Search

SummaryThe controlled release of promoter-proximal paused RNA polymerase II (Pol II) into productive elongation is a major step in gene regulation. However, functional analysis of Pol II pausing is difficult because factors that regulate pause release are almost all essential. In this study, we identified heterozygous loss-of-function mutations inSUPT5H, which encodes SPT5, in individuals with β-thalassemia unlinked toHBBmutations. During erythropoiesis in healthy human cells, cell cycle genes were highly paused at the transition from progenitors to precursors. When the pathogenic mutations were recapitulated bySUPT5Hediting, Pol II pause release was globally disrupted, and the transition from progenitors to precursors was delayed, marked by a transient lag in erythroid-specific gene expression and cell cycle kinetics. Despite this delay, cells terminally differentiate, and cell cycle phase distributions normalize. Therefore, hindering pause release perturbs proliferation and differentiation dynamics at a key transition during erythropoiesis, revealing a role for Pol II pausing in the temporal coordination between the cell cycle and differentiation.

Among histone deacetylases, HDAC6 is unusual in its cytoplasmic localization. Its inhibition leads to hyperacetylation of non-histone proteins, inhibiting cell cycle, proliferation and apoptosis. Ricolinostat (ACY-1215) is a selective inhibitor of the histone deacetylase HDAC6 with proven efficacy in the treatment of malignant diseases, but anaemia is one of the most frequent side effects. We investigated here the underlying mechanisms of this erythroid toxicity. We first confirmed that HDAC6 was strongly expressed at both RNA and protein levels in CD34

Awarding the 2021 Nobel to Ardem Patapoutian for the discovery of the PIEZO mechanotransducers has emphasized the importance of touch-sensing mechanisms in cell physiology. It is well known that PIEZO1 is expressed at the surface of red blood cells where it adjusts their hydration status under mechanical constraints. Besides this, recent findings suggest that PIEZO1 plays a broader role in erythroid lineage. This review aims to actualize the knowledge on PIEZO1 functions all along erythropoiesis.PIEZO1 is expressed in erythroid progenitors, and controls proliferation and differentiation of nucleated cells, as well as maturation of reticulocytes. As PIEZO1 detects displacements in the range of cell-cell interactions, it might mediate the interaction between the differentiating cells and their microenvironment through an inside-out activation of integrins on human erythroblasts as suggested by in-vitro data. Moreover, PIEZO1 is also expressed at the surface of macrophages where it regulates red blood cells clearance through erythrophagocytosis.These new findings on PIEZO1 suggest a continuous effect of mechanotransduction all over erythropoiesis from progenitors to clearance of red blood cells. Therefore, they open a new era in the understanding of hereditary xerocytosis pathophysiology, helping identify new potential therapeutic targets for the future.

The Gluthation peroxidase (GPX) enzymes are part of the protective system against lipid peroxydation that includes prevention of oxydation and reduction of already oxidized lipid through enzymatic reactions catalyzed by GSH. GPX4 is one of the five GPX able to incorporate selenium. It is also the only GPX able to directly reduce in the membrane the oxidized fatty acids and cholesterol. Recent reports identified GPX4 as the central inhibitor of ferroptosis, a process during which iron-induced peroxydation of membrane lipids causes a specific cell death that can be reverted by lipophilic antioxydants or by iron chelators. GPX4 has recently been involved during mice erythropoiesis: GPX4-/-mice present a hemolytic anemia and a high apoptotic rate in spleen erythroid progenitors. Although transcriptomics and proteomics found it expressed in human erythroid precursors, its role during human erythropoiesis has not been described. Using an in-vitroerythroid differentiation protocol from CD34+cells obtained from apheresis, we confirmed that GPX4 expression was induced at RNA and protein level during differentiation. RSL3, a specific GPX4 inhibitor, didn't affect early steps of erythropoiesis (i.eclonogenic potential and progenitor amplification) nor the early maturation of erythroid precursors (assessed by sequential CD49d/CD235/CD71 staining) but led to a significant decrease in the enucleation rate as assessed by Hoechst staining using flow cytometry (74%±9 DMSO versus 35%±6 RSL3, p Using Western Blot, we observed that RSL3 exposure induced a strong GPX4 depletion in erythroid progenitors while it didn't affect GPX1, another member of the GPX family expressed in erythroid cells. In order to confirm that enucleation defect was related to GPX4 knockdown, we used an Sh-RNA strategy that allowed a 62%±6 GPX4 decrease at RNA level and a 46%±5 at protein level. We observed a significant defect in terminal enucleation in the cells transduced with shGPX4-lentiviruses in comparison with sh-Scramble (59%±5 Sh-Scr versus 39%±6 Sh-Gpx4, p We investigated then whether GPX4-knock-down affected quantitatively or qualitatively the membrane lipid content, which was shown to be involved in the enucleation process. Addition of Cholesterol to RSL3 in the medium partially restored the enucleation rate. However, lipidomics failed to show any significant difference in the total membrane lipid content (and particularly in the cholesterol content) after RSL3 exposure in comparison to DMSO. Since cholesterol is particularly abundant in the lipid rafts, we investigated whether the lipid distribution was qualitatively altered within the cell membrane. We observed a disruption of membrane lipid rafts when cells were exposed to RSL3, as shown by a 60%±12 decrease in the mean cholera toxin fluorescence intensity. GPX4 presence in lipid rafts was confirmed using immunofluorescence showing their co-localization at cell surface in human primary erythroblasts. Since lipid rafts play a role in the contractile ring that separates pyrenocyte from reticulocyte, we evaluated the myosin-light chain phosphorylation using flow cytometry and Western Blot and found it drastically decreased in GPX4-knockdown conditions. In summary, we identified GPX4 as a new actor of human terminal erythroid differentiation, independently to its function in ferroptosis control. We described its interaction at cell surface with lipid rafts that are required for the assembly of the contractile ring and cytokinesis leading to the nucleus extrusion. Disclosures No relevant conflicts of interest to declare.

To compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection. In this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement. The three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response. Imaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML. • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution “the milky way,” and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.

Steroid-refractory graft-versus-host disease (SR-GVHD) is a challenging complication of allogeneic hematopoietic stem cell transplantation, and leads to high morbidity and mortality rates. The orally administered, selective Janus-associated kinase 1/2 inhibitor ruxolitinib gives overall response rates (ORR) of more than 70 % in acute and chronic SR-GVHD. However, several studies have highlighted an elevated risk of cytomegalovirus (CMV) reactivation in patients with ruxolitinib-treated SR-GVHD.We therefore analyzed risk of CMV and Epstein-Barr virus (EBV) primary infection or reactivation in 57 patients with ruxolitinib-treated GVHD, while taking account of the competing risk (CR) of death prior to the first reactivation.Initiation of ruxolitinib treatment was a significant adverse prognostic factor for the CR of first CMV reactivation (hazard ratio (HR)= 1.747, 95 % confidence interval (CI): 1.33-2.92, p 0.0001) and first EBV reactivation (HR=2.657, 95 % CI: 1.82-3.87, p 0.0001) during GVHD. In our cohort of ruxolitinib-treated patients, the ORR (48 % and 58 % for acute and chronic GVHD, respectively) and the toxicity profile (haematological adverse events in 29.8 % of the patients) were similar to the literature values.Given ruxolitinib's efficacy in SR-GVHD, use of this drug should not be limited by the fear of viral reactivation; however, our present results emphasize the importance of monitoring the viral load.

Monoclonal gammopathy of unknown significance (MGUS), smouldering multiple myeloma (SMM), and multiple myeloma (MM) are very common neoplasms. However, it is often difficult to distinguish between these entities. In the present study, we aimed to classify the most powerful markers that could improve diagnosis by multiparametric flow cytometry (MFC). The present study included 348 patients based on two independent cohorts. We first assessed how representative the data were in the discovery cohort (123 MM, 97 MGUS) and then analysed their respective plasma cell (PC) phenotype in order to obtain a set of correlations with a hypersphere visualisation. Cluster of differentiation (CD)27 and CD38 were differentially expressed in MGUS and MM (P < 0·001). We found by a gradient boosting machine method that the percentage of abnormal PCs and the ratio PC/CD117 positive precursors were the most influential parameters at diagnosis to distinguish MGUS and MM. Finally, we designed a decisional algorithm allowing a predictive classification ≥95% when PC dyscrasias were suspected, without any misclassification between MGUS and SMM. We validated this algorithm in an independent cohort of PC dyscrasias (n = 87 MM, n = 41 MGUS). This artificial intelligence model is freely available online as a diagnostic tool application website for all MFC centers worldwide (https://aihematology.shinyapps.io/PCdyscrasiasToolDg/).

International audience; Hereditary xerocytosis is a dominantly inherited red cell membrane disorder caused in most cases by gain-of-function mutations in PIEZO1, encoding a mechanosensitive ion channel that translates a mechanic stimulus into calcium influx. We found that PIEZO1 was expressed early in erythroid progenitor cells, and investigated whether it could be involved in erythropoiesis, besides having a role in the homeostasis of mature red cell hydration. In UT7 cells, chemical PIEZO1 activation using YODA1 repressed glycophorin A expression by 75%. This effect was PIEZO1-dependent since it was reverted using specific short hairpin-RNA knockdown. The effect of PIEZO1 activation was confirmed in human primary progenitor cells, maintaining cells at an immature stage for longer and modifying the transcriptional balance in favor of genes associated with early erythropoiesis, as shown by a high GATA2/GATAI ratio and decreased alpha/beta-globin expression. The cell proliferation rate was also reduced, with accumulation of cells in G0/G1 of the cell cycle. The PIEZO1-mediated effect on UT7 cells required calcium-dependent activation of the NFAT and ERK1/2 pathways. In primary erythroid cells, PIEZO1 activation synergized with erythropoietin to activate STATS and ERK, indicating that it may modulate signaling pathways downstream of erythropoietin receptor activation. Finally, we studied the in-vitro erythroid differentiation of primary cells obtained from 14 PIEZO1-mutated patients, from 11 families, carrying ten different mutations. We observed a delay in erythroid differentiation in all cases, ranging from mild (n=3) to marked (n=8). Overall, these data demonstrate a role for PIEZO1 during erythropoiesis, since activation of PIEZO1 both chemically and through activating mutations - delays erythroid maturation, providing new insights into the pathophysiology of hereditary xerocytosis.

Hereditary xerocytosis is a rare red blood cell disease related to gain-of-function mutations in the FAM38A gene, encoding PIEZO1, in 90% of cases. PIEZO1 is a broadly expressed mechano-transducer that plays a major role in many cell systems and tissues that respond to mechanical stress. In erythrocytes, PIEZO1 adapts the intracellular ionic content and cell hydration status to the mechanical constraints induced by the environment. Until recently, the pathophysiology of hereditary xerocytosis was mainly believed to be based on the "PIEZO1-Gardos channel axis" in erythrocytes, according to which PIEZO1-activating mutations induce a calcium influx that secondarily activates the Gardos channel, leading to potassium and water efflux and subsequently to red blood cell dehydration. However, recent studies have demonstrated additional roles for PIEZO1 during early erythropoiesis and reticulocyte maturation as well as roles in other tissues and cells such as lymphatic vessels, hepatocytes, macrophages and platelets that may affect the pathophysiology of the disease. These findings, presented and discussed in this review, broaden our understanding of hereditary xerocytosis beyond that of primarily being a red blood cell disease and identify potential therapeutic targets. This article is protected by copyright. All rights reserved.

CPX-351 is a liposomal formulation of cytarabine and daunorubicin approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). We retrospectively analyzed the efficacy and safety of CPX-351 in a real-world setting in 103 patients from 12 French centers, including the evaluation of molecular abnormalities at baseline and minimal residual disease (MRD) in responding patients, compared with a historical data set from Bordeaux-Toulouse DATAML registry. A favorable safety profile was observed, with a low frequency of alopecia (11%) and gastrointestinal toxicity (50%). The overall response rate after induction was 59%, and MRD

International audience

International audience; No abstract available

Multiple myeloma (MM) is rare in young patients, especially before age 40 years at diagnosis, representing

International audience; In Europe, two CAR T-cell products, tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™), were approved in 2018. While these treatments are available for use, allogeneic hematopoietic stem cell transplantation centers still need to set up a dedicated care process inspired by established procedures in the field. In order to determine necessary resources and actors, each step of the CAR T-cell care process must be planned in advance. This process, implemented by the center's coordinating nurse, should be able to be adapted to each center's needs. The purpose of this workshop is to provide the organizational basis for such a process so that each center wishing to set up CAR-T cell activity can do so effectively. After detailing the coordinating nurse's role, we explain each step of the care process and specify essential additional tests.

Purpose of the study Atypical serum protein electrophoresis (SPE) profiles may arise in patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), but little is known about their clinical significance. Atypical SPE combine either monoclonal and oligoclonal components, suspected on SPE and confirmed by immunofixation. The aim of the study is to analyze the incidence, the etiology and the clinical significance of atypical SPE profiles in patients who received allo-HSCT. Patients and methods This retrospective study enrolled 117 patients with myeloid malignancies who received an allo-HSCT between 2012 and 2018. We excluded patients with lymphoid malignancies or multiple myeloma, patients presenting atypical electrophoresis prior to transplantation and patients who died within 100 days post-transplant. Results Atypical SPE occurred in 42.7% of patients. The cumulative incidence of atypical profiles was significantly higher in patients with acute Graft Versus Host Disease (GVHD, p = 0.019) and in patients with Cytomegalovirus (CMV) reactivation (p = 0.0017). We observed for the first time that atypical SPE profiles mostly occurred in patients transplanted from a CMV+ donor (p = 0.031). CMV reactivation preceded the occurrence of atypical SPE in the majority of patients. We show that atypical SPE delay the relapse of the underlying malignant disease (486 vs 189 days, p = 0.006), and significantly improve overall survival (OS; 33.1 months vs 28.3 months, p = 0.049). In both univariate and multivariate analyzes, the presence of an atypical SPE is the only factor that significantly improves OS. Conclusions The occurrence of atypical SPE profiles after allo-HSCT may reflect an adapted post-transplant immune response leading to favourable outcomes.

Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden. We established an erythroid vs myeloid transcriptome-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, >25% of AEL patients, including in the genetically undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1-binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid, or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicate that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells.

A hematopoietic chimerism assay is the laboratory test for monitoring engraftment and quantifying the proportions of donor and recipient cells after hematopoietic stem cell transplantation recipients. Flow cytometry is the reference method for determining the purity of CD3

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), causing the COVID-19, has been declared as pandemic by the World Health Organization. Epidemiological and clinical characteristics of patients with COVID-19 have been largely reported but biological risk factors have not yet been well described. In this retrospective and monocentric study, we explored 35 hematological and biochemical parameters, routinely measured at the Amiens University Hospital laboratory, between February 21, 2020 and March 30, 2020 for patients diagnosed with COVID-19. 154 patients were included in this study. We compared biological parameters collected at hospital admission between patients who survived or not after hospitalization. Non survivor patients displayed lower hemoglobin (p=0.02) and bicarbonate concentrations (p=0.03) and higher potassium concentration (p=0.03) compared to the survivors. We then compared these biological parameters between patients hospitalized in conventional care units and patients hospitalized in intensive care units (ICU). Numerous biological examinations had significant variations, including lymphocyte and neutrophil counts, bicarbonate, calcium and C Reactive Protein concentrations. In multivariate Cox analysis, risk factors for aggravation (defined as ICU admission or death) included low bicarbonate levels and hyponatremia. A significant worse overall survival was associated with hyponatremia, hyperkaliemia and prothrombin time > 16.8 seconds. We then proposed a prognostic score, to be validated in a future prospective study. Thus, these biological parameters, easily available, could help clinicians to identify high risk patients at an early stage of infection.

INTRODUCTION : HSCT remains the best curative treatment in eligible AML patients with adverse or intermediate cytogenetics according to the ELN classification, and for those with unfavorable molecular markers at diagnostic or with a positive measurable residual disease (MRD) after intensive chemotherapy. MRD-positivity after HSCT confers an inferior outcome and a recently published study demonstrated that the evaluation of WT1 MRD before HSCT or 3 months after HSCT is highly predictive of post-transplant relapse. Besides, the impact and the kinetics of MRD positivity on prognosis are still unclear. Here we assess the impact of both pre- and post-transplant MRD on long term survival and incidence of relapse among a real-life cohort of 117 AML patients who underwent HSCT. PATIENTS AND METHOD: From November 7, 2012 to December 17, 2019, 117 patients diagnosed with AML and aged over 18 years underwent HSCT in Amiens University Hospital Center. MRD status was assessed using RQ-PCR (sensitivity 10 -4 to 10 -5) or multiparametric flow cytometry (sensitivity 10 -3 to 10 -4) before HSCT, depending on the markers available at diagnosis, at day 30, day 100 and a year after HSCT. Overall survival (OS) and cumulative incidence of relapse (CIR) were evaluated at the same time-points in landmark analysis for patients surviving beyond d100 to reduce the impact of early death on CIR. Statistical analyses were performed with SPSS Statistics 20 (IBM). RESULTS: Median age was 55 years (range 18-72) with 67/117 males. 85% patients had de novo AML. Cytogenetic ELN risk stratification was favorable for 15 (13%), intermediate for 72 (62%) and adverse for 28 (25%). At the time of HSCT, 76% were in complete remission (CR) after intensive chemotherapy. 30 patients (25%) had myeloablative conditioning (MAC) or toxicities-reduced regimens (TRC), 34 patients (30%) had reduced-intensity regimens (RIC) and 53 patients (45%) underwent sequential-based conditioning regimens (Seq). For the 100 patients who survived beyond d100, median time follow-up was 23.5 months (3.0-85.0). OS at 1 and 3 years was respectively 80% (75.9-84.1) and 61.7% (56.1-67.3) and CIR at same time-points was 19,3% (15.2-23.4) and 29,8% (24.6-35.0). No OS and CIR differences were observed according to the conditioning regimen, stem cell source and ELN score. A progressive disease before HSCT increased the risk of relapse but didn't worsen the OS. Before HSCT, MRD was positive in 48 patients (58.5%) with analyzable markers, either at molecular or flow cytometry level. OS and CIR were not impacted by the pre-HSCT MRD. Strikingly, performing HSCT resulted in MRD negativation at day 100 for 85.4% of patients with previous positive MRD, significantly improving OS and CIR (p grade 2 (HR=5.4, 95CI=1.8-16.1; p=.002) and positive MRD at day 100 (HR=19.2, 95CI=6.0-61.1; p DISCUSSION/CONCLUSION In this real-life cohort of patients diagnosed with AML, we show that HSCT procedure consistently allows MRD negativation, subsequently improving the outcome of patients surviving beyond d100. Persistence of positive MRD after HSCT was the main predictor of long-term adverse outcome after transplant. Our data highlight the importance of MRD negativation at day 100 regardless of pre-transplant status, conditioning regimen or initial ELN classification. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

In Europe, two CAR T-cell products, tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™), were approved in 2018. While these treatments are available for use, allogeneic hematopoietic stem cell transplantation centers still need to set up a dedicated care process inspired by established procedures in the field. In order to determine necessary resources and actors, each step of the CAR T-cell care process must be planned in advance. This process, implemented by the center's coordinating nurse, should be able to be adapted to each center's needs. The purpose of this workshop is to provide the organizational basis for such a process so that each center wishing to set up CAR-T cell activity can do so effectively. After detailing the coordinating nurse's role, we explain each step of the care process and specify essential additional tests.

Introduction CPX-351 is a liposomal formulation of cytarabine and daunorubicin packaged at a 5:1 molar ratio. This drug has recently been approved by FDA and EMEA for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). The primary objective of this study was to analyze the efficacy of CPX-351 in a real-life setting, evaluating the impact of mutations on response and minimal residual disease (MRD) in responding patients. Methods We retrospectively collected data from patients treated by CPX-351 in eleven centers in France. Clinical, biological and treatment information were available for all patients. NGS (19 genes or more) was performed in 67 patients (84%) at diagnosis. Overall response rate (ORR) was defined by complete remission (CR) and CR with incomplete haematological recovery (CRi). Among the patients in CR or CRi, 25 (56%) had MRD evaluation assessed by NGS or flow cytometry. Overall survival (OS) was calculated from the date of AML diagnosis to the date of death or last follow-up. All statistical analyses were performed using SPSS v.22 software (IBM SPSS Statistics). Results Between April 2018 and July 2019, 80 patients treated with CPX-351 were included in this study. Sex ratio M/F was 43/37 and median age was 66 years old (range 20-83). AML subtypes were MRC-AML (61%) including AML with prior myelodysplastic syndrome (MDS-AML) (33%), prior chronic myelomonocytic leukemia (CMML-AML) (7%), or t-AML (29%). Sixteen patients (20%) had received prior treatment by hypomethylating agents (HMA), at the time of MDS diagnosis, before AML evolution. According to ELN 2017 classification, genetic risk was favorable, intermediate and adverse in 1 (1%), 31 (38%) and 47 (58%), respectively. 36% and 28% patients had complex and monosomal karyotypes, respectively. Assessed by NGS the most frequent mutated gene were : RUNX1 (n=17, 25%), TP53 (n=15, 22%), ASXL1 (n=14, 21%), TET2 (n=13, 19%), DNMT3A (n=11, 16%), srsf2 (n=9, 13%), FLT3-ITD (n=8, 12%), CBL (n=7, 10%), WT1 (n=7, 10%), and EZH2 (n=7, 10%). According to a genetic ontogeny-based classifier (Lindsley et al., Blood 2015), 23 patients (34%), 29 (43%), 15 (22%) had de novo/pan-AML, secondary type mutations AML, and TP53 mutated AML, respectively. Only 4 patients discontinuing treatment due to prolonged haematological toxicity. Early death rate was 5% and 8.75% through day 30 and day 60, respectively. Median time to neutrophil recovery (>0,5 G/L) and platelet recovery (>20G/L) after induction was 29 days (range 19-78) and 28 days (range 12-77), respectively. Seventy-five patients (95%) had at least one grade 3 or more AEs, including 69 (86%) febrile neutropenia. We observed gastrointestinal toxicity 32 patients (40%) (nausea/vomiting (30%/11%), mucositis (15%)) including 4% with grade 3 or more and alopecia in only 12%. ORR was 45/80 (56%) after induction 1 including 53% CR and 3% CRi. ORR increased to 58% after induction 2. Among the 45 CR/CRi patients, 25 were evaluable for MRD at the time of the 1st consolidation. 72% had MRD below 10-3 (64% below 10-4). Prior treatment by HMA and presence of monosomal karyotype were identified as factors predicting a lower rate of CR/CRi (P=0.001 and P=0.002, respectively). Lindsley's classifier predicted significantly a better chemosensitivity in de novo/pan-AML mutations (P= 0.037). Poor molecular prognosis subgroups defined by 2017 ELN risk stratification (n = 53) as TP53, ASXL1, RUNX1 and EVI1 mutations were not associated with a lower response rate with CPX-351 (Table 1). Twenty-one (26%) patients underwent an allogeneic haematopoietic stem cell transplant (HSCT) with an improved median OS compared to non-transplanted patients (non reached vs 8 months, P= 0.004). With a median follow up of 8.5 months, median OS was not reached. Survival analysis in subgroups will be available for the ASH meeting. Conclusion These data confirmed the efficacy and safety of CPX-351 in poor risk AML (t-AML and MRC-AML). The high rate of CR with low MRD compares favorably with previous report using 7+3 in elderly unfavorable AML (Sylvie D. Freeman et al., JCO 2013) and may explain the favorable outcome observed in patients after HSCT. Moreover, CPX-351 erases the poor prognosis associated with unfavorable mutations defined in 2017 ELN risk stratification. Lindsley's classifier was the best prognostic scoring system in patients treated by CPX-351. Disclosures Bertoli: Daiichi Sankyo: Consultancy; Astellas: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Peterlin:Jazz Pharma: Consultancy; AbbVie Inc: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy. Chevallier:Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria. Thomas:INCYTE: Honoraria; DAICHI: Honoraria; PFIZER: Honoraria; ABBVIE: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Pigneux:Daichi: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Roche: Honoraria; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Recher:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Astellas: 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. Ades:Amgen: Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Cluzeau:Abbvie: Consultancy; Jazz Pharma: Consultancy; Menarini: Consultancy.

Purpose We developed a prognostic scoring system to evaluate the prognosis of myelodysplastic syndrome (MDS) patients surviving more than 100 days allogeneic hematopoietic cell transplantation after (allo-HCT). Patients and methods We performed a landmark analysis on a derivation cohort of 393 cases to identify prognostic factors for 3-year overall survival. Potential predictor variables included demographic and clinical data, transplantation modalities and early post-transplant complications. The scoring system was tested against a validation cohort which included 391 patients. Results Complications occurring before day 100 such as relapse [HR = 6.7; 95%CI, 4.5-10.0] (4 points), lack of platelet recovery [HR, 3.6; 95%CI, 2.2-5.8] (2 points), grade-II acute GVHD [HR = 1.7; 95%CI, 1.2-2.5] (1 point) and grade-III/IV [HR = 2.6; 95%CI, 1.8 -3.8] (2 points) were the only independent predictors of 3-year OS. The 3-year OS associated with low (0), intermediate (1-3) and high (≥4) risk scores was respectively 70%, 46% and 6%. The model performed consistently in both cohorts, with good calibration. Conclusion This post-transplant scoring system is a powerful predictor of outcome after allo-HCT for MDS, and can provide useful guidance for clinicians. Additional studies are required to evaluate this scoring system for other hematologic malignancies.

Background : Patients with acute myeloid leukemia in relapse or refractory to induction therapy have dismal prognosis. Response rates to common salvage regimens are low and allogenic hematopoietic stem cell transplantation is the only curative option. Several studies have demonstrated that salvage chemotherapy with sequential conditioning could reduce leukemia relapse risk with an acceptable toxicity profile for unfavorable acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). [1] Therefore, we decided to assess this procedure in our center at Amiens University Hospital. Methods We conducted a monocentric retrospective study, including 53 patients aged over 18 years undergoing a hematopoietic stem cell transplant (HSCT) with sequential conditioning between January 2012 and December 2018, for relapse/refractory AML or high risk MDS. 44 (83%) patients received sequential conditioning containing clofarabine (SET-RIC) or Amsacrine (FLAMSA) and 9 (17%) thiotepa based (TEC-RIC) with post-transplant cyclophosphamide for mismatched donors. Patients who were GVHD free after immunosuppressors withdrawal received immunomodulation as relapse prevention with azacytidine 37.5mg/m²/day 5 days every 4 weeks for 12 cycles with 3 donor lymphocyte infusions (DLI) alterned between azacytidine cycles. Results The median age was 52 years (range 18-70). Before conditioning, 48 patients had unfavorable AML with ELN intermediate score refractory to at least one course of induction therapy or in relapse, or unfavorable ELN score; 5 patients had high risk MDS with complex karyotype. 32 patients (60,5%) had active disease and 21 (39,5%) were in complete remission (CR) including 12 with positive MRD. 13 (24,5%) patients had HLA-identical sibling donors, 27 (51%) match unrelated donors (MUD), 4 (7,5%) mismatch unrelated donors (MMD) and 9 (17%) haploidentical donors. Majority of patients (90,5%) received peripheral blood stem cell (PBSC) PBSC with median CD34+ count of 7,94.106/kg (1,84-8,44). Acute GvHD prophylaxis with Ciclosporin A, in combination with Mycophenolate mofetil for MUD/MMR/Haplo, was withdrawal with a median time of 90 days. With a median follow-up of 40 months, overall survival (OS) at 1 and 2 years was 68% and 52%. Median OS was 18,7 months (0-72,4 months) and median disease free survival (DFS) was 14,9 months (0-72,4 months). 17 patients (32%) experienced relapse after HSCT with a median time from HSCT to relapse of 6 months (1-35 months). 22 (41,5%) of patients presented with grade I-II acute graft versus host disease (GVHD) and 6 (11,3%) with grade III IV aGVHD . GVHD free relapse free survival (GRFS) at 1 and 2 years was 53% and 34,2%. One-year cumulative incidence of disease related death and non-relapse mortality was 12,6% and 17% respectively. 19 patients received immunomodulation with 5 Azacitidine and DLI if no GVHD occurred within day 120. OS was 79 % in the 19 patients receiving DLI. In univariate analysis immunomodulation post HSCT (Figure 1) was significantly associated with overall survival and leukemia free survival (p=0,0164 and p=0,0359 respectively) but not the disease status before HSCT (p=0,7). Immunomodulation administration with azacytidine and DLI was not significantly associated with cGVHD occurrence (p=0.31). Benefit of immunomodulation OS persisted in multivariate analysis (p=0.0284). Conclusion: Sequential conditioning regimen on refractory AML with secondary immunomodulation with azacytidine and DLI shows very good results with an acceptable toxicity profile in unfavorable AML. We achieve very good OS and DFS whatever disease status before HSCT. GRFS is also encouraging comparing to previously report datas [1]. Reference: [1] Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. Decroocq et al. Am J Hematol 2018 ;93 :416-423. Figure 1 Disclosures No relevant conflicts of interest to declare.

Introduction: Corticosteroid-refractory graft-versus-host disease (GVHD) remains a serious complication of hematopoietic stem cell transplantation (HSCT) with high morbidity and mortality rates. Unfortunately, no standard therapy exists for this setting. Ruxolitinib (ruxo), an oral selective Janus-associated kinase (JAK) inhibitor, achieved good results for corticoresistant acute and chronic GVHD in preclinical and clinical studies, with 80% overall response rates. Recent studies showed an increased risk of infections in patients treated with ruxo, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations. Patients and methods: In order to assess the efficacy and the safety of ruxo, we reviewed here the outcome of 57 patients who received ruxo for corticosteroid-refractory GVHD (in case of digestive tract involvement or in the absence of available ongoing clinical trials) or as a steroids-sparing medication. EBV and CMV reactivation risks were also assessed in the 137 consecutive patients received HSCT between January 1, 2012 and December 31, 2017 and who presented acute or chonic GVHD (57 of whom received ruxo). For this purpose, each reactivation were analyzed separately as a competing risk with death in a cause specific Cox model of survival after the first GVHD occurrence and the onset of ruxo therapy was coded as time dependent covariate. Results: The median age of 57 patients with ruxo was 55 years (range, 49 to 61). Indication for HSCT was acute myeloid leukemia for 25% patients, lymphoma for 30%, acute lymphoblastic leukemia for 11%, myeloproliferative neoplasm for 14% and myelodysplastic syndrome for 7%. Only 9% of this patients received ruxo before HSCT. Unrelated donor was used for 60% patients and main source of hematopoietic stem cells was peripheral stem cells (93%). T cell depletion with polyclonal anti-thymocyte globulin was performed for 89% of patients. Conditioning with high doses cyclophosphamide was used for 21% patients. A lymphopenia 4 log or increasing viral charge of 0.5 log) occurred in 19 patients after ruxo with a 6-weeks cumulative incidence (6WCuI) of 22% (95CI [95% confidence interval]: 15-34). It was the first reactivation in 13 patients. CMV reactivation (> 3 log) occurred in 8 patients after ruxo with a 6WCuI of 4% (95CI: 7-25). It was the first reactivation in 3 patients (Figure 1). The distribution of first reactivation before ruxo and in the remaining 80 patients is shown in Table 1. Thus, 6WCuI of first EBV and CMV reactivation after the first episode of GVHD was 24% (95CI: 19-31) and 20% (95CI: 15-25) respectively. Finally, onset of ruxo coded as time dependent covariates retained a significant adverse prognostic value for the competing risks of death and first episode of EBV reactivation (HR [Hazard Ratio]: 2,657, p Discussion /Conclusion: Ruxo initiation coded as a time-dependent covariate was significantly associated with the overall risk of viral reactivation after the first episode of GVHD and the viral reactivations incidences after ruxo were similar with the incidence of reactivation at the onset of GVHD. Thus, it might be linked to the immuno-compromised state induced by both HSCT and GVHD. Furthermore, as we used ruxo for serious gastro intestinal GVHD, we could have selected patients with a more severe GVHD, requiring multiple immunosuppressive therapy, worsening immune reconstitution. To our knowledge it is the first study to assess the competing risk of CMV and EBV reactivation during ruxo treatment for GVHD. Given its effectiveness in corticoresistant GVHD, ruxo use must not be limited by the fear of viral reactivation at the light of our data, conditioned upon a close monitoring of viral loads in the first weeks. Disclosures No relevant conflicts of interest to declare.

Introduction Rituximab maintenance (RM) (375mg/m2 per infusion every 2 months for 3 years) in transplanted patients with mantle-cell lymphomas (MCL) prolongs disease control (LyMa trial, Le Gouill et al NEJM; NCT00921414). However, post-transplant RM might also induce long-term immune deficiency and thus increases risk of infection. To address these issues, we performed an ancillary pre-planned study based on the LyMa trial, a phase III trial that compared RM versus observation (Obs) after ASCT in MCL patients. We compared post-transplant immune-deficiency and its impact on PFS and OS in the RM vs Obs groups. Method All transplanted and randomized patients enrolled in the LyMa trial were eligible for the present study. The following data were collected during the post-ASCT period and monitored according to protocol procedure: febrile event, clinically documented infection, hospitalization for infection, neutropenia, hypogammaglobulinemia and T CD4 lymphocytes count. We also retrospectively collected the use of immune globulin (Ig) substitution. In the LyMa trial, patients were randomized between RM vs Obs after transplantation. To decipher the implication of ASCT or RM in immune recovery, treatment periods were divided in 4: < 6 months after randomization, from 6 to 12 months after randomization, from one to two year after randomization, and from 2 to 3 years after randomization (respectively periods A, B, C and D). Chi-square or Fisher's exact tests were used as appropriate to investigate differences between arms in each treatment period. For all tests, a two-sided p-value Results 240 patients were eligible, 120 in each arm. Patients' characteristics at diagnosis and inclusion were similar in the two arms. Number of hospitalizations due to infections was not statistically different in RM vs Obs in all periods. As previously shown, grade 3/4 infections incidence did not differ in the 2 arms. However, febrile events were more frequent in the RM arm (32 pts vs 11; 38 events vs 12) but this was statistically significant only in C and D periods; p=0,03 for the 2 periods. In all, 51 infections in 44 pts were reported in Obs vs 127 events in 82 pts in RM arm. This difference was also only statistically significant during the C period, p=0,001. Grade 4 neutropenia incidence and T CD4 count did not differ between the two arms in all tested periods. Hypogammaglobulinemia was statistically more frequent in RM during C and D periods (p=0,0001 and p< 0,0001, respectively). Mean level of gammaglobulinemia on D period was 6,50 g/L (range 0,6-11,7) in obs arm versus 4,99 (range 1,0-9,5) in RM arm (p< 0,0001). 36 pts in RM arm vs 10 pts in obs arm were substituted with Ig and the difference was statistically significant only in period D, p Febrile and infectious episodes; neutropenia and T CD 4 lymphopenia did not modify PFS and OS. Patients with gammaglobulinemia < 6g/L in RM arm and in the whole cohort had longer PFS compared to pts who did not present hypogammaglobulinemia : 3-years PFS 93,2% vs 63,5% in RM arm HR = 0,294, 95% CI (0,113-0,767 and), p=0,01 and 3-years PFS 85,6% vs 63,6% in the whole cohort, HR adjusted on treatment arm=0,488 95% CI (0,287-0,830), p=0,008 . PFS was not modified by gammaglobulin level in the Obs arm and it did not modified OS in both arms. We performed a multivariate analysis to determine which data were predictive of infectious events and delayed immune recovery (neutropenia, hypogamma, T CD 4 lymphopenia). This included all univariate parameters with p value < 0,2, among clinical and biological characteristics at diagnosis, response after induction and number of rituximab injections. Interestingly, among others expected parameters, complete response assessed by TDM was predictive of hypogamma with Odd Ratio 2,972 (1,263-6,994) p=0,0126. No value was predictive of neutropenia or T CD4 cytopenia. Conclusion As compared to observation, the use of post-transplant RM does not increase risk of neutropenia and T CD4 lymphopenia. However febrile and infectious events, hypogammaglobulinemia and Ig substitution are more frequent after one year post transplantation. Hypogamma < 6g/L is associated with longer PFS and complete morphologic response. This suggests that hypogammaglobulinemia could be a surrogate for disease response quality and duration. Our findings deserve to be confirmed. Disclosures Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Cellectis: Speakers Bureau; Janssen: Honoraria; University Employement: Current Employment. Bouabdallah:Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Oberic:Roche, Janssen: Other: Travel, Accommodations, Expenses; Roche: Honoraria; Roche, Janssen: Consultancy. Hermine:AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Celgene BMS: Consultancy, Research Funding; Novartis: Research Funding; Alexion: Research Funding; Roche: Consultancy. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria.

The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen. We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure. Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH. This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd.

Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30 ml/min per 1.73 m(2) and post-treatment dFLC under 40 mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival.

Consolidation with VTd significantly improves the complete remission rate and time to progression following VTd induction and single autologous stem cell transplantation in multiple myeloma

La maladie des depots d'immunoglobulines monoclonales (MDIM) est une complication rare des proliferations plasmocytaires monoclonales, definie par des depots rouge Congo negatifs, de chaineslegeres (LCDD), lourdes (HCDD), ou les 2 (LHCDD), le long des membranes basales. L'atteinte renale est quasi constante. Les strategies therapeutiques, incluant des inhibiteurs du proteasome, sont mal definies. Nous avons analyse de maniere retrospective 49 patients atteints de MDIM ayant recu une mediane de 4.5 cure d'un schema a base de bortezomib (1.3mg/m2)+dexamethasone (BD, n=25), BD+cyclophosphamide (n=18), ou BD+thalidomide ou lenalidomide (n=6). L'hemopathie sous jacente est une gammapathie monoclonale de signification renale (n=38), un myelome symptomatique (n=10) ou une maladie de Waldenstrom (n=1). La reponse hematologique globale, basee sur la difference entre la chaine legere impliquee et la non impliquee (dFLC) est de 91%. Apres 54 mois de suivi median, 5 patients sont decedes, et 2 ont evolue vers l'insuffisance renale terminale. La reponse renale a ete obtenue chez 26 patients (53%), avec 35% d'amelioration du debit de filtration glomerulaire estime (DFGe), et 86% de diminution de la proteinurie des 24h. Les facteurs predictifs de la reponse renale sont : DFGe>30mL/min/1.73m2 avant traitement, et dFLC

Abstract 3096 Background. Several studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However there are limitations to these studies, especially that no data is available regarding the role of VTd consolidation in the context of bortezomib-triple based VTd induction regimen followed by a single auto. At completion of therapy, the response rate (ORR, PR and better) was 89%, VGPR+CR rate 74%, CR rate 29%, relapse rate and median PFS was 53% and 26 months (median F-up 32 months) in the VTd arm of the phase 3 IFM2007-02 trial conducted for newly diagnosed MM (Moreau et al, Blood 2012). In this study, only a minority of patients had received a consolidation or maintenance. On the other hand, Cavo et al. (Blood 2012) reported 97.5%, 92%, 61%, 39% 3-year progression and 62% estimated 5-year PFS (F-up 43 months) respectively in the VTd arm. VTd was given as induction before and consolidation after double auto in this upfront GIMEMA phase 3 trial (Cavo et al, Lancet 2010). We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen). Method. This study has included a first group of 121 newly diagnosed MM from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto upfront, aged less than 65 and treated with VTd-auto-VTd regimen. The second cohort included MM treated with VTd-auto without consolidation from the IFM2007-02 trial (n=76). A third cohort comprised MM that received upfront a triplet Vd-based combination induction (VCd, VRd) -auto without consolidation (n = 40). Results. In the whole study, the median age was 56 years, the sex ratio was 1,49, 50% had ISS 2 and 3, 22% had adverse FISH [t(4;14); del17p] (similar in the 3 groups). Overall, the ORR was identical in the 3 cohorts at completion of therapy, 104 (86%), 72 (94%) and 32 (80%) for the cohort 1 to 3, respectively. Nevertheless, the CR rate was significantly greater in patients that received a consolidation (cohort 1), as compared to the cohorts 2 and 3 that did not receive any consolidation, 59 (53%) vs. 26 (34%) and 13 (32.5%), respectively (p=0.0001). Interestingly, the CR rates were identical at the end of the induction in the 3 cohorts, 13%, 15% and 22.5%, respectively. With a median follow-up of 25 months, the incidence rate of relapse was significantly greater in the cohort 2 and 3 versus 1, further demonstrating the importance of the consolidation, 25 (21%), 42 (55%) and 13 (32.5%) patients (p=0.0001), respectively; and 9 (8%), 6 (8%) and 8 (20%) had died in cohorts 1 to 3 (p=0.07). The median (95%CI) PFS was not reached in cohort 1, and was 32 (28;36) months and 30 (26;33) months in cohort 2 and 3, respectively. Importantly, 54.5%, 32% and 32% of patients were free of relapse at 32 months in the 3 cohorts, respectively. Similar data were obtained for TTP. The median (95%CI) OS was not significantly different in cohorts 1 to 3, although not reached for the first 2 cohorts and 38 (33;43) months for the 3rdcohort. The 3-year survival was 84%, 91% and 76%, respectively (p=ns). A longer follow up will certainly demonstrate greater survival end points benefit in favor for consolidation. The safety profile of the cohort that contained a consolidation was superimposable to that of the remaining 2 cohorts without consolidation. The incidence rate of hematological EIs of grade 3 and 4 was 4%, 6% and 8% in the 3 cohorts (p=ns), respectively. The incidence rate of neuropathy grade 1–2 and 3–4 was 5% and 2% in the cohort 1 with consolidation, but only 1% occurred during the consolidation. This data compares favorably to the 3% reported in the cohort 2 (Moreau et al. Blood 2012). We have also observed 9 (9%) thromboembolic events (TE), 8 of venous type and 1 arterial. None of them happened during the consolidation, and again, this incidence rate if superimposable to that reported in the IFM2007-02 vTd cohort. Conclusion. This study showed an impressive increase in CR rate in relation to the consolidation that translated into a lower relapse rate. This study also demonstrated that the VTd regimen, used both as induction and consolidation, in the context of a single auto upfront in MM, significantly contributed to improve clinical outcomes with an acceptable toxicity profile. VTd-auto-VTd compared very favorably to the other upfront protocols, and may become in the near future a standard of care in newly diagnosed patients with Myeloma. Disclosures: Leleu: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Onyx: Honoraria, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau. Off Label Use: Pomalidomide. Roussel:celgene: Honoraria; janssen: Honoraria. Facon:onyx: 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; millenium: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

Background With the ever-rising number of patients undergoing allogeneic stem cell transplantation (allo-SCT), the number of those requiring admission to the intensive care unit (ICU) has also increased over the last two decades. Indeed, allo-SCT is associated with potentially life-threatening complications such as conditioning-regimen toxicity, graft-versus-host disease (GVHD) and relapse. Several studies suggest that ICU admission may fail to provide benefits with a mortality rate attaining 95% in a subset of allo-SCT patients. Therefore, ICU triage policies have been set in order to identify patients who have the best chances of recovering from life-threatening complications. Not only were those policies based on studies that were restricted to patients admitted to ICU, but they also included very heterogeneous cohorts of patients in terms of underlying disease, patients characteristics and transplantations modalities. In addition, interpretation of the data is confounded by the inclusion of both autologous and allogeneic SCT patients and the absence of a clear distinction between acute, chronic and refractory GVHD. With the purpose of identifying factors that affect overall survival (OS), we conducted a retrospective multicenter study on a homogenous cohort. The aim of this study was to establish a new prognostic score usable in screening patients requiring ICU and bases on early post-transplant complications. Patients and methods Transplantation modalities were made as homogeneous as possible using the following inclusion/exclusion criteria: (i) Patients with myelodysplastic syndrome aged more than 18 years referred for first allo-SCT following RIC with at least one year of follow-up (ii) source of stem cell was marrow or blood from either a sibling or an HLA-identical unrelated donor at allelic level (so called 10/10). Patients who received allo-SCT from an HLA-mismatched donor, cord blood or T-cell-depleted graft were excluded as well as patients with CMML. Consequently, 275 consecutive patients with MDS who underwent allo-SCT between January 1999 and December 2009 in 24 French and Belgian centers were identified. Patient and donor characteristics, transplantation modalities and complications occurred within 100 days after transplant were considered for univariate analysis. Multivariate Cox proportional hazards regression was used to investigate prognostic factors by backward stepwise analysis of the factors considered significant in univariate analysis. A prognostic score for 3-year OS was designed using the variables from the multivariate model and according to the rounded HRs values. Risk categories derived from this score were compared using log-rank test. Results In multivariate analysis, 3-year OS was influenced by grade III/IV acute GVHD [HR=2.8; CI95=1.8-4.3; p Conclusion Our new score based on early post-transplant complications appears to be simple and helpful in screening RIC allo-SCT patients who require ICU. This prognostic score should be validated in larger cohorts. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.