ALBERT

Description: Background: In standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, 2015). In high risk APL (WBC〉 10G/l), it is still unclear if CT can be avoided or greatly reduced, but addition of ATO to ATRA + CT reduces relapses (Powell, Blood 2010). In a randomized trial (APL2006 trial) in high-risk APL patients (pts) who received ATRA + CT induction treatment, we evaluated the addition of ATO to CT during consolidation. Methods: Between 2006 and 2015, newly diagnosed APL pts 10 G/L, after an induction of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, were randomized for consolidation between CT and CT+ATO. The CT group (standard group) received a first consolidation with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and 2-year maintenance with intermittent ATRA and continuous 6 MP + MTX. The CT+ATO group received the same treatment except that ATO 0.15 mg/Kg/d d1 -25 was added during both consolidation courses. After a first interim analysis in Sept 2010, based on 81 pts, AraC was deleted from consolidation cycles of the CT+ ATO group. The primary endpoint was EFS from CR achievement. Results: 211 pts 10 G/L were included (after the exclusion of 8 diagnostic errors) in 58 centers. 95.7% achieved CR, 3.3% had early death and 1% resistant leukemia. 193 pts were randomized for consolidation, 97 in the CT and 96 the CT+ ATO groups. Pre-treatment characteristics were well balanced between the 2 groups. 7 pts (3 CT vs 4 CT+ATO) had relapsed (5-year cumulative incidence of relapse (CIR) of 2.5% vs 3.9%; p= 0.39) and 9 pts had died in CR :7 (7.8%), 2 (5.1%), 0 (0%) in the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively (p=0.04). Causes of death in CR were bleeding (n=5), infection (n=2), previous cancer relapse (n=2). One patient in the CT+ATO arm developed AML/MDS. 5-year OS was 93% vs 94% (p=0.56) and 5-year EFS was 89% vs 93% (p=0.47) in the CT and CT+ATO groups, respectively. Omission of AraC (after the amendment) in the CT+ATO group did not increase CIR (5 year CIR 5.3% with and 3.3% without AraC, p=0.57). In the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively, median time to ANC〉1 G/L after consolidation 2 was 22, 25 and 19 days (p50G/l was 24, 26 and 20 days (p

Description: Background L-asparaginase (L-ASP) is a key drug in the treatment of acute lymphoblastic leukemia (ALL). However the toxicity profile, especially hypersensitivities up to acute allergic reactions is a major drawback. GRASPA (eryaspase (proposed INN) or E-Coli L-Asparaginase encapsulated into red blood cells) is a new product under development with the aim of improving the tolerance of this enzyme. Asparagine is actively transported through the membrane of red blood cells (RBC) where it is hydrolyzed by the encapsulated L-ASP, the erythrocytes acting as "bioreactors". The RBC membrane shields against the anti-L-ASP antibody then avoiding binding to encapsulated L-ASP. Recently, a Phase III pivotal study of GRASPA in combination with COOPRALL chemotherapy protocols in patients with relapsed ALL demonstrated highly significant safety profile and clinical activity compared to control. However, there is an unmet medical need for patients who cannot receive current formulations of L-ASP. An expanded access program has recently been initiated in France to provide access for treatment with GRASPA in patients who are unable to receive other forms of L-ASP. Methods: This is a non randomized multicenter open label study, currently initiated in France. The primary objective of the EAP is to evaluate the tolerability of GRASPA. Patients under 55y of age presenting with de novo, relapsed or refractory ALL who are at risk to receive any other available L-ASP formulation are enrolled into this program. Patients with known allergic reactions to E.Coli L-ASP are also eligible. GRASPA is administrated every 2 to 3 weeks at a dose equivalent to 150 IU/kg of L-ASP during all chemotherapy courses intended to contain an asparaginase. Chemotherapy protocols are given according to the Investigator's choice. Patients are assessed regularly for safety and tolerability. The primary endpoint is tolerability; Key secondary endpoints include asparaginase activity, asparagine depletion, and clinical remission rates. An independent Safety Monitoring Board (DSMB) is set up, which will assess toxicities on yearly basis. Results As of time of June 2015, 13 patients were enrolled into the program. The first DSMB meeting reviewed the outcome of the first 7 patients enrolled into the program. Of the 7 pts (range 3 - 49 years), 5 males and 2 females were enrolled. Four pts presented with refractory disease and 3 with relapse, with all patients had evidence of allergies to 2 prior asparaginases (double allergies). There were 2 pts presenting with limiting toxicities, in the form of myelosupression, and streptococcal infection. There was no modification to the protocol recommended by the first DSMB An updated safety and clinical activity information on all patients will be provided. Conclusion: The EAP provides a potential treatment alternative for ALL patients, who are unable, or at risk of developing hypersensitivity reactions to prior asparaginases. The initial results from this program suggests that GRASPA is well tolerated, and may have a potential benefit in patients with double allergies. The program will be expanded to other European countries Disclosures Bertrand: ERYTECH Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salako:ERYTECH Pharma: Employment. Godfrin:ERYTECH Pharma: Employment. El Hariry:ERYTECH Pharma: Employment.

Description: Background: The bromodomain-containing protein 4 (BRD4) activates the transcription elongation factor b (P-TEFb) which regulates RNA polymerase II. Conversely, hexamethylene bisacetamide (HMBA) inducible protein 1 (HEXIM1) inactivates P-TEFb. BRD4/HEXIM1 interplay influences cell cycle progression and tumorigenesis. It has been widely demonstrated that BRD4 knockdown or inhibition by JQ1 is associated with c-MYC downregulation and antileukemic activity. We recently reported that the small molecule BRD2/3/4 inhibitor OTX015 (Oncoethix, Lausanne, Switzerland), currently in clinical development, mimics the effects of JQ1 (Braun et al, ASH 2013). We evaluated the effect of OTX015 on c-MYC, BRD2/3/4, and HEXIM1 in human in vitro leukemic models. Methods: c-MYC, BRD2/3/4 and HEXIM1 expression was assessed in six acute myeloid leukemia (AML; K562, HL-60, NB4, NOMO-1, KG1, OCI-AML3) and two acute lymphoid leukemia (ALL; JURKAT and RS4-11) cell lines after exposure to 500 nM OTX015. Quantitative RT-PCR and Western blotting were performed at different time points (24-72h). A heatmap was computed with R-software. Results: c-MYC RNA levels were ubiquitously downregulated in all AML and ALL cell lines after 24h exposure to OTX015 (Figure 1). c-MYC protein levels decreased to a variable extent at 24-72h in all cell lines evaluated other than KG1. BRD2, BRD3 and BRD4 mRNA expression was significantly decreased in K562 cells (known to be OTX015-resistant) after 48h exposure to OTX015 but was increased in HL60 and NOMO-1 cells, while minimal to no increases were observed in other cell lines. OTX015 induced a decrease in BRD2 protein expression in most cell lines, but not in K562 cells. In contrast, decreased BRD4 protein expression was only seen in the OCI-AML3, NB4 and K562 cell lines. BRD3 protein levels were not modified after OTX015 exposure in all cell lines evaluated other than KG1. HEXIM1 mRNA expression increased after 24h exposure to 500 nM OTX015 in all cell lines except OTX015-resistant K562 cells in which the increase was considered insignificant (less than two-fold). Increases in HEXIM1 protein levels were observed in OCI-AML3, JURKAT and RS4-11 cell lines at 24-72h but not in K562 cells. Conclusion: Taken together, these results show that BRD inhibition by OTX015 modulates HEXIM1 gene and protein expression, in addition to c-MYC decrease and BRD variations. HEXIM1 upregulation seems to be restricted to OTX015-sensitive cell lines and was not significantly affected in OTX015-resistant K562 cells. Further studies are needed to clarify the role of HEXIM1 in antileukemic activity of BRD inhibitors. Figure 1: Heatmap of gene expression after exposure to 500 nM OTX015 for 24 or 48h in AML and ALL cell lines. Repression in blue. Overexpression in red. Figure 1:. Heatmap of gene expression after exposure to 500 nM OTX015 for 24 or 48h in AML and ALL cell lines. Repression in blue. Overexpression in red. Disclosures Riveiro: OTD: Employment. Herait:OncoEthix: Employment. Dombret:OncoEthix: Research Funding.

Description: Abstract 1868 Aim: Erythropoiesis stimulating agents (ESA) or lenalidomide (in case of del 5q) are the usual first line treatments of anemia of low/int-1 IPSS (lower) risk MDS. After their failure, IST with ATG+/−CsA is among the approaches considered, with 30 to 50% erythroid response (Sloand, JCO 2008; Lim, Leukemia 2007, and others), including durable red cell transfusion independence (RBC-TI). In multivariate analysis, predictors of response to IST in MDS include low/Int-1IPSS (especially int-1 without excess blasts due to presence, in addition of anemia, of thrombocytopenia or intermediate (int) karyotype) and, depending on studies, age ≤60 y and HLA DR-15 positivity. Pts with those good prognostic factors were however overrepresented in several MDS series treated with IST and analysis of the first 400 pts included in the European LeukemiaNet lower risk MDS registry found only 2 pts treated with IST (De Witte, personal communication). We reviewed the characteristics and outcome of MDS pts treated with IST in our centre and assessed the frequency of low/int-1 MDS pts potentially candidates to IST, based on published prognostic factors, in the Groupe Francophone des Myélodysplasies (GFM) patient database. Methods: From Jan 2004 to Feb 2010, we treated in our center 12 MDS by IST. From mid 2003 to end of 2008, 1311 MDS pts with IPSS scoring, were entered into the GFM registry. We computed in this registry the frequency of pt subsets potentially good candidates to IST based on age, having anemia with low/int-1 IPSS, or int-1 with 65 y responded. With a median follow-up of 21.5 months (6-68), erythroid response was ongoing after 17, 21, 44, 47 and 62 months, respectively. Three NR pts died at 11, 16 and 18 months (one Int-2 pt with RAEB and +8, from AML progression, and 2 pts from marrow failure). In the GFM database, pts with transfusion dependent anemia and IPSS low or int-1, and IPSS int-1 with

Description: Background: Clonal heterogeneity of the AML blast cell population has been well documented using next generation sequencing (NGS) strategies. This heterogeneity extends to the presence of LSC fraction among the leukemic population: a dynamic compartment evolving to overcome cell selection pressure during disease progression and its treatment including allogeneic Hematopoietic Stem Cell Transplantation (HSCT). However, it remains difficult to discriminate between LSC and nHSC or other myeloid progenitors as MPP, LMPP or GMP. Here we present how to combine FLOWSom and KALUZA software to obtain robust identification among tumoral and normal progenitors. We compared the flowLSC Profile with stemness 17 genes score to identify patients with adverse outcome. Methods: 11 AML patients from ALFA07-01 clinical trial diagnosed in Lyon University Hospital between 2009-2010 were included in this study. The quantification of CD34+CD38- fraction at diagnosis from total bulk leukemia was made as previously described. To better discriminate between LSC and nHSC we designed MFC panel based on 2-tube antibody combinations to identify the pattern of LSC in the CD34+CD38- cell compartment. CD34/CD38/CD45/CD117« backbone » was used in both tubes, completed by lineage defined markers CD7/CD56/CD19/CD13/CD33/ and/or LSC identified markers CD123 +/- CD90/CD45RA, CLL1, TIM3, CD97. Results: As seeing in Table Nr 1, between 11 AML patients we observed a strong correlation identifying patients with adverse prognostic using previously published threshold by Flow (〉 1% CD34+CD38- from bulk leukemia cells). 4 from 11 patients showed a discrepancy between GES 17 LSC and Flow CD34+CD38-: one from four patients (Nr 3) was classified as "high" by Flow (high CD34+ expression) and "low" by GES LSC 17 and three other patients (Nr 8, 10, 11) were classified inversely as "low" by Flow (

Description: Background: Despite the availability of new therapies for acute lymphoblastic leukemia (ALL), older patients have historically poor responses to treatment and poor outcomes versus younger patients, with 5-year survival rates of approximately 20% or less. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells and is approved for the treatment of relapsed or refractory (r/r) B-cell precursor (BCP) ALL and for minimal residual disease-positive ALL in the US. In the phase 3 TOWER study in patients with r/r Philadelphia chromosome-negative (Ph-) BCP ALL who received blinatumomab compared with standard-of-care (SOC) chemotherapy, overall survival was improved (median, 7.7 vs 4.0 months; P=0.01; Kantarjian H, et al. N Engl J Med. 2017;376:836-847), and posttreatment health-related quality of life (HRQoL) across all EORTC QLQ-C30 scales was better (Topp MS, et al. Blood. 2018;131:2906-2914). TOWER efficacy results did not differ by age group. In this subgroup analysis of TOWER, we assessed the HRQoL of older patients versus younger patients who received blinatumomab or SOC chemotherapy. Methods: Patients (N=405) with r/r Ph- BCP ALL were randomized 2:1 to receive 2 cycles of induction blinatumomab by continuous intravenous infusion (n=271) or SOC (n=134). Patients could receive transplant at any time following cycle 1. Those in remission could receive up to 3 consolidation cycles; 12 months of maintenance was allowed for those who received up to 3 consolidation cycles and had bone marrow response. HRQoL was assessed using the EORTC QLQ-C30 Questionnaire on days 1 (baseline), 8, and 15, on day 29 of cycle 1; day 1, 15, and 29 of each consolidation cycle; and at the safety follow-up. The questionnaire included 1 global health status scale, 5 functioning scales, 3 symptom scales, and 6 single-symptom items. For global health status and functioning scales, a higher score indicates better HRQoL; for symptom scales/items, a lower score indicates better HRQoL. A 10-point change was viewed as the minimum clinically important difference in EORTC QLQ-C30 (Zikos E, et al. EORTC. 2016). In this analysis, HRQoL in TOWER was assessed using two different age cutoffs:

Description: BACKGROUND: Invasive fungal infections (IFIs) including invasive candidiasis(IC), pulmonary invasive aspergillosis (IA) and other fungal species as mucor mycosis (IM), remain a major clinical problem in neutropenic patients receiving intensive chemotherapy for acute myeloid leukemia (AML) due to their high morbidity and mortality. DESIGN: We performed a prospective observational study on antifungal (AF) prophylaxis used in a prospective clinical trial of intensive chemotherapy within the Acute Leukemia French Association (ALFA 0702 study, ClinicalTrials.gov Identifier: NCT00932412). A total of 677 AML patients from 34 different centers were included, 45% were males, and median age was 46 years (18-60). Prognosis according to cytogenetics was favorable in 23% of patients, intermediate in 53% and unfavorable in 18%. All patients received daunorubicine and aracytine intensive induction chemotherapy. The trial protocol recommended posaconazole suspension as AF prophylaxis at the dose of 200 mg three times a day from day 4 after induction chemotherapy and until neutrophils recovery. Patients were considered evaluable for this study if they received posaconazole for a minimum duration of 7 days and not later than 10 days after the beginning of the induction chemotherapy. IFI were classified by the local investigators and were reviewed later by an independent expert according to the EORTC classification (possible, probable and proven), scanner images were requested for further investigations when needed. The objective of this study was to describe the IFI prophylaxis strategies used in the different centers, to calculate the cumulative incidence of IFI according to different strategies, and to evaluate the overall survival and IFI related mortality. RESULTS: Among the 677 patients, 383 (57%) received posaconazole as AF prophylaxis for a median duration of 25 days (7-253). Posaconazole was introduced after a median time of 3 days after the beginning of the chemotherapy. We distinguished 4 groups, Group 1: patients without any prophylaxis (n = 203, 30%), Group 2: posaconazole alone (n=241, 36%), Group 3: posaconazole plus other prophylaxis (n=142, 21%), and Group 4: patients receiving other prophylaxis (n= 91, 13%). Overall, there were 72 IA [34 (47%) possible, 38 (53%) probable/proven], 17 IC (all probable/proven) and 7 IM [1 possible, 6 probable/proven]. The median delay between posaconazole prophylaxis and IFI occurrence was 22 days (7-50) for IA, 18 days (15-60) for IC and 26 days (13-28) for IM compared to 10 days (3-180), 8 days (3-32) and 21 days (10-32) in case of other prophylaxis. The cumulative incidence of IFI was 2.4% at 10 days (IA: 2.4%, IC : 0%, IM : 0%), 11,2% at 30 days (IA: 8.4%, IC: 2%, IM: 0.7%), 14.2% at 60 days ( IA: 10.6%, IC : 2.5%, IM : 1%), and 14.2% at 100 days (IA:10.6%, IC : 2.5%, IM : 1%). When considering the prophylaxis groups, the cumulative incidence of probable/proven IA at day 60 was 8.37% for Group 1; 4.7% for Groups 2 and 3 combined and 3.3% for Group 4 (Figure 1). After a median follow-up of 27.5 months (0.4- 73.4), 418 patients are alive and 259 (38.3%) died with 5.4% from IFI. Concerning the overall survival, the results were analyzed according to the presence or absence of IFI and AF prophylaxis (Figure 2) we observed a better survival without any IFI whatever the AF prophylaxis was and in case of AF prophylaxis there was an improvement of 2-years survival after chemotherapy induction. Concerning the global mortality and the IFI related mortality, the results were analyzed according to the prophylactic groups and the timing of prophylaxis, the multivariate analysis showed the negative impact of 2 factors on the mortality at day 100: Unfavorable cytogenetics: HR= 3.34 (1-11.20) p=0.05 and presence of IFI: HR = 5.63 (2.62-12.08) p

Description: Background: For many years the ALFA Group has used high dose DNR, i.e 80 mg/m2/day for 3d as part of the induction regimen for untreated adult AML pts. As the equivalence of DNR and Ida is not known we conducted a phase III study to compare high dose DNR to Ida. We also tested the effect of IL2 for maintenance. Methods: Newly diagnosed AML, aged 50 to 70 years, were randomized to receive AraC 200 mg/m2/day IV x 7 d with either DNR: 80 mg/m2/d x 3 d (arm 1) or Ida: 12 mg/m2/d x 3 d (arm 2) or x 4 d (arm 3). Pts who failed could receive a salvage course with Mitoxantrone x 2 d and AraC1g/m2 12 hrs x 4d. Response was assessed after induction+/− salvage chemotherapy. CR pts received 2 consolidation courses according to the induction arm with DNR: 80 mg/m2 or Ida:12 mg/m2 for 1 day (first course) or 2 days (2nd course) and AraC:1g/m2/12 hrs x 4 days. Pts in CCR after the two consolidation courses were randomized to receive or not a maintenance immunotherapy with IL2: 5.106/m2 for 5 days monthly for12 months. Results: From 2001 to 2006, 468 pts were included (median age: 60 years). The 3 treatment arms were well matched for pretreatment characteristics. CR was achieved in 360/468 pts (77%): 109 (70%) pts arm 1, 129 (83%) arm 2, 122 (78%) arm 3 (p=0.02).70 pts, (45%) pts in the DNR arm reached CR after 1 course vs 97 (62%) and 90 (57%) in Ida arms (p= 0.006). Pts in Ida arms experienced more grade 3 or 4 mucositis (p=0.004) but no differences were observed between the 3 arms for duration of hospitalization, time to PMN or plts recovery, incidence of grade 3 or 4 infectious episodes and treatment related mortality. 3 year cumulative incidence of relapse was 69%, 63%, 62% resp in arms 1,2,3 (p=NS). 3 year EFS was 19%, 30%, 26% resp (p=0.06 for arm 1 vs arms 2 and 3). 3 year OS was 31%, 40% 41% resp in arms 1,2,3 (p=NS). Age (〈 or 〉60 years), sex, initial WBC counts, initial LDH (nl or 〉nl), DNR or Ida arms, need for a salvage course were not predictive for relapse, while 2yCIR was 43%, 64%, 77% among respectively fav, intermediate and unfav cytogenetic risk groups resp (p=0.0046). Of the 219 pts alive in CR after consolidations, 161 (73%) were randomized for maintenance. Only 22 of the 77 pts randomized for IL2 completed the 1 year treatment. 32 and 23 pts stopped IL2 resp because of relapse or intolerance. There were no differences in relapse or OS in both maintenance arms. Conclusion: Ida treatment even when compared to high doses of DNR yields higher CR rate and more CR after one course. This effect translated in slightly better EFS but not better CIR or OS. IL2 maintenance treatment at least as scheduled in this trial was difficult to apply and showed no impact on disease course.

Description: The C-Myb transcription factor is essential for hematopoiesis, including in the T-cell lineage. The C-Myb locus is a common site of retroviral insertional mutagenesis, however no recurrent genomic involvement has been reported in human malignancies. Here, we identified 2 types of genomic alterations involving the C-MYB locus at 6q23 in human T-cell acute leukemia (T-ALL). First, we found a reciprocal translocation, t(6;7)(q23;q34), that juxtaposed the TCRB and C-MYB loci (n = 6 cases). Second, a genome-wide copy-number analysis by array-based comparative genomic hybridization (array-CGH) identified short somatic duplications that include C-MYB (MYBdup, n = 13 cases of 84 T-ALL, 15%). Expression analysis, including allele-specific approaches, showed stronger C-MYB expression in the MYB-rearranged cases compared with other T-ALLs, and a dramatically skewed C-MYB allele expression in the TCRB-MYB cases, which suggests that a translocation-driven deregulated expression may overcome a cellular attempt to down-regulate C-MYB. Strikingly, profiling of the T-ALLs by clinical, genomic, and large-scale gene expression analyses shows that the TCRB-MYB translocation defines a new T-ALL subtype associated with a very young age for T-cell leukemia (median, 2.2 years) and with a proliferation/mitosis expression signature. By contrast, the MYBdup alteration was associated with the previously defined T-ALL subtypes.

Description: Abstract 1083 Aim: Since combining differentiating agents and chemotherapy, acute promyelocytic leukemia (APL) is associated with a high cure rate. One remaining issue is the significant rates of early death and relapse observed in patients with high count APL (initial white blood cell count [WBC] ≥ 10.109/L). Early death rate might be underestimated in clinical trials, due to an unknown proportion of patients not registered because of initial severity. For this reason, we reviewed individual histories of all patients with APL referred to our institution during the last 10 years (09/2000-06/2010), with a special focus on admission in intensive care unit (ICU) and inclusion or non-inclusion in recruiting APL trials (European group APL-2000 and APL-2006), as well as long-term follow-up. Patients: A total of 100 patients with newly-diagnosed previously untreated APL, including 8 children, were admitted during this time period. Diagnosis was based on morphology and subsequently confirmed by the presence of the t(15;17) translocation and/or PML/RARA fusion transcript. Results: The rate of patients not enrolled within recruiting trials was 29% (n= 29). This rate was higher in children (n= 5/8, 62.5%) than in adults (n= 24/92, 26%) and remained stable during the two protocol periods (n=17/62, 27% for APL-2000; n= 12/38, 32% for APL-2006). Reasons for non-enrollment were inability to give informed consent in 10 patients (mechanical ventilation or neurological deficiency), physician's decision in 5 patients (2 very high leucocytosis, 1 severe infection, 2 severe liver dysfunction), and concomitant disease in 4 patients (2 HIV patients, 2 other cancers), refusal in 5 patients (including 1 Jehovah witness who eventually survived), and various administrative reasons in 5 patients. Non-enrolled patients had similar sex ratio (F/M=15/14 vs 35/36; p=.99), median age (40.5 [range, 4–79] vs 46 years [4-81]; p=.97), and frequency of additional chromosomal abnormalities (24% vs 28%; p=.80) than enrolled patients. Conversely, they had a higher rate of WBC ≥ 10.109/L (n=15/29 vs 22/71; p=.07) or ≥ 50.109/L (n=8/29 vs 5/71; p=.01), a lower rate of platelet count 〈 40.109/L (28/29 vs 46/71; p=.001), and a higher frequency of microgranular M3-variant subtype (11/29 vs 8/71; p=.004) and BCR3 PML-RARA isoform (14/25 vs 24/70; p=.09). Among the 29 non-enrolled patients, 24 nevertheless received the whole planned standard induction therapy, 2 received arsenic trioxide-based induction, and 3 early died before or the day after chemotherapy initiation. Ninety-nine patients were evaluable for response to induction (1 patient ongoing). Due to a higher early death rate (21% vs 3%; p=.007), the complete remission (CR) rate was lower in non-enrolled patients (79% vs 97%; p=.007). At 5 years, event-free survival (EFS) was estimated at 62% (95%CI, 37–79) vs 84% (95%CI, 72–91) (p=.02) and overall survival (OS) at 63% (95%CI, 36–81) vs 85% (95%CI, 72–93) (p=.03) in the non-enrolled and enrolled group, respectively. Once CR had been reached, non-enrolled patients displayed, however, a good post-CR outcome with 5-year remission duration at 78% and OS from CR at 80%. Of note, only one patient from this cohort died in first CR from a second neoplasia. Twenty-six patients (26%) were admitted in ICU for or during induction (13, 8, and 4 of them requiring mechanical ventilation, amine therapy, and dialysis, respectively). Chemotherapy was initiated in ICU in 19 of them. The rate of trial enrollment was 54% (n= 14/26) in ICU patients compared to 77 % (n= 57/74) in non-ICU patients (p=.04). Again, CR rate (p