ALBERT

Description: Introduction. AML standard intensive induction chemotherapy ("3+7" or equivalent) combined with wide spectrum antibiotics can dramatically alter the composition of the gut microbiota, leading to dysbiosis which is characterized by loss of microbial diversity. Such dysbiosis status can promote a pathological condition involving uncontrolled local immune responses, systemic inflammation and increased incidence of adverse events. The development of FMT-based drugs to restore microbial communities could offer novel therapeutic possibilities to reduce such adverse events and potentially improve outcomes in AML. We therefore conducted this single arm prospective phase I/II multicenter trial (NCT02928523) to evaluate the use of a FMT-based drug in association with AML induction treatment to restore the gut microbiota diversity. Patients and methods. A total of 62 consecutive patients aged between 24 and 69 years old with a diagnosis of de novo AML were screened in 7 French sites. At time of admission and AML diagnosis (Step 1=S1), patients' faeces were collected, rigorously screened, prepared following a standardized process, and stored at -80°C until later administration. The drug was administered as an enema after hematopoietic recovery (S2) and before consolidation chemotherapy (Conso). The primary endpoint was the recovery of at least 70% of microbiota diversity (based on the Simpson index) after drug administration and the reduction of multidrug resistant bacteria carriage. Blood and feces samples were collected at S1, S2, and around 10 days post-FMT before Conso (S3). Microbiome diversity restoration was assessed by metagenomics analysis through Illumina HiSeq shotgun sequencing. Antibiotic resistance gene carriage (ARGC, also known as resistome) was evaluated through mapping of readouts on the MEGARES database. Secondary objectives included safety and analysis of host response with assessment of blood and fecal markers by ELISA and Luminex. Results. Overall, 25 patients were actually treated with FMT, and 20 were included in the per-protocol population. Induction Chemotherapy (IC) induced a dramatic shift in microbial communities, with a significant 42.3% decrease of mean α-diversity Simpson index between S1 and S2 at species level (0.85 to 0.50; p

Description: Key Points The prognostic impact of time from diagnosis to treatment in AML is offset by other factors such as age, secondary AML, or genetic abnormalities. Waiting a short period of time to characterize leukemias better and design adapted treatments at diagnosis seems possible.

Description: Platelet transfusion refractoriness (PTR) is defined by the repeated failure to appropriately increment platelet count after platelet transfusion. PTR represents a real concern in the management of patients (pts) who require iterative platelet transfusions, in particular those undergoing intensive treatment (Stanworth, Br J Haematol 2015). PTR can be secondary to non-immune and immune causes and is associated with adverse events including longer hospital stays, severe hemorrhages and increased risk of early deaths. After induction chemotherapy for acute myeloid leukemia (AML), intensive transfusion support is required during the 4-6 weeks of treatment-induced aplasia. There is few data regarding management and outcome of AML pts with PTR in this setting. This study included all consecutive pts treated by intensive chemotherapy for non-promyelocytic AML in Toulouse University Hospital between January 2001 and December 2014 who developed PTR during the induction phase. Platelet count is measured daily and transfusion of ABO-identical platelets is performed when

Description: Background: Myelofibrosis (MF) is the less frequent Philadelphia-negative myeloproliferative neoplasms (MPN). We have included in a nationwide database primary (P), post-polycythemia (PPV) and post-essential thrombocythemia (PET) MF diagnosed in France since 2005. Methods: Inclusion criteria were: diagnostic of MF after 2005; according strictly to WHO (bone marrow biopsy mandatory); informed consent. The registry was launched in Oct. 2013, and 26 hematology centers included patients (pts). Summary statistics were reported, namely median [Interquartile range, IQR] or percentage. Baseline characteristics were compared across IPSS groups using chi-square test or Mann and Whitney test. Kaplan-Meier survival curves were plotted and compared by the log-rank test. Results: At time of analysis (June 2016) a total of 527 pts were included in the registry, complete baseline data were available in 499 (95%), and follow-up (FU) data in 433 (87%). Median [IQR] age and M/F sex ratio were 71 [63-78] years and 315/184 (1.7), respectively (resp). 301 (60%) pts had PMF, 182 (36%) had secondary MF (including 64 PPVMF and 118 PETMF) and 16 had pre-fibrotic MF. Five percent of pts had a familial history of hematologic malignancy, and 22% a history of thrombosis or hemorrhage. Splenomegaly was present in 386 (77%) with a median [IQR] spleen size of 4 cm [1-8] below costal margin, and was symptomatic in 11% of pts. Constitutional symptoms were present in 107 (21%) (weight loss in 56, night sweats in 61, fever in 14), and ECOG score was 0, 1, 2, and 3 in 53%, 36%, 11% and 0.3% of pts, resp. Median [IQR] Hemoglobin, WBC and platelet counts were 109 g/L [94-122], 9.3 G/L [5.7-16.0] and 257 G/L [138-430], resp. Circulating blast cells were present in 41%, LDH was above normal value in 95% of pts, median EPO level was 54 [11 - 57] U/L. Grade of fibrosis (WHO) was 1, 2, and 3 in 2%, 66% and 32% of pts, resp. Karyotype was done in 321 pts, normal in 173 (54%), abnormal with favorable prognostic value in 89 (30%) and unfavorable in 30 (10%) (29 failures). A total of 461 (92%) pts had molecular testing: 60% were JAK2V617F positive, 4% had MPL and 7% had CALR mutations, and 99 (28%) over the 352 pts with triple testing were triple negative. IPSS risk categories were low, int-1, int-2 and high in 68 (14%), 168 (34%), 158 (32%), and 105 (21%) pts, resp. In addition to constitutional symptoms, there was a significant increase in the prevalence of clinical signs across IPSS categories (from low to high risk): symptomatic spleen (p=0.016) -though no difference in spleen size was found (p=0.18)-, early satiety (p=0.013), ECOG score (p= 0.0001), bone pain (p=0.002). Moreover, among biological parameters, there was an increase across IPSS groups in WBC (p=0.029), LDH (p=0.0007), ferritin (p=0.003), circulating CD34+ cells (p=0.020), EPO level (p=0.035). In contrast, a decrease was seen for hemoglobin and platelets (p=0.0001 for both). Lastly, frequency of grade 3 fibrosis increased with IPSS (p=0.043), while no evidence of difference was found regarding abnormal karyotype and mutational pattern. Median FU was 33 months [9-63 months]. Among those 433 pts with FU data, median FU was 38 months [19-68], and 124 (29 %) pts had died at the time of analysis, including 13%, 17%, 31%, and 40% of pts from the Low, Int-1, Int-2, and High risk groups, resp (p= 0.0001, figure 1). In the 450 pts with treatment data, treatments received during FU included cytoreductive drug (41%), Jak-inhibitors (35%), Interferon alpha (18%), IMIDs (4%). Splenectomy was performed in only 14 (3%) pts. Forty percent of pts received packed red blood cells, and 12% platelets transfusions. 49 (11%) patients participated in a clinical trial, and 27 (6%) were allografted. Conclusion: This is the first analysis of the French MF observatory after inclusion of more than 500 pts diagnosed and treated during the past 10 years. Complete baseline data and follow-up information available for the majority of pts should allow for new studies of outcomes and influence of clinical and biological parameters, as well as reassessment of prognostic models in the era of new targeted therapies. Figure 1 Comparison of overall survival according to IPPS Figure 1. Comparison of overall survival according to IPPS Figure 2 Figure 2. Disclosures Etienne: Pfizer: Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Tavitian:Novartis: Membership on an entity's Board of Directors or advisory committees. Ugo:Novartis: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: The majority of relapses in acute myeloid leukemia (AML) patients occur in the first or second year following complete remission. In routine, AML patients are followed during five years because few relapses can occur after three or five years. These late or very late relapses remain poorly described, particularly at the molecular level, with only few consistent series in the literature. (Medeiros B et al., Leuk Lymphoma 2007; Verma D et al., Leuk Lymphoma 2010; Watts J et al., Leuk Res 2014). We retrospectively studied all AML relapses occurring after complete remission (CR) obtained with one or two induction cycles between 2000 and 2012 in Toulouse University Hospital, France. Our analyses focused on late relapses (LR, 〉3 years from CR) and very late relapses (VLR, 〉5 years from CR) in comparison to early relapses (ER, ≤3 years from CR). Between 2000 and 2012, out of 636 CR patients, 346 had morphological relapses (54.4%). The median time to relapse was 0.9 years (range, 0.1-11.9 years; interquartile range [IQR], 0.5-1.5 years). There were 198 relapses during the first year (57.2%), 82 during the second year (23.7%), 24 during the third year (6.9%) whereas 42 relapses occurred after 3 years (12.1%) and 16 after 5 years (4.6%). Characteristics at diagnosis, i.e., age, AML status, WBC count, karyotype, FLT3-ITD mutation, CEBPA mutation and induction regimen did not differ between ER and LR or VLR. However, NPM1 mutations were more frequent in LR (NPM1m at diagnosis in relapses 〉3 years: 46% vs. 28% in relapses 5 years: 67% vs. 27% % in relapses 5 years: 2.5%; 〉8 years: 0.6%; P=.0317, .0037 and .0783 respectively). NPM1m relapses represented one half of LR (48%) and two thirds of VLR (67%). Among them, genotype was NPM1m/FLT3-wild type in most patients (75% in LR and 88% in VLR patients). In LR and VLR, NPM1 mutational status had no impact on CR2 and OS2: CR2LR/NPM1m: 42% vs. CR2LR/NPM1-WT: 38% (P=.8702); CR2VLR/NPM1m: 50%vs. CR2LR/NPM1-WT: 50% (P=1.0000); OS2LR/NPM1m: 7.4 months vs. OS2LR/NPM1-WT: 19.4 months (P=.2019); OS2VLR/NPM1m: 7.8 months vs. OS2VLR/NPM1-WT: 29.8 months (P=.0917). Our data show that LR and VLR are not infrequent in AML patients with NPM1 mutations. Although this finding needs to be validated in updated multicentric cohorts with a very long follow-up, it strongly suggests that AML patients with NPM1 mutations should benefit from a prolonged follow-up beyond 5 years from CR. Table Table. Disclosures No relevant conflicts of interest to declare.

Description: NPM1 mutations are frequent in acute myeloid leukemia (AML) and define a distinct entity according to the 2016 WHO classification. NPM1 mutations are generally associated with chemosensitivity and a favorable prognosis. However, outcome may vary according to co-mutational events, and still approximately 40% of patients relapse after achieving complete response. Wild-type NPM1 is mainly located in the nucleolus where it plays a key role in the regulation of ribosome biogenesis, protein synthesis and tumor suppression through TP53 activation. Mutated NPM1 loses its predominant nucleolar location and accumulates in cytoplasm contributing to leukemogenesis (Falini B, Blood 2011). Moreover, this mutational event leads to haploinsufficiency and cytoplasmic retention of wild type NPM1 creating a vulnerability to nucleolar stress. Indeed, complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug (Falini B, NEJM 2015). Here, we report our experience of off-label dactinomycin in untreated or relapsed/ refractory NPM1-mutated AML. Inclusion criteria for this retrospective study were: age ≥ 18 years-old, AML with NPM1 mutation, relapsed or refractory disease as well as treatment-naive patients unfit for intensive chemotherapy. Patients should also have completed one cycle of dactinomycin 12.5 µg/kg/day for 5 days every 28 days. From September 2015 to February 2019, 26 patients received dactinomycin. Median age was 62.5y, WBC count was 〉 50 giga/L in 8 patients (31%), 13 patients (50%) had FLT3-ITD mutation whereas 10 (38%) and 11 (42%) patients were classified as favorable or intermediate-I according to the ELN-2010 classification. There were 7 (27%) relapses post-allogeneic transplantation. Median number of dactinomycin cycle was 1 (1-8) and 7 patients (27%) received more than 3 cycles. Sorafenib was added in 6 patients with associated FLT3-ITD mutations whereas 2 others patients received ATRA in combination with dactinomycin. Dactinomycin was administered in different situations: front-line treatment in 4 unfit patients (16%); morphologic (n=16, 62%) or molecular relapses (n=4, 16%) following intensive chemotherapy, refractory disease (n=1, 13%) or post remission therapy in second complete response (CR) following salvage chemotherapy (n=1, 13%). Three out of 17 patients (18%) in morphologic relapse or refractory to chemotherapy reached complete remission after the first cycle of dactinomycin. The duration of response was 4 and 6 months in 2 patients whereas the third patient is still in CR 3 years after dactinomycin. One out of 4 patients in molecular relapses achieved a complete molecular remission with dactinomycin. None of the 4 patients unfit for intensive chemotherapy responded to dactinomycin as front-line therapy. The only patient treated in post-CR2 with dactinomycin achieved a complete molecular remission before allogeneic transplantation. Overall, 5 patients (19%) appeared to benefit from dactinomycin treatment. Grade 3-4 adverse events were thrombocytopenia (n=11, 42%), neutropenia (n=11, 42%), GI toxicity (n=6, 23%), mucositis (n=5, 19%), lung infection (n=5, 19%) and skin rash (n=2, 7.6%). Dactinomycin is an inexpensive and easily available drug that may induce significant responses in AML patients with NPM1 mutations with an acceptable safety profile. Prospective and controlled clinical trials are mandatory to clearly define the role of this agent in AML with NPM1 mutations. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Bertoli:Sanofi: Honoraria. Huguet:Incyte Biosciences: Honoraria; Servier: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria. Bories:Abbvie: Consultancy. Recher:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; 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; Celgene: Consultancy, 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; Astellas: 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; Sunesis: 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. OffLabel Disclosure: NPM1 mutations are frequent in acute myeloid leukemia (AML) and define a distinct entity according to the 2016 WHO classification. Wild-type NPM1 is mainly located in the nucleolus where it plays a key role in the regulation of ribosome biogenesis, protein synthesis and tumor suppression through TP53 activation. Mutated NPM1 loses its predominant nucleolar location and accumulates in cytoplasm contributing to leukemogenesis (Falini B, Blood 2011). Moreover, this mutational event leads to haploinsufficiency and cytoplasmic retention of wild type NPM1 creating a vulnerability to nucleolar stress. Indeed, complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug (Falini B, NEJM 2015).

Description: Patients with AML and hyperleukocytosis (HL) are at increased risk for early death and relapse. HL is associated with a leukostasis syndrome that can potentially lead to acute respiratory distress syndrome or strokes. HL is independently associated with a shorter RFS (Rollig C, Blood 2015). Mediators of inflammation induced by leukemic blasts and endothelial cells contributed to the pathogenesis of leukostasis and could induce chemoresistance (Stucki A, Blood 2001). We hypothesized that a short course of Dexamethasone (DEX) at induction chemotherapy could improve outcome of HL AML pts. From Jan 2004 to Dec 2013, 662 pts (18-75y) were treated in our center by intensive chemo: dauno (60-90 mg/m² d1-3) or idarubicin (8 mg/m² d1-5) with AraC (100-200 mg/m² d1-7); lomustin 200 mg/m² (d1) being added in patients 〉60y. Hydroxyurea (HU) could be started promptly at diagnosis. Leukapheresis were not performed. Starting from Jan 2010, DEX 10 mg bid d1-3 was systematically added on the chemo backbone of all pts with a WBC 〉 100 x109/L or 50 x109 /L with leukostasis. Supportive care was given according to standard guidelines that did not change across the study period. This retrospective study included 137 patients with WBC 〉50 x109 /L. The median age was 59.7y (47% ≥60y). Median FU was 4.2 years. 49 pts received DEX and were more likely to have poorer PS, leukostasis syndrome, de novo AML and higher WBC count compared to the 88 pts of the non-DEX group whereas cytogenetics risk and ELN classification were similar. HU was given in 27 pts of the DEX group and in 51 pts of the non-DEX group. AlloSCT was performed in 14 pts of the DEX group and in 19 pts of the non-DEX group. CR rate were 78% (DEX) and 74% (no-DEX), respectively (p=0.357). At d60, 7 pts (14%) had died in the DEX group compared to 17 pts (19%) in the no-DEX group (p=0.457). There were no difference in fungal (p=0.351) or bacterial (p=0.96) infections during induction. There were more grade 3-4 bleeding events (18% vs 7%, p=0.038) and more admissions in ICU (31% vs 15%, p=0.028) in the DEX group. DEX significantly improved DFS (HR 0.41; 95% CI, 0.23-0.74, p=0.003) and OS (HR 0.62; 95% CI, 0.39-0.99, p=0.046) (Figure). In a Fine and Gray model, DEX was associated with a lower risk of relapse (aHR ratio 0.13; 95% CI, 0.05-0.33, p

Description: Acute Myeloid Leukemia (AML) is one of the hematological malignancies in which no key development in specific treatment has been achieved in opposition to B-cell malignancies or CML. Yet, few recent studies have reported an improvement in overall survival (OS) of adult AML patients (pts) (Sant, Lancet Oncol 2014; Derolf, Blood 2009; Pulte, Haematologica 2008). However, these studies are mainly based on registries or compilation of clinical trials and reasons for this improvement are not defined. We analyzed the outcome of AML pts treated between 2000 and 2014 by intensive chemotherapy in order to determine whether there has been an improvement in OS over time and independently of classic prognostic factors. From January, 1st, 2000 to December, 31st, 2014, 976 AML pts received intensive chemotherapy at the Toulouse University Hospital. With regards to routine practice evolution, voriconazole or caspofungin were used from 2003 as prophylaxis of fungal infections (Chabrol, Haematologica 2010), then posaconazole from 2008. Indications for alloSCT have evolved from geno to pheno-identical (Id) in first complete response (CR) and more recently to haplo-Id in high risk pts, whereas autologous-SCT was progressively abandoned. Molecular stratification for alloSCT indications based on NPM1, FLT3-ITD and CEBPA mutations started from 2006. A specific unit dedicated to acute leukemia was created in the Hematology department in 2005. Starting from 2010, dexamethasone was added to chemotherapy in pts with WBC〉100 or 〉50 G/L with leukostasis. Since therapeutic strategies differed between younger and older pts, we analyzed separately the outcome of pts 50 G/L (HR 0.62, 95%CI 0.46-0.85; p=0.003). Characteristics of pts 60y+ were: median age (68.0, 68.7 and 66.9y), secondary AML (34.6; 20.2 and 25.7%), PS〉1 (28.4, 20.0 and 21.7%), median WBC count (10.7, 8.3 and 11.2 G/l), favorable/unfavorable karyotypes (3.1/24.2, 3.8/21.3 and 4.8/19.8%), FLT3-ITD (12.0, 25.9 and 21.2%) or NPM1 mutations in intermediate-cytogenetic risk (41.3, 34.6, 32.8%) according to 2000-2004; 2005-2009 and 2010-2014 periods. Median FU of pts still alive was 52.5 months (84.0, 70.6 and 35.6 months for 2000-2004, 2005-2009 and 2010-2014, respectively). There was no difference in OS over time (table 2). However, there was a significant interaction between period of time and WBC in the multivariate analysis for OS meaning that the 2010-2014 period had an impact only in pts with WBC 〉 50 G/L (HR 0.41, 95%CI 0.24-0.71; p=0.002). The same interaction was also found for CR achievement (OR 3.90, 95%CI 1.30-11.7; p=0.015). Progresses have been made in each phase of the therapeutic course of younger AML pts (less early deaths, more alloSCT without increased NRM, less relapses, more second remissions) resulting in survival improvement. In older pts, though outcome of hyperleukocytic patients has improved, significant advances remain to be made. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Attal:sanofi: Consultancy; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding; amgen: Consultancy, Research Funding. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Somatic mutations of isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are found in 7-14% and 8-19% of AML. IDH1R132, IDH2R140 and IDH2R172mutations are most frequent in cytogenetically normal AML (25-30% of cases) and significantly associated with NPM1 mutations (except for IDH2R172). Their prognostic significance depends on mutational context (NPM1 and FLT3-ITD status) and on type of mutation: IDH1R132 has a possible adverse effect, IDH2R140 is associated with a favorable effect while the IDH2R172 effect remains controversial (Green C, Blood 2011; Papaemmanuil E, NEJM 2016). IDH1/2 mutations induce a neomorphic enzyme that overproduces the 2-hydroxyglutarate oncometabolite and thus have emerged as promising therapeutic targets. Indeed, AG-120 (IDH1 inhibitor) and AG-221 (IDH2 inhibitor) have shown encouraging activity in phase I trials including Rel/Ref AML pts though median OS are not yet reported. The prognosis of IDH mutated pts at this phase of the disease is not well described in routine practice outside clinical trials. The primary objective of this study was to describe characteristics and outcome of AML pts with IDH1/2 mutations treated in routine practice by intensive chemotherapy from both diagnosis and Rel/Ref phase of the disease. This study included 1603 pts admitted at the Toulouse University Hospital and/or registered in the Oncomip regional Network from January, 1st, 2000 to December, 31st, 2014. This database included all cases of AML pts treated by intensive chemotherapy since 2000 then, starting from 2007, all consecutive patients whatever their treatment (Bories P, Am J Hematol 2014; Bertoli S, Blood 2013). Molecular analyses were performed at diagnosis or retrospectively from stored samples. Only first relapses after standard intensive chemotherapy were considered for this analysis and refractory disease was defined as failure following one course of induction chemotherapy including or not a second course for patients with more than 5% bone marrow blasts at day 15. Treatment distributions were as follows: 984 pts received intensive chemotherapy, 224 azacitidine and 312 best supportive care. Mutational status of IDH1 and IDH2 was available for 465 pts of whom, 422 received intensive chemotherapy as first line therapy, 21 azacitidine and 20 BSC. The study focalized on pts treated by intensive chemotherapy: 349 IDH1/2wt (82%), 32 IDH1R132 (7.5%), 31 IDH2R140 (7.3%) and 11 IDH2R172 (2.6%). IDH2R140 (59y, IQR, 54-66.5) and IDH2R172 (60y, 42.5-64) pts were older than IDH1R132 (53y, 43.8-59.3) and IDHwt (52y, 39-62) pts. IDH2R172 pts had lower WBC count (2.1 G/l, 1.35-4.6) as compared to IDHwt (18 G/l, 4.3-66.9), IDH1R132 (14.7 G/l, 2.1-47.5) and IDH2R140 (21.5 G/l, 4.1-43). De novo AML was found in 85%, 94%, 74% and 73% of IDHwt, IDH1R132, IDH2R140 and IDH2R172 pts, respectively. Only 3 IDH1R132 and 3 IDH2R140 pts had unfavorable karyotype whereas 2 IDH2R140 pts had CBF-AML. Complete response was achieved in 80%, 91%, 74% and 100% of IDHwt, IDH1R132, IDH2R140 and IDH2R172 pts, respectively. Median overall survival (OS) from diagnosis was 23.6, 20.9, 35.8 and 41.1 months in IDHwt, IDH1R132, IDH2R140 and IDH2R172 pts, respectively. 185 Rel/Ref patients with IDH1/2-defined mutational status received salvage therapy with intensive chemotherapy (68%); azacitidine (18%) or other treatments (14%): 144 IDHwt (36 Ref/108 Rel), 18 IDH1R132 (3 Ref/15 Rel) and 23 IDH2R140/R172 (8 Ref/15 Rel). Complete response was achieved in 62 IDHwt (43%), 9 IDH1R132 (50%) and 12 IDH2R140/R172 (52%) pts, respectively. Median OS and 3-year OS from failure or relapse were: IDHwt: 7.6 months/19%; IDH1R132: 5.9 months/8% and IDH2R140/R172: 11 months/23%. Observational data should be considered complementary to that provided by randomized clinical trials. They provide data collected in a non-selected general population, while participants in clinical trials are generally under very restrictive eligibility criteria. In refractory or relapsed patients who received salvage therapy, substantial differences may be observed according to the subtype of mutations, IDH1R132 having the poorest prognosis. IDH2R172 appears to confer a more favorable outcome (3-year OS from diagnosis: 61%). Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Intermediate dose cytarabine (IDAC) defined by daily intravenous bolus of 1g/m² during 5 days has been recently defined as the standard control arm in phase 3 placebo-controlled randomized trials for patients with relapsed or refractory acute myeloid leukemia (R/R AML). In these trials assessing clofarabine/IDAC (CLASSIC-1 study, Faderl S et al., JCO 2012) or vosaroxin/IDAC (VALOR study, Ravandi F. et al., Lancet Oncol 2015) vs placebo/IDAC, complete remission rates and median overall survival with placebo/IDAC were 17.8%/18.9% and 6.3/6.1 months in the CLASSIC-1 and VALOR studies, respectively. However, the dose-intensity of this IDAC regimen remains questioned in routine practice since many centers still use higher doses of cytarabine often in combination with an anthracycline and a third drug including fludarabine, etoposide or gemtuzumab ozogamycin (FLAG-ida, MEC or MIDAM regimen for example) although these regimen have proved little efficacy and higher toxicity. We assessed the outcome of R/R AML patients that fulfilled main VALOR inclusion criteria consecutively treated in our center with intensive salvage regimen. All patients with a diagnosis of AML in first relapse or with refractory disease were eligible for this study. Acute promyelocytic leukemia were excluded. Relapse was defined as re-emergence of at least 5% leukemia blasts in bone marrow or at least 1% blasts in peripheral blood 90 days to 24 months after first complete remission or complete remission with incomplete platelet recovery. Refractory AML was defined as persistent disease at least 28 days after initiation of induction therapy, or relapse less than 90 days after first complete remission (CR) or CR with incomplete platelet recovery (CRi). All patients have received previous induction therapy with an anthracycline. Salvage regimen used were mainly cytarabine 3 g/m²/12h, d1-4 plus idarubicine 12 mg/m²/d, d1-3 or dauno 60 mg/m²/d, d1-2 or amsacrine 200 mg/m²/d, d1-3; less frequently MiDAM (mitoxantrone 12mg/m² d1-3, cytarabine1 g/m²/12h d1-5, GO 4-6mg/m², d4) or FLAG-Ida. Cytarabine dose for patients 〉60 was reduced to 1g/m²/12h, d1-5. We found, in our database, 151 R/R AML according to VALOR criteria treated between 2000 and 2013: 72 patients (48%) had refractory diseases (primary refractory: n=60, 40% and relapse less than 90 days after CR: n=12, 8.0%) and 79 (52%) had relapsed (early relapse more than 90 days after CR and less than one year: n=52, 66%; late relapse between one and two years: n=27, 34%). Patients characteristics were as follows: 85 (56%) were male, median age was 48 years (interquartile range [IQR], 36-60.5; 38 (27%) were 60 years or older). Cytogenetics at diagnosis was favorable in 18 (12%); intermediate in 93 (62%); adverse in 38 (25%) or unknown in 2 (1%) patients, respectively. They were treated as first line therapy with one (42%) or two cycles (58%). Early death rates at day 30 and day 60 were 7% and 17% in the whole cohort; 6% and 12% in younger patients and 12% and 29% in patients 60 years or older. Combined CR rate (defined as CR and CRi) was 53% for the whole cohort, and 57%/42%/56%/52%/63%/50% for