeneic transplant (pt had AML with 20–30% BM blasts and SD as best response), after 4 cycles of AZA. Conclusion: In 2 independent cohorts of pts with AML treated with AZA, most pts with 20–30% BM blasts who survived ≥2 years (16/18, 89%) did so despite a lack of CR or PR. This finding appeared less clear in patients with >30% blasts. These results warrant confirmation in larger pt numbers but suggest that, as in MDS, traditional morphological responses of CR/PR may not be required to obtain prolonged survival in pts with AML, especially pts with 20–30% BM blasts, treated with AZA. Disclosures: Off Label Use: Azacitidine in Acute Myeloid Leukemia with >30% marrow blasts. Beach: Celgene: Employment. Swern: Celgene: Employment. Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding.

Abstract 976 Background: Lenalidomide (LEN) is particularly effective on anemia of lower risk MDS with del 5q (List et al, NEJM, 2006). A compassionate program (ATU) of LEN in RBC transfusion dependent (TD) low and int 1 (lower) risk MDS with del 5q was opened by the French health agency between Jan and Sept 2007. The concern raised by EMEA that LEN may trigger progression to AML in some MDS with del 5q lead us to compare the outcome of our cohort to that of RBC transfusion dependent lower risk MDS with del 5q that never received LEN. Methods: 95 RBC -TD lower risk MDS pts with del 5q, diagnosed between 1988 and 2007 in GFM centers, received 10 mg of LEN/day, 3 weeks on, 1 week off. Median age was 70.4 years, median interval from diagnosis to LEN was 29 months. IPSS was low in 31% and intermediate-1 in 69% patients. Del 5q was isolated, with 1 additional and > 1 additional abn in 79%, 14%, and 6% patients, respectively. 60 (63%) pts achieved transfusion independence (TI). We compared the risk of progression to AML and survival from diagnosis of this cohort and of a historical cohort of 99 similar RBC TD lower risk MDS with del 5q deletion diagnosed between 1985 en 2005 in GFM centers and treated before LEN was available in France (part of those pts have been reported in Kelaidi,Leuk Res 2008). For this non randomized comparison, we used the propensity score method. This method can estimate unbiased treatment effects from observational studies based on a propensity score, ie re-create the exchangeability between two treatments groups. We determined a propensity score defined as a subject's probability of receiving LEN conditionally on his observed covariates. For this purpose, we modeled through multivariate logistic regression, in pts with RBC transfusion dependent lower risk MDS with del 5q the probability of receiving LEN conditionally on a set of baseline characteristics (including age, gender, WHO diagnosis, IPSS score, cytogenetics). The estimated propensity was then used to match 1:1 patients with similar propensity to receive LEN. Results: In the LEN cohort, with a median follow up of 18.5 months from onset of LEN, 6 (6.3%) pts had progressed to AML, after 30 to 67 weeks (median 45 weeks), including 2 pts who had achieved TI. At onset of LEN, 4 of them had an IPSS of 1, and 2 of 0.5. Two had isolated del 5q and 4 had one additional cytogenetic abn. Baseline characteristics of the LEN cohort and the historical cohort treated without LEN were similar, except for age (median 73 years in the latter, vs 70.4, p= 0.03), and % of RARS (14% vs. 4%, p= 0.05). The propensity score was derived from a multivariate logistic model incorporating pt age at diagnosis, gender, WHO, IPSS and cytogenetics. Then, a matched-dataset was constituted between pts who received or not LEN. Seventy-one pts in each group could be matched, erasing differences in covariates between the two treatment groups. In those 71 matched pairs, the 4 year-cumulative incidence of AML from diagnosis was 8.9% in the 71 matched pts treated with LEN and 15.8% in the 71 matched pts who received no LEN (HR= 0.46, 95%CI: 0.16–1.35; p=0.14) (figure 1). Median overall survival was 150 months in the 71 pts treated with LEN vs 72.8 months in the 71 pts treated without LEN (HR= 0.54, 95%CI: 0.26–1.11; p= 0.10). Conclusion: Using a propensity score methodology, we found the incidence of progression to AML from diagnosis, in the present cohort treated with LEN, not to be greater than that of a comparable historical cohort of RBC transfusion dependent lower risk MDS with del 5q treated without LEN. Likewise, no significant survival difference was found between the 2 groups. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Abstract 4283 Introduction In recent area, management of CML has benefited from important changes with the development of targeted therapies and monitoring therapeutic response. Respect of good practices in rural countries, geographically isolated as the Limousin, requires patient's (pts) care in an health network like HEMATOLIM that includes 13 private or public health care facilities. The outcome of all new pts suffering CML, treated or not according a clinical trial and included in a regional database was analysed for estimate the impact of these new practices in real world. Patients and methods we conducted a retrospective observational, descriptive and analytical study of epidemiological data of consecutive pts with CML and in care into the regional network HEMATOLIM. Included criteria were cytogenetic or molecular proved CML, in regional pluridisciplinary staff and cytogenetic results and molecular response. Clinical data, biological data, therapeutic response, survival were collected in the database and statistically analysed by StatView. Results 176 pts diagnosed between 1978 and 2009, resident in Limousin for 75% (n=132), in limit departments 25% (n=44), sex ratio 1.2 and median age 59 years [22-84]. Between 2001 and 2007, regional incidence is 1.084/100000 pop per year versus 1 in France. At diagnosis, pts were in chronic phase 92% (n=162), accelerated phase 5.7% (n=10), blast crisis 0.6% (n=1), missing (ND) 1.7% for n=3 pts. Sokal was 1.2 11% (n=19), ND 4% (n=7). Cytogenetic t(9,22) or BCR-ABL expressing in initial molecular biology was 100% with another cytogenetic abnormality in 8%. Treatment was done by inclusion in a clinical trial (n=36) for 20% of pts. Treatment was Imatinib (IMB) for 72% (127/176) of pts with CML: 54% (n=68) in 1st line, 20% (n=26) 2nd line and 26% (n=33) 3rd line or more. RCC at 6, 12 and 24 months were respectively 57% (75 pts evaluable), 66% (71), 83% (58). RMC at 6, 12 and 24 months were respectively 14% (59), 23% (66), 37% (73). During treatment, 12% pts had resistance to IMB (n=15): 2 of them had a mutation of resistance to the IMB (2/15). Toxicity to IMB was observed in 12% (n=15). Pts have developed another malignancy during or after tyrosine kinase inhibitor (TKI) treatment for 9.5% (n=12) localized to prostate 3, colon 2, breast 1, pancreas 1, lung 1, parotid 1, melanoma 1, kidney 1 and bladder 1. Median survival of pts receiving TKI in 1st line is not reached, receiving TKI in 2nd line or more: 18 years and for pts never receiving TKI (1978-) 4 years (p Conclusion In real life, impact of TKI and monitoring of molecular response on the survival of pts with CML is strongly illustrated by this retrospective cohort network study. The better survival since the XXI century included elderly patients CML, having already received several lines of treatment and often excluded of clinical research due to comorbidity. A long term follow-up of these cohorts of pts will be interesting in term of incidence of ITK resistance, emergence of second malignancies and medico-economic impacts. Disclosures: No relevant conflicts of interest to declare.