ALBERT

Description: Abstract 1773 Poster Board I-799 Background Patients aged ≥ 80 years account for as many as 30 to 35% of MDS in large registries (Rollison Blood 2008; Germing Ann Hematol 2008). Those patients (pts), when they have high risk MDS, are rarely candidates for chemotherapy (CT), even at low dose like low-dose araC, due to the risk of myelosuppression, and generally receive best supportive care (BSC) only, with very poor survival. Azacytidine (AZA) improves survival in higher-risk MDS pts, including RAEB-t and in pts aged 〉 75, with more limited myelosuppression than CT (Lancet Oncol 2009). Methods An AZA compassionate program (ATU) was opened in France between Dec 2004 and Dec 2008 for higher risk MDS, and for AML not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed the outcome of MDS (including RAEB-t and CMML) pts ≥ 80 years from the 42 centers with complete patient (pt) reporting, and having received ≥ 1 cycle of AZA. Results The study population included 41 pts (M/F: 22/19; median age 83y, range 80-91) WHO diagnosis was RMCD in 2, RAEB-1 in 12, RAEB-2 in 16, and RAEB-t in 8, CMML in 3; IPSS cytogenetic risk favorable (fav) in 16, intermediate (int) in 10, and unfavorable (unfav) in 9 (karyotype failure/not done in 6); IPSS was int-1 in 8, int-2 in 18 and high in 13, undetermined in 2. Six pts had previously been treated unsuccessfully with low-dose AraC. With a median follow-up of 12 months, pts had received a median of 4 cycles (1-12) of AZA, at FDA/EMEA-approved schedule (75 mg/m2/d x7d/4 w) in 54% or a less intensive schedule (5d/4w, or

Description: Abstract 1697 Background Abnormal and clonal hematopoiesis resulting in peripheral blood cytopenias, and risk of progression to acute myeloid leukemia (AML) are the main characteristics of myelodysplastic syndromes (MDS) which present a high diversity of somatically mutated genes. Recently, mutations targeting genes whose products participate to the early steps of RNA splicing (SF3B1, SRSF2, ZRSR2, and U2AF35) have been reported. Mutations in ASXL1, DNMT3, EZH2, IDH1/2 and TET2, suggest deregulation of the epigenetic control of transcription. Additional genes known to be mutated in MDS include RUNX1, TEL/ETV6, TP53 and NRAS The alteration of some of these genes may carry prognostic value. Next-generation sequencing analyses of AML and related disorders recently identified mutations in two chromosome X genes, BCOR and BCORL1, that code for related transcriptional co-repressors interacting with histone deacetylases and presenting specific properties. BCOR interacts with BCL6 and constitutional inactivating mutations have been described in the Oculo-Facial-Cardio-Dental syndrome. BCOR is also affected by mutations or translocations in retinoblastoma and sarcoma. BCORL1 has been implicated in chromosomal rearrangements in hepatocellular carcinoma. In this study, we have investigated BCOR and BCORL1 gene by Sanger sequencing in a cohort of 221 MDS samples. Methods The 221 MDS samples were collected at diagnosis in multicenter clinical trials in France between 1999 and 2011. The coding sequences of BCOR (ENST00000378444) and BCORL1 (ENST00000218147) were analyzed by Sanger sequencing. Mutational analyses of ASXL1, CBL, DNMT3A, ETV6, EZH2 IDH1/2, JAK2, NRAS, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF35, and ZRSR2 were previously reported. Non tumoral material (buccal swab or CD3+ cells) was analyzed for the presence of the identified variations of BCOR or BCORL1 when available (n=9). The prognostic impact of BCOR mutations was evaluated in MDS patients with available follow-up information (n=203). Results BCOR and BCORL1 coding sequences were analyzed in the cohort of 221 MDS patients and we found mutations in 8.6% (n=19) and 2.3% (n=5) respectively. Alterations were distributed all over the coding regions. Strikingly, two patients presented concomitant inactivating mutations of BCOR and BCORL1. Among the 19 BCOR alterations, 9 were missense, 3 nonsense, 5 frameshift and 2 splice site mutations. No significant difference in age, sex, karyotype, blood counts or bone marrow blasts between BCORmut and BCORwt patients was observed. Mutations were found in patients of all IPSS risk-groups and WHO subtypes. Comparison of cytological bone marrow reports revealed a trend for a higher rate of dysgranulopoiesis in BCORmut patients (P=0.06). Because only truncating mutations (splice, frameshift and nonsense mutations) are unambiguously expected to affect BCOR function, statistical analyses were restricted to truncating BCOR mutations (n=10/221, 4.5%). Truncating BCOR mutations were frequent in RUNX1mut patients (19% versus 3% in RUNX1wt patients; P=0.027). They were by trend associated with SRSF2 and DNMT3A mutations (P=0.09) and were exclusive with IDH1/2, JAK2, NRAS, TP53, and ZRSR2 mutations. In univariate analysis, Overall Survival (OS) and AML transformation rate did not differ between patients with either missense or truncating BCOR mutations and BCORwt patients (Figure A&B). However, inferior OS (P=0.034) and higher AML transformation rate by trend (P=0.051) were observed for patients with truncating BCOR mutations (Figure C&D). Multivariate analysis demonstrated that a truncating BCOR mutation was an independent unfavourable prognostic factor for OS (HR 3.3; 95%CI 1.4 – 8.1; P=.008). The low number of BCORL1 mutated patients precludes any statistical analyses but clinical follow-up was available for 4 out of 5 patients. Three patients died 7, 17 and 27 months after MDS diagnosis. The fourth patient received allogeneic bone marrow transplantation after AML transformation and is in complete remission 5 years after transplantation. Conclusion In summary, truncating mutations of BCOR were independently associated with a worse OS in MDS. These data support the idea that BCOR mutations appear as associated with RUNX1 and DNMT3A mutations as reported in AML. Moreover, and despite a relatively low mutation frequency in MDS, BCOR might be considered as a key gene in risk stratification. Disclosures: No relevant conflicts of interest to declare.

Description: The transcription factor C/EBPα is crucial for differentiation of mature granulocytes. Recently, differentCEBPA gene mutations likely to induce differentiation arrest have been described in nearly 10% of patients with acute myeloid leukemia (AML). In the present study, we retrospectively analyzed the prognostic significance of CEBPA mutations in 135 AML patients (French-American-British [FAB]-M3 excluded). All patients were prospectively enrolled between 1990 and 1996 in a multicenter trial of the ALFA (Acute Leukemia French Association) Group (median age 45 years, median follow-up 5.7 years). Mutations were assessed using direct sequencing of the CEBPA gene. Twenty-two mutations were found in 15 (11%) of 135 patients tested. Twelve patients had at least one mutation located in the N-terminal part of the protein leading to the lack of expression of the full-length C/EBPα protein. CEBPA mutations were present only in patients belonging to the intermediate cytogenetic risk subgroup and associated with the FAB-M1 subtype (P = .02). FLT3 internal tandem duplication (ITD) was found in 5 of 15 CEBPA-mutated as compared with 30 of 119 CEBPA-nonmutated cases tested (P = .54). Presence of CEBPA mutations was identified as an independent good prognosis factor for outcome even after adjustment on cytogenetics and FLT3 status (estimated 5-year overall survival 53% vs 25%, P = .04).FLT3-ITD appeared to act as a major bad prognosis factor in patients with CEBPA-mutated AML. We thus propose a risk classification that includes in the favorable subgroup all patients from the intermediate subgroup displaying CEBPA mutations when not associated with FLT3-ITD.

Description: Background: Findings, that activation of the DDR-pathway in preneoplastic lesions of solid neoplasms slows tumorigenesis, could also underly progression of MDS to AML. We previously showed (ASH 2006, abstr n° 2649), that - in contrast to the de novo AML-derived KG-1 cells - irradiated MDS/AML-derived cell lines P39 and MOLM-13exhibit earlier and greater cell cycle arrest in G2/M and a higher percentage of apoptotic cells;upregulate the crucial checkpoint kinase Chk1-P-Ser317;decrease G2/M-arrest upon inhibition of Chk1 (and to a lesser extent upon inhibition of ATM). Methods: We further analyzed this differential checkpoint regulation in MDS versus AML cell lines by assessing irradiation-induced apoptosis in the presence of Chk1- and ATM-inhibitors and the functional role of H2AX, situated below the crucial checkpoint kinase Chk1. Myeloid cell lines P39, MOLM-13, MV4-11, and KG-1 were g-irradiated and their ability to undergo apoptosis (DIOC/PI staining) quantified in the absence and presence of the Chk1 inhibitor UCN-01 and the ATM inhibitor KU-55933. Protein expression of activated H2AX was quantified by immunoblot analysis with an anti-H2AX-P-Ser139 antibody. Histological staining of bone marrow biopsies from patients with low and high risk MDS, and AML was made with an anti-H2AX-P-Ser139 antibody. Staining was considered positive if at least 20% of the biopsy surface exhibited 50% or more stained cells. Results: In the presence of the ATM inhibitor irradiated KG-1 cells retained their apoptosis-resistance, and irradiated P39, MOLM-13 and MV4-11 cells exhibited the same degree of apoptosis as seen in the absence of the inhibitor. In contrast, inhibition of Chk1 (newly) established apoptosis-sensitivity in KG-1 cells (which showed about 30% of DIOC-low cells following 24 hours of irradiation with 10 Gy), while having only minor effects on the other cell lines. Determining the concomitant activation status of H2AX, which is a downstream target of Chk1, showed that irradiation induced a comparable expression of H2AX-P-Ser139 in MDS and AML cell lines. Co-incubation with the Chk1 inhibitor was associated with lower expression of activated H2AX in the irradiated MDS cell lines P39 and MOLM-13 as compared to irradiated KG-1 cells. Histological staining of marrow biopsies with an anti-H2AX-P-Ser139 antibody demonstrated that activation of H2AX is less frequent in low risk MDS (1/10 samples) than in high risk MDS (9/18 samples) and AML (4/6 samples). Conclusion: Further analyzing the different capacities of MDS and AML cells to employ DDR-pathways, we provide additional insights into the functional relevance of ATM and Chk1 inhibition in the apoptotic DDR, and give preliminary evidence for a differential activation of H2AX in irradiated cell lines and patient samples of MDS and AML.

Description: Introduction: IDH2 mutations (mIDH2) are recurrent in ~5% of patients (pts) with MDS and ~15% of pts with acute myeloid leukemia (AML). mIDH2 proteins have neomorphic enzymatic activity and are associated with DNA and histone hypermethylation, altered gene expression, and blocked differentiation of hematopoietic progenitor cells. Enasidenib (AG-221/CC-90007) is a small-molecule allosteric inhibitor of mIDH2 protein that induces hematological responses in pts with mIDH2 AML, including relapsed or refractory (R/R) AML (Stein, Clin Cancer Res, 2016). The current analysis is the first to evaluate the safety and clinical efficacy of enasidenib monotherapy in pts with mIDH2-positive MDS. Methods: This analysis includes pts ages ≥18 years with MDS and mIDH2 who participated in a phase 1 study with a dose-finding period followed by an expansion phase in which all pts received daily oral enasidenib 100 mg QD in 28-day cycles. Pts had R/R MDS or were not candidates for standard therapies. Response was measured using peripheral blood (PB) and bone marrow (BM) samples from days 15, 29, 57, and every 56 days thereafter, and by objective investigator report. Overall response rate (ORR) reflects the best response achieved by pts, and includes complete remission (CR), partial remission (PR), marrow CR (mCR), and any hematologic improvement (HI) (IWG 2006 MDS criteria). Evaluable pts required a response assessment at Cycle 2 Day 1 or later, or discontinued before assessment. Overall survival (OS) was estimated using Kaplan-Meier methods. Next-generation sequencing identified pre-existing co-occurring genomic alterations using the FoundationOne® Heme test on purified mononuclear cells from BM or PB, to assess relationships between co-mutational status and clinical response. Results: Of 16 pts with MDS in this study, 12 pts had discontinued and 4 pts continued to receive enasidenib at interim database lock (15 April 2016). Reasons for discontinuation included disease progression (n=1), adverse event (AE; n=1), death (n=4), investigator decision (n=2), and other (n=1); 3 pts proceeded to transplant. Median age was 67 years (range 45-78) (Table 1). R140 mutations were more common than R172 mutations (88% vs 12%). At entry, 3 pts (19%) had relapsed following allogeneic stem cell transplant and 11 (69%) had failed prior treatment (Tx) with a hypomethylating agent (HMA). Six pts (38%) had received ≥2 prior anticancer Tx for MDS. MDS pts in the dose-finding phase received daily enasidenib doses of 60 mg (n=1), 150 mg (1), 200 mg (3), or 300 mg (1); 10 pts received enasidenib 100 mg QD. Median number of Tx cycles was 3 (range 1-25); 5 pts (31%) received ≥6 enasidenib cycles and 4 pts (25%) received ≥12 cycles. Grade 3-4 Tx-emergent AEs (TEAEs) were reported for 13 pts (81%); the most frequent were hyperbilirubinemia (n=5, unconjugated), pneumonia (n=4), thrombocytopenia (n=3) and hypokalemia (n=3). Seven pts (44%) had a grade 3-4 drug-related TEAE. One pt was not evaluable for response. ORR was 53% (8/15), including 1 pt who achieved CR (Figure 1). Of 10 evaluable pts who had received prior HMA Tx, 5 (50%) had a response with enasidenib, including the pt in CR. Of the 4 pts with no prior MDS Tx, 2 responded (1 PR, 1 mCR). Median time to CR, PR, or mCR (sustained ≥4 weeks) was 24 days (range 17-87) from beginning enasidenib Tx, and to HI (sustained ≥8 weeks) was 11 days (11-60). Two pts experienced disease progression. Median OS was not reached after a median follow-up of 4.7 months. FoundationOne® data were available for 12 pts; the most frequently observed known somatic co-occurring mutations were ASXL1 and SRSF2 (Figure 2). Although trends between response and co-occurring ASXL1 and/or SRSF2 mutations were observed, the small number of pts tested prevents definitive conclusions. Discussion: Daily Tx with oral enasidenib monotherapy was well tolerated and induced responses in more than one-half of these MDS pts with mIDH2, 50% of whom had higher-risk disease, and two-thirds of whom had failed prior HMA Tx. Notably, one-half of evaluable MDS pts who had failed prior HMA Tx had a response, including a CR, with enasidenib monotherapy. Only 2 pts experienced disease progression during Tx. Mutational testing is rapidly becoming essential to diagnosis and prognostication in MDS, and assessment of IDH2 mutations can identify MDS pts who may benefit from targeted Tx with enasidenib. Disclosures Stein: Seattle Genetics: Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Consultancy. Fathi:Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. DiNardo:Novartis: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding. Pollyea:Celgene: Other: advisory board, Research Funding; Ariad: Other: advisory board; Glycomimetics: Other: DSMB member; Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding. Roboz:Celgene: Consultancy; Astex: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Genoptix: Consultancy; Amgen: Consultancy; MEI Pharma: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Onconova: Consultancy; Sunesis: Consultancy; Novartis: Consultancy; Roche/Genentech: Consultancy; MedImmune: Consultancy; Celator: Consultancy; Amphivena: Consultancy. Sekeres:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Stone:Pfizer: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Juno Therapeutics: Consultancy; ONO: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Roche: Consultancy; Xenetic Biosciences: Consultancy. Attar:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Tosolini:Celgene: Employment, Equity Ownership. Xu:Celgene: Employment, Equity Ownership. Amatangelo:Celgene: Employment, Equity Ownership. Gupta:Celgene: Employment, Equity Ownership. Knight:Celgene: Employment, Equity Ownership. De Botton:Agios, Celgene, Pfizer, Novartis, Pierre Fabre, Servier: Consultancy, Honoraria, Research Funding. Kantarjian:Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Description: Background : Following FDA approval of AZA for MDS and activation of a phase III trial randomizing AZA to conventional treatment in higher risk MDS, a compassionate program for the use of AZA (ATU nominative) was started in France for MDS with exclusion criteria for this trial. Patients (pts) : IPSS int-2 and high-risk MDS (and some int-1) with contra-indication to the trial (ie therapy related (t-MDS) or already treated by cytoreductive agents or having progressed to AML or patient refusal), received AZA 75 mg/m/d (d 1–7) (SC) every 4 weeks. Results : From Sept 2004 to May 2006, 90 pts from 31 centres were included, of whom 77 had completed at least one course of AZA : M/F: 52/25, median age 71 y [42–88]. WHO at inclusion : 15 RAEB1, 30 RAEB2, 14 AML post-MDS, 7 CMML, 3 RA, 3 RAS, 2 RCMD, 3 unclassified MDS. 22 pts had previously received intensive Anth-AraC, 9 low dose AraC, 16 EPO and 13 other treatments (alkylators, Arsenic, androgens, Thal) and 1 had t-MDS. 32 (42%), 16 (21%) and 29 (37%) pts had fav, int and unfav karyotype, resp. 37 pts (48%) were IPSS high, 26 pts (34%) int-2 and 14 pts (18%) int-1. Pts received a median of 4 cycles [range 1–16]. Response was generally assessed after 4 cycles, unless pts progressed before. Thus, 16 pts were not yet evaluable for response. Of the remaining 61 pts, 10 (16%) achieved CR (IWG criteria), 15 (25%) achieved PR and 13 (21%) achieved HI (Overall response rate OR=62%). 23 pts (38%) were considered failure of whom 4 died before evaluation and 10 of them were considered failure because early evaluation after only 2 cycles showed stable disease only, and AZA was then stopped. OR was 73%, 57%, 67% and 36% for RAEB1, RAEB2, CMML and AML post-MDS resp (p

Description: All-trans retinoic acid (ATRA) plus anthracycline chemotherapy is the reference treatment of newly diagnosed acute promyelocytic leukemia (APL), whereas the role of cytosine arabinoside (AraC) remains disputed. We performed a joint analysis of patients younger than 65 years included in Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) LPA 99 trial, where patients received no AraC in addition to ATRA, high cumulative dose idarubicin, and mitoxantrone, and APL 2000 trial, where patients received AraC in addition to ATRA and lower cumulative dose daunorubicin. In patients with white blood cell (WBC) count less than 10 × 109/L, complete remission (CR) rates were similar, but 3-year cumulative incidence of relapse (CIR) was significantly lower in LPA 99 trial: 4.2% versus 14.3% (P = .03), although 3-year survival was similar in both trials. This suggested that AraC is not required in APL with WBC count less than 10 × 109/L, at least in trials with high-dose anthracycline and maintenance treatment. In patients with WBC of 10 × 109/L or more, however, the CR rate (95.1% vs 83.6% P = .018) and 3-year survival (91.5% vs 80.8%, P = .026) were significantly higher in APL 2000 trial, and there was a trend for lower 3-year CIR (9.9% vs 18.5%, P = .12), suggesting a beneficial role for AraC in those patients.

Description: In a large series of patients with Ph1-ALL treated in the LALA-94 trial, negative BCR-ABL minimal residual disease (MRD) and allogeneic donor availability were two independent good-risk factors for survival in those reaching hematological complete remission (HCR) after standard induction followed by intensive HAM consolidation (Dombret et al. Blood2002;100:2357). The HAM regimen included intermediate-dose cytarabine (1 g/m2/12h Day 1 to 4) and mitoxantrone (10 mg/m2 Day 3 to 5). The fraction of HCR patients in molecular CR (MCR) after HAM was 38%, with a median RT-PCR sensitivity of 10−5. In the present Phase I/II study, we combined increasing dosages of imatinib with HAM (HAMI regimen) in an attempt: 1) to increase the fraction of MCR patients from 38 to 75% (as primary objective); and 2) to evaluate the safety of the combination regimen and the feasibility of autologous peripheral blood stem cell (PBSC) collection after HAMI (as secondary objectives). Patients aged 18–60 years with Ph1-ALL in HCR after 1 or 2 cycles of chemotherapy were eligible in the absence of counter-indication for further stem cell transplantation. Imatinib was administered daily from Day 1 of HAM. MRD was assessed by RQ-PCR at Day 0 and Day 45 of HAMI. MCR was defined as a BCR-ABL level lower than 10−5 at Day 45. Twenty-two patients have been enrolled. Results observed in the first 18 patients treated in 3 consecutive 6-patient cohorts at 400, 600, and 800 mg/d imatinib, respectively, are available. Main results may be summarized as follows: 1) an excessive toxicity was observed in the 800 mg/d cohort leading to recommend the 600 mg/d dosage for further combinations of imatinib and intensive chemotherapy; 2) only 5 of the 15 patients tested (33%) reached MCR at Day 45 of HAMI and no clear correlations were found between molecular response and imatinib dosage or Day 0 MRD level; 3) after HAMI, PBSC collection was feasible under imatinib administration in 9 out of 14 patients (64%) with an apparent relationship between failure to collect and no MCR (P=.08); 4) only 3 patients were not able to receive allogeneic or autologous transplantation as further consolidation (1 early relapse, 1 severe infection, 1 too high MRD level); and 5) estimated 18-month disease-free and overall survival were 58% and 78%, respectively, with 8/15 patients receiving imatinib during the post-transplant period. In conclusion, failure to improve the MCR rate as compared to our no-imatinib historical control could be explained by the relatively short exposure to imatinib and/or by the absence of in vivo synergism between imatinib and cytarabine or mitoxantrone. More benefit might be anticipated by incorporating imatinib earlier in the treament i.e. first induction course. Further studies are needed to evaluate the role of post-transplant maintenance with imatinib.

Description: Introduction. One frequent option for consolidation chemotherapy in younger patients with AML-CR1 is based on repeated cycles of high-dose cytarabine (HDAC), according to the CALGB schedule (RJ. Mayer, NEJM 1994). Nevertheless, relapse incidence remains high, especially in those with non-favorable AML. CLARA combination (1,000 mg/m2/d cytarabine d1-5, 40 mg/m2/d clofarabine d2-6) has been associated with promising response rate in high-risk AML patients (S. Faderl, Blood 2005 and 2006). In this pilot study, we compared the feasibility and safety of CLARA vs HDAC for CR1 consolidation. Methods. Between 2004 and 2007, 36 patients aged 17–63y (median, 38y) with AML-CR1 (16 favorable, 12 intermediate, 8 unfavorable cytogenetics) and non eligible for allogeneic transplantation received a total of 75 consolidation cycles (12 CLARA, 63 HDAC). All had previously received remission induction according to ALFA protocols. As CLARA was tested only in non-favorable patients, cytogenetics was unbalanced (P=0.004). Approximately half of HDAC patients but no CLARA patient had CBF-AML. However, median age was similar between both groups. All patients received oral antibacterial prophylaxis with amoxicillin or levofloxacin. Results. Grade ≥ 2 nausea/vomiting was observed during most CLARA cycles while not during HDAC. Myelosuppression appeared to be more rapid and profound but not longer after CLARA as compared to HDAC. After CLARA, the median time to reach a PMN count 〈 0.5 × 109/L was 8 days (6–10), while it was 11 days (5–20) after HDAC (P=0.0001). The percentage of patients requiring platelet transfusion was 100% in the CLARA group vs 52% in the HDAC group (P=0.001). A trend for a more rapid recovery (PMN count ≥ 0.5 × 109/L) was observed after CLARA (P=0.07). At day 30 after the onset of chemotherapy, all CLARA patients had recovered while 25% of HDAC patients had not. This trend was observed after the first as well as after subsequent cycles. Median time between recovery and onset of the subsequent cycle was 6 days (3–10) and similar in both groups. Mucositis (mostly Grade 1) was more frequent after CLARA than after HDAC (58% vs 5%; P

Description: Mutations of the CCAAT/enhancer binding protein alpha (CEBPA) gene have been associated with a favorable outcome in patients with acute myeloid leukemia (AML), but mainly in those with a normal karyotype. Here, we analyzed the impact of associated cytogenetic abnormalities or bad-prognosis fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in 53 patients with CEBPA+ de novo AML treated in the Acute Leukemia French Association trials. We found that only those with a normal karyotype and no FLT3-ITD displayed the expected favorable outcome. In this context, relapse-free, disease-free, and overall survival were significantly longer than in corresponding patients without the CEBPA mutation (P = .035, .016, and .047, respectively). This was not observed in the context of an abnormal karyotype or associated FLT3-ITD. Furthermore, after adjustment on age, trial, and mutation type, these features were independently predictive of shorter overall survival in the subset of patients with CEBPA+ AML (multivariate hazard ratio = 2.7; 95% confidence interval, 1.08-6.7; and 2.9; 95% confidence interval, 1.01-8.2; with P = .034 and .05, for abnormal karyotype and FLT3-ITD, respectively).