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Allogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2–4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32–1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28–1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome.

We report the results from a multicentre retrospective study of 220 adult patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) for therapy-related acute myeloid leukemia (t-AML). Median age at t-AML diagnosis was 56 years, with a prior history of haematological (45%) or gynaecological neoplasia (37%). Median time from cytotoxic exposure to t-AML diagnosis was 54.7 months. At transplant, around 20% of patients had measurable residual disease and 3% of patients were not in complete remission. The median follow-up was 21.4 months (Q1-Q3, 5.9–52.8). At 12 months, overall survival (OS), event-free survival (EFS), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS) were 60.7% (95% CI 54.6–67.5), 52.8% (95% CI 46.5–68.4), and 44.1% (95% CI 37.6–51.8), respectively. At 5 years, OS, EFS, and GRFS were 44.1% (95% CI 37.4–52.1), 40.4% (95% CI 33.9–48.1), and 35.3% (95% CI 28.8–43.3), respectively. At last follow-up, 44% of patients were in complete remission (n = 96) and transplant-related mortality accounted for 39% of all deaths (n = 119). Multivariable analysis revealed that uncontrolled t-AML at transplant was associated with lower EFS (HR 1.94, 95% CI 1.0-3.7, p = 0.041). In conclusion, alloHSCT for t-AML shows encouraging results and offers additional opportunity with the emergence of novel pre-graft therapies.

International audience; Several scoring systems have been developed to assess suitability of individual patients for intensive acute myeloid leukemia (AML) therapy. We sought to compare the performance of these scores in a cohort of 428 consecutive adults with AML who received conventional induction chemotherapy in five academic centers in France. All scoring systems identified a subset of patients with increased 28 and 56-day mortality although the prediction accuracy was overall limited with C-statistics of ranging from 0.61 to 0.71 Overall survival (OS) prediction was more limited and restricted to scoring systems that include AML-related parameters. The outcome of 104 patients (24%) considered unsuitable for intensive chemotherapy based on criteria used in recent randomized trials was similar to that of the other 324 patients (28-day mortality, odds ratio [OR] = 1.88, P = 0.2; 56-day mortality, OR = 1.71, P = 0.21; event-free survival, hazard ratio [HR] = 1.08, P = 0.6; OS, HR = 1.25, P = 0.14) with low discrimination (C-statistic: 0.57, 0.56, 0.50, and 0.52 for 28-day, 56-day mortality, EFS, and OS, respectively). Together, our findings indicate that the accuracy of currently available approaches to identify patients at increased risk of early mortality and shortened survival after intensive AML therapy is relatively limited. Caution regarding the use of available scoring systems should be warranted in clinical decision-making.

Introduction. Approximately 40% of patients (pts) with newly diagnosed AML either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission (CR1 6 months), the probability of response for PIF/ER pts is particularly poor (~12%) with median expected overall survival of ~3.5 month and no approved therapy for this specific population. We have recently shown that increased immune infiltration of the tumor microenvironment (TME) is associated with induction failure and poor prognosis; conversely, an infiltrated TME predisposes for immunotherapy response1. We provide an update of the first-in-human study of flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule currently in clinical development for PIF/ER AML pts. Methods. In this phase of the study, PIF is defined as being refractory to induction with: ≥1 high-intensity cytarabine-based chemotherapy (CTx) cycles, or ≥2 but ≤4 Bcl-2 inhibitor-based combinations, or gemtuzumab ozogamicin only. ER is defined as relapse following CR1 < 6 months. Pts who receive up to one prior salvage attempt are included. Pts whose AML recurred following HSCT are excluded. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day administered as a continuous infusion in 28-day cycles following a step-up ('priming') lead-in dose during Cycle 1 Week 1. Disease status is assessed by modified IWG criteria. Duration of response is measured from initial response to relapse or death. Results. As of July 1, 2020, 38 PIF/ER (as defined above) AML patients have been treated at the RP2D (median age 63yrs [range 28-81]; 31.6% [12] pts female). Most pts (63.2%, 24/38) were PIF and the large majority (94.7%, 36/38) had non-favorable risk by ELN 2017 criteria (25 pts adverse, 11 pts intermediate); 34.2% (13/38) had secondary AML. For ER pts, median duration of CR1 was 2.9 months (range: 0.7-4.0 months). Cytokine release syndrome (CRS) was the most frequently reported treatment related adverse event (TRAE), with all pts experiencing mild-to-moderate (grade ≤ 2) CRS. No grade ≥ 3 CRS events have been reported in this cohort. Most CRS events (51.5%) occurred in the first week of treatment during step-up dosing. The incidence of CRS progressively decreased during dosing at RP2D (34.8% in week 2, 4.5% in week 3, and 6.1% in week 4), allowing outpatient treatment in most cases. Neurologic AEs have been infrequent, with the most prominent event being grade 1 or grade 2 headache in 23.7% (9/38) treated at the RP2D. Two pts experienced grade 3 confusion of short duration (1-2 days) that was fully reversible. Over half (57.9%) of pts had evidence of antileukemic activity (reduction in blast count) with a median decrease of 92.7% in BM blasts (Fig. 1). The overall complete response rate (CRR, Conclusion: FLZ demonstrated encouraging activity in pts with PIF/ER AML, a population with poor prognosis and high unmet medical need, with 42.1% achieving CRR and over half of those receiving a stem cell transplant. Treatment is tolerable with a minimum 8 day inpatient treatment. The study is currently enrolling patients [NCT02152956] 1 Vadakekolathu J, Minden MD, Hood T, Church SE, Reeder S, Altmann H et al. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci Trans Med 2020. Disclosures Aldoss: abbvie: Consultancy, Research Funding; agios: Honoraria; kite: Consultancy; autolus limited: Consultancy; JAZZ: Honoraria, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy. Uy:Genentech: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Emadi:Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Walter:Aptevo Therapeutics: Research Funding. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Arellano:Hanmi: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cephalon Oncology: Research Funding. Wieduwilt:Amgen: Research Funding; Macrogeneics: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Advani:Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Takeda: Research Funding; OBI: Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Wermke:MacroGenics: Honoraria. Erba:AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; Glycomimetics: Other: member of Scientific Steering Committee; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins:IQVIA: Other: I have worked as a contractor for IQVIA in the past, within the past 24 months.; MacroGenics: Current equity holder in publicly-traded company, Other: I currently work as a contractor for MacroGenics. Guo:Macrogenics: Current Employment. Tran:MacroGenics: Current Employment. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Patel:MacroGenics: Current Employment. Bakkacha:MacroGenics: Current Employment. Jacobs:MacroGenics: Current Employment. Seiler:MacroGenics: Current Employment. Rutella:Kura Oncology: Research Funding; MacroGenics Inc.: Research Funding; NanoString Technologies Inc.: Research Funding. Bonvini:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson-Moncada:Macrogenics: Current Employment. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

We have recently shown that bone marrow (BM) RNA profiles stratify patients with acute myeloid leukemia (AML) into immune-infiltrated and immune-depleted subtypes and that type I/II interferon (IFN)-related gene signatures associate with complete response to flotetuzumab (FLZ), an investigational CD123×CD3 bispecific DART molecule. Within the AML tumor microenvironment CD8+ T cells exhibit features of immune exhaustion and senescence (IES). IES are dysfunctional states driven by metabolic alterations in the tumor microenvironment (TME) and emerging targets for cancer immunotherapy. The aim of the current study was to determine whether IES predicts response of relapsed-refractory (R/R) AML to FLZ in the CP-MGD006-01 clinical trial. Based on prior knowledge and gene set enrichment analysis, we derived a 61-gene IES signature score from RNA-sequencing datasets (TCGA and Beat-AML Master Trial; 162 and 281 patients, respectively). The immunotherapy cohort included 139 BM samples from 71 patients with R/R AML treated with FLZ at the RP2D of 500 ng/kg/day (NCT02152956). BM samples were collected at time of study entry (n=71; n=66 with response data) and longitudinally post-cycle (PC)1 (n=40), PC2 (n=18), PC3 and 4 (n=4) and end of treatment (n=6). AML status at study entry was classified as primary induction failure (PIF, defined as lack of response to at least 2 induction treatment cycles), and early (ER) or late relapse (LR), defined as complete remission (CR) of 50% decrease or decrease to 5-25% BM blasts. RNAs were profiled on the PanCancer IO 360™ gene expression panel on the nCounter® platform. Formalin-fixed paraffin embedded BM biopsies were profiled using the human IO protein and RNA panels on the GeoMx® digital spatial profiler (DSP). The 61 genes in the IES signature included T/NK-cell markers (granzymes, CD8A, KLRD1, KLRK1), immune checkpoints (ICOS, CTLA4, EOMES), IFNG and IFN-stimulated genes (CXCR6, IFIH1, IL10RA, GBP1), and were enriched in KEGG pathways related to Th1/Th2 differentiation, TCR signaling, cytokine-cytokine receptor interaction, NK-mediated cytotoxicity and CD28 costimulation (false discovery rate In conclusion, features of IES were associated with response to FLZ. T-cell functional rejuvenation by FLZ could benefit patients with R/R AML by counteracting pre-existing immune dysfunction. Figure Disclosures Church: NanoString Technologies, Inc.: Current Employment. Uy:Pfizer: Consultancy; Agios: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas Pharma: Honoraria; Daiichi Sankyo: Consultancy. Emadi:Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Walter:Aptevo Therapeutics: Research Funding. Foster:Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Arellano:Cephalon Oncology: Research Funding; Hanmi: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wieduwilt:Amgen: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Macrogeneics: Research Funding. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Advani:Takeda: Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding. Wermke:MacroGenics: Honoraria. Erba:AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Glycomimetics: Other: member of Scientific Steering Committee; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee. Ravandi:Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Macrogenics: Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Topp:Amgen, KITE, Novartis, Regeneron, Roche: Consultancy; Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Gojo:Amgen: Research Funding; Merck: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Luznik:AbbVie: Consultancy; WindMil Therapeutics: Patents & Royalties: Patent holder; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Davidson-Moncada:Macrogenics: Current Employment. Rutella:NanoString Technologies, Inc.: Research Funding; MacroGenics, Inc.: Research Funding; Kura Oncology: Research Funding.

Introduction: CRS is a potentially life-threatening toxicity observed following T cell-redirecting therapies. CRS is associated with elevated cytokines, including IL6, IFNγ, TNFα, IL2 and GM-CSF. Glucocorticosteroids (GC) and the IL6 receptor blocking antibody tocilizumab (TCZ) can reduce CRS severity; however, CRS may still occur and limit the therapeutic window of novel immunotherapeutic agents. Disruption of cytokine signaling via Janus kinase (JAK) pathway interference may represent a complementary approach to blocking CRS. Ruxolitinib (RUX), an oral JAK1/2 inhibitor approved for the treatment of myelofibrosis and polycythemia vera, interferes with signaling of several cytokines, including IFNγ and IL6, via blockade of the JAK/STAT pathway. We hypothesized that RUX may reduce the frequency and severity of CRS in R/R AML patients (pts) undergoing treatment with flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule. Methods: Relapse/refractory (including primary induction failure, early relapse and late relapse) AML pts were included in this study. RUX pts were treated at a single site, Washington University, St. Louis, MO. RUX was dosed at 10 mg or 20mg BID days -1 through 14. Comparator (non-RUX) pts (n=23) were treated at other clinical sites. FLZ was administered at 500 ng/kg/day continuously in 28-day cycles following multi-step lead-in dosing in week 1 of cycle 1. CRS was graded per Lee criteria1. Results: As of July 1st, 2020, 10 R/R AML pts, median age 65 (range 40-82) years, have been enrolled and treated in the RUX cohort (6 at 10mg, 4 at 20 mg of RUX). All pts had non-favorable risk by ELN 2017 criteria (8 adverse and 2 intermediate); 1 (10.0%) pt had secondary AML; pt characteristics in the RUX and non-RUX cohorts were balanced, except for median baseline BM blasts which was higher in non-RUX pts: 15% (range 5-72) vs (40% (range 7-84), RUX and non-RUX pts respectively. Cytokine analysis showed statistically significant (p Conclusion: Prophylactic RUX produced a clear difference in cytokine profiles but no discernable improvement in clinical CRS or response rates in FLZ treated patients. A larger study may be required to determine the prophylactic role of RUX in CRS. References: 1. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124(2): 188-195. doi: 10.1182/blood-2014-05-552729 Disclosures Uy: Pfizer: Consultancy; Agios: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Aldoss:abbvie: Consultancy, Research Funding; kite: Consultancy; agios: Honoraria; autolus limited: Consultancy; JAZZ: Honoraria, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy. Arellano:Cephalon Oncology: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Research Funding. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Ravandi:Celgene: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Advani:Takeda: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding. Wieduwilt:Macrogeneics: Research Funding; Amgen: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Emadi:Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Macrogenics: Research Funding; Kite, a Gilead Company: Research Funding; Delta-Fly: Research Funding; Unum: Research Funding; Atara: Research Funding; Gamida Cell: Research Funding; Amgen: Research Funding. Wermke:MacroGenics: Honoraria. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins:MacroGenics: Current equity holder in publicly-traded company, Other: I currently work as a contractor for MacroGenics; IQVIA: Other: I have worked as a contractor for IQVIA in the past, within the past 24 months.. Guo:Macrogenics: Current Employment. Tran:MacroGenics: Current Employment. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Patel:MacroGenics: Current Employment. Bakkacha:MacroGenics: Current Employment. Jacobs:MacroGenics: Current Employment. Seiler:MacroGenics: Current Employment. Rutella:MacroGenics Inc.: Research Funding; Kura Oncology: Research Funding; NanoString Technologies Inc.: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Bonvini:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson-Moncada:Macrogenics: Current Employment. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

The anti-CD38 monoclonal antibody daratumumab is approved as a single agent for the treatment of patients with relapsed and refractory multiple myeloma (RRMM) who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMID), or who are double refractory to a PI and an IMID. To date, no real-life data on the efficacy and tolerance of daratumumab in this setting are available. We report here the results of a single-center series of 41 RRMM patients treated with single-agent daratumumab outside clinical trials. Patients received a median number of 4 prior therapies. All patients were previously exposed to PI and IMID and all patients were refractory to the last line of therapy. Most patients presented with high-risk characteristics, including 24% adverse cytogenetics (del17p/t(4,14)), 31% extramedullary disease and 12% circulating plasmacytosis at time of daratumumab therapy. The overall response rate was 24%, including 5% very good partial response or better. After a median follow-up of 6.5 months, all patients experienced disease relapse. The median progression-free survival was 1.9 months. At the time of disease progression, 44% of patients did not receive subsequent therapy. The median overall survival was 6.5 months. No new safety signal was identified. These real-life results revealed modest efficacy of single-agent daratumumab in advanced patients with RRMM in comparison with data from clinical trials.

International audience

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative procedure in patients with Shwachman–Diamond syndrome (SDS) with bone marrow abnormalities. The results of 74 patients with SDS (6 acute myeloid leukemia, 7 myelodysplastic syndrome, and 61 bone marrow failure) treated with HSCT between 1988 and 2016 are reported. The donor source was: 24% sibling, 8% parent, and 68% unrelated donor. The stem cell source was: 70% bone marrow, 19% peripheral blood stem cells, and 11% cord blood. The conditioning regimen was myeloablative in 54% and reduced intensity in 46%. Neutrophil engraftment was achieved in 84% of patients after a median time of 17.5 days. Graft failure occurred in 15% of HSCTs. Grades I–IV acute and chronic GVHD were observed in 55% and 20% of patients, respectively. After a median follow-up of 7.3 years (95% CI 4.8–10.2), 28 patients died for progression/relapse (7) or toxicity (21). The 5-year overall survival and nonrelapse mortality were 63.3% (95% CI 50.8–73.4) and 19.8% (95% CI 10.8–30.8), respectively. In conclusion, this is the largest series so far reported and confirms that HSCT is a suitable option for patients with SDS. Further efforts are needed to lower transplant-related toxicity and reduce graft failure.

Introduction: While many publications have studied immune reconstitution after allogeneic stem cell transplantation (allo-SCT), data exploring whether the pre-transplant immune status (IS) of the recipients has any impact after this procedure are still lacking. Material and Methods: Since May 2017, in our department, the IS of allo-SCT recipients has been systematically investigated at the time of pre-graft check-up. Data of this monocentric retrospective study on post-allo-SCT outcomes are reported here. Information was retrieved from complete blood counts (CBC) in terms of lymphocytes (normal range [NR] 1.5-4x109/L) and monocytes (NR: 0.15-0.9 x109/L). Classical multiparameter flow cytometry and a double platform were used to assess absolute counts of lymphocyte subsets, i.e. CD3+ (NR: 0.9-1.8 x109/L), CD4+ (NR: 0.5-1.2 x109/L), CD8+ (NR: 0.3-0.7 x109/L), CD19+ (NR: 0.1-0.4 x109/L) and CD56+ (NR: 0.1-0.4 x109/L). All patients also benefited from standard serum electrophoresis allowing to appreciate their global level of immunoglobulins (Ig) (NR: 8-13.6 g/L). The impact of pre-graft immune parameters was investigated for overall (OS) and disease-free (DFS) survivals as well as acute and chronic graft-versus-host disease (GVHD) incidence. Results: Between May 2017 and December 2019, 195 consecutive adults were checked for immune status before allo-SCT. They were 117 males and 78 females at a median age of 59 years-old (range: 23-71). The median follow-up for the whole cohort was 21.7 months (range: 5.77-37.5). The majority of patients had a myeloid disease (n=141) and received a reduced intensity (RIC) regimen (n=149, myeloablative [MAC] n=23; sequential n=23). The disease-risk index was low/intermediate and high/very-high for respectively 91 and 104 patients. GVHD prophylaxis included anti-thymocytes globulins (ATG) for 102, post-transplant cyclophosphamide (PTCy) for 54 and both ATG+PTCy for 39. Donors were siblings in 39 cases, matched-unrelated (MUD) in 86, haplo-identical in 66 and 9/10 mis-matched in 4. The IS was evaluated at a median of 20 days (range: 8-72) before allo-SCT. Except for monocytes (median: 0.48 x109/L, range: 0-26), all median immune cell populations were lower than the NR before allo-SCT: lymphocytes (0.84 x109/L, range: 0-8.4), CD3+ (0.7 x109/L, range: 0-3.5), CD4+ (0.37 x109/L, range: 0-2.37), CD8+ (0.25 x109/L, range: 0-2.56), CD19+ (0.005 x109/L, range: 0-0.56), CD56+ (0.097 x109/L, range: 0-0.77). Conversely, the Ig median level was in the NR (8.6 g/L, range: 1.4-28). The percentages of patients with immune cells and Ig above the lowest NR were as follows: lymphocytes: 14.8%, monocytes: 80%, CD3: 37.4%, CD4: 37.4%, CD8: 38.9%, CD19: 16.4%, CD56: 47.6%, Ig: 56.7%. Only 5 patients (2.5%) had a fully normal IS before transplant. Considering the whole cohort, 2-year OS and DFS were 55.6+3% and 50.4+3%, respectively, while incidences of day 100 grade 2-4 and 3-4 acute GVHD and 2-year moderate/severe chronic GVHD were 34.7%, 19.4% and 19.8%, respectively. The comparison of survivals between patients partitioned using either the median of the NR values for immune cells and Ig, showed no difference between subgroups. Similarly, IS had no impact on the incidence of acute nor chronic GVHD. Finally, no difference either was seen according to the conditioning regimen (RIC) or GVHD prophylaxis (ATG, PTCY or both). Conclusion: As expected, almost all pre-ASCT patients present with immune depression. However, pre-transplant IS does not appear to impact survival nor GVHD. This suggests that there is no need to decrease or replace immunosuppressive treatments commonly used in recipients before allo-SCT in the hope to provide better outcomes. Disclosures Touzeau: GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy. Moreau:Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Honoraria.

Introduction: Around fifty thousand autologous stem cell transplantations are done each year worldwide, using cryopreserved peripheral blood stem cells (PBSC). Cryopreservation is time consuming and expensive. Since 2007, several retrospective studies have shown that PBSC can be stored at 4Dg C for two to three days, allowing autologous stem cell transplantation (ASCT) in patients with multiple myeloma receiving high dose melphalan. Data with non-cryopreserved PBSC in patients autografted for lymphoma following longer preconditioning regimens are limited. In addition, there has been no controlled comparison able to possibly detect unforeseen differences. Patients and methods: We compared outcomes of 94 consecutive adult patients with lymphomas (66 with Hodgkin Lymphoma) autografted in our department in Oran (Algeria), using PBSC stored at 4 dg C, from 2009 to 2018 with patients receiving cryopreserved stem cells reported to the EBMT registry. Patient's autografted in Oran were matched with patients receiving cryopreserved PBSC in the registry (4 controls per Oran Patient). Results: Neutrophil engraftment was significantly faster with cryopreserved PBSC (p= 0.003): by day 10, only 17% of patients receiving non-cryopreserved PBSC engrafted versus 48% for cryopreserved PBSC. Likewise, platelet recovery to 20 000/mm3 was significantly faster in patients receiving cryopreserved PBSC (p=0.01). However, all patients in both groups had recovered by day 20. There were no significant differences in Non Relapse Mortality (9% versus 7%; p=0.4), Relapse Incidence (22% versus 32%; p=0.13), Progression Free Survival (70% versus 61%; 0.4) or Overall Survival (85% versus 75%; p=0.3). Conclusion: This analysis suggests that, in patients with lymphomas receiving pretransplant regimens such as the BEAM, PBSC stored at 4dg C for up to six days can be used safely in centers with no cryopreservation facility. The kinetics of recovery of hematopoiesis however did show a significant, albeit small, delay of engraftment for both neutrophils and platelets, which favors the use of cryopreservation if available. Disclosures Blaise: Jazz Pharmaceuticals: Honoraria. Peggs:Autolus: Consultancy. Salles:Karyopharm: Consultancy; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Genmab: Consultancy; Novartis: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; MorphoSys: Consultancy, Honoraria, Other; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Epizyme: Consultancy. Milpied:Roche: Honoraria, Other: Travel support; Astellas: Honoraria; Sandoz: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria; Gilead Sciences: Other: consultancy or advisory role; Celgene: Other: Travel support.

Introduction Chez les patients en bon etat general atteints d’un lymphome cutane agressif, une allogreffe peut etre proposee. Une etude prospective nationale (CUTALLO) est en cours pour evaluer l’efficacite de ce traitement. En cas de rechute apres allogreffe, plusieurs options therapeutiques sont possibles, dont les reinjections de lymphocytes du donneur (DLI). Elles sont pratiquees par analogie a d’autres hemopathies mais n’ont jamais ete evaluees dans l’indication specifique des lymphomes cutanes. Patients et methodes Nous avons inclus l’ensemble des patients atteints d’un lymphome cutane T ayant recu des DLI pour une rechute apres allogreffe en France entre le 1er janvier 2000 et le 31 decembre 2017 (104 allogreffes sur cette periode pour cette indication). Les donnees ont ete extraites de la base de donnees ProMISe, apres accord des membres de la Societe francophone de greffe de moelle et de therapie cellulaire. Resultats Treize patients ont ete inclus dont 8 mycosis fongoide, 2 syndromes de Sezary et 3 autres lymphomes cutanes T. Ils avaient recu une mediane de 4 lignes therapeutiques avant allogreffe (min 3–max 7). La rechute survenait en mediane a 659 jours de l’allogreffe. Les patients avaient recu 1 a 4 DLI (mediane 2), en mediane 563 jours apres allogreffe. Le taux de reponse objective aux DLI etait de 62 %. Le delai median de meilleure reponse aux DLI etait de 181 jours. Soixante-quinze pour cent des patients repondeurs ont presente une rechute a un delai median de 405 jours apres DLI. La survie sans progression a 1 et 5 ans des DLI etait de respectivement 46 % et 19 %. La survie globale etait de 100 % a 1 an et de 59 % a 5 ans. Six patients (50 %) ont presente une reaction du greffon contre l’hote apres DLI, dont 3 avaient deja presente une GVH chronique apres allogreffe ; 4 d’entre eux ont rechute a un delai median de 377 jours. Seuls 4 patients de notre cohorte etaient decedes au 1er janvier 2018, dont 2 suite a une evolution de la maladie. Discussion Il s’agit a notre connaissance de la premiere cohorte disponible evaluant les DLI dans les lymphomes cutanes T. Le caractere exhaustif et consecutif du recrutement permet d’avoir un panorama des pratiques actuelles en France. Les donnees manquantes sont peu nombreuses grâce a l’utilisation d’une base de donnees nationale standardisee. La principale faiblesse de cette etude reside dans le fait qu’elle ne comporte pas de groupe temoin. Ce type d’etude therapeutique, pour des raisons ethiques, comporte difficilement un groupe temoin. Notre effectif est faible, mais il s’agit de la plus large cohorte disponible traitant de ce sujet. Conclusion Avec une survie globale de 100 % a 1 an et 59 % a 5 ans, les DLI semblent etre un traitement efficace, en termes de survie, pour les rechutes apres allogreffe des lymphomes cutanes T a un stade actuellement hors de toute ressource therapeutique curative.

Background Patients with advanced B-cell non-Hodgkin's lymphoma (NHL) refractory to initial chemotherapy or relapsing after autologous stem-cell transplantation have a poor prognosis. Allogeneic stem-cell transplantation after reduced-intensity conditioning (RIC) regimen can be a therapeutic option. However, the high incidence of relapse remains a challenging issue. We speculated that the incorporation of 90Y-Ibritumomab tiuxetan into a fludarabine-based RIC regimen would improve the lymphoma control without overwhelming toxicity. Our aim was to evaluate the safety of 90Y-Ibritumomab tiuxetan in association with such a regimen in a prospective multicenter phase II trial. Patients and methods Thirty-one patients with advanced lymphoma from five distinct institutions were included between February 2008 and October 2010. Thirty patients in complete or partial response after failure of a median of 3 (range, 2–4) previous chemotherapy regimens including autologous transplant in 29 were evaluable for nonrelapse mortality (NRM) at day 100 post-transplant that was the primary end point. Results With a median follow-up of 32 months (range, 29–60 months), the 2-year event-free and overall survivals of the whole study group were both 80% [95 confidence interval (CI) 60.8% to 90.5%). The 100-day and 2-year post-transplant cumulative incidences of NRM were 3.3% (95% CI 0.2% to 14.9%) and 13.3% (95% CI 5.4% to 33.2%), respectively. The 2-year cumulative incidence of relapse was 6.7% (95% CI 1.7% to 25.4%). The cumulative incidences of grade II–IV and extensive chronic graft-versus-host disease were 27% and 14%, respectively. Conclusions For chemosensitive advanced high-risk B-cell lymphoma, the addition of 90Y-Ibritumomab tiuxetan to a RIC regimen based on fludarabine, busulfan and antithymocyte globulin followed by allogeneic transplant is safe and highly effective. clinicaltrials.gov : NCT00607854.

Sclerotic chronic GvHD (cGvHD) is one of the most severe complications after allo-hematopoietic stem cell transplantation (HSCT). Risk factors associated with this complication remain not very well defined. With the aim to define a pre-transplantation risk profile, we have conducted a French retrospective analysis in 705 consecutive patients between 2005 and 2010. Analyses to determine pre-transplantation risk factors included as variables: patient and donor age, kind of donor, HLA matching, ABO matching, sex-matching, diagnosis, stem cell source, gender, GvHD prophylaxis and antithymocyte globulin (ATG) in the conditioning regimen. The cumulative incidence of sclerotic cGvHD was 18% (95% CI, 16.6-19.6) 3 years after onset of cGvHD. In univariate analysis, we found a significantly lower number of sclerotic cGvHD form in patients transplanted from cord blood cells (P=0.0021), in patients with a one mismatched donor (P=0.041) and in patients who had received ATG in the conditioning regimen (P=0.002). In multivariate analysis, factors associated with an increased risk of sclerotic cGvHD were young patient age, multiple myeloma and PBSC as the stem cell source. ATG in conditioning regimen and cord blood unit as the stem cell source were associated with a lower risk.

Despite major improvements in the treatment of multiple myeloma (MM), the majority of patients will eventually relapse.[1][1] Those patients may benefit most from the potentially curative effect of graft versus myeloma effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its

Because the indication of allograft (allogeneic stem cell transplantation [alloSCT]) for multiple myeloma (MM) has widened in recent years, thanks to the development of reduced-intensity conditionings (RIC), it is still unclear if myeloablative conditioning (MAC) remains appropriate. This study compares retrospectively outcomes of patients undergoing either RIC or MAC regimens for MM. Based on the SFGM-TC registry, we included 446 MM patients receiving alloSCT between 1999 and 2009 for whom a minimal data set was available. Median follow-up for the entire cohort was 33.6 months (range, 0 to 164.5). RIC and MAC populations were different regarding age (53.5 versus 47.1 years, respectively), number of prior autologous (auto)SCTs (93.2% versus 79.6% had at least 2 autoSCTs), and stem cell source (90.2% versus 61.2% received peripheral blood). For RIC and MAC populations the nonrelapse mortality at 2 years was 24.6% and 22.4%, respectively, progression-free survival 35.5% and 51.1%, and overall survival 59.5% and 66.7% (not significant). These outcomes were not affected by conditioning intensity either on univariate or multivariate analysis. Despite some limitations in the study design, these results indicate that MAC should remain a valuable option in alloSCT for MM, especially for young and less-treated patient with no comorbidity. The constant progress in induction treatments of MM and supportive care after alloSCT could improve these results in the near future.

This study addressed the question of upfront allo-SCT in untreated PTCL patients (n = 49). The 2-year OS rate was 59% but 72.5% for transplanted patients (n = 29). Disease status at the time of transplantation was predictive marker for PFS/OS. This work shows that upfront allo-SCT is feasible with low TRM and provide long-term disease control in PTCLs but one-third of patients is chemo-refractory. Background Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases with dismal outcome when treated with chemotherapy alone. Because allogeneic stem-cell transplantation (allo-SCT) can cure relapse/refractory patients, we hypothesized that upfront allo-SCT may provide a better outcome. Therefore, all patients that presented with advanced PTCL in our institution at diagnosis were scheduled to undergo upfront allo-SCT after induction chemotherapy. Patients and methods The aim of the present work was to assess the feasibility and toxicity of upfront allo-SCT. From 2004 to 2012, 49 newly diagnosed PTCL patients were scheduled to receive upfront allo-SCT. A human leukocyte antigen-matched donor was found for 42 patients: related to the patient in 15 cases, unrelated in 20 cases, and suitable cord blood units were used in 7 cases. Results After induction chemotherapy, 17 patients reached complete remission and 29 (60%) proceeded to upfront allo-SCT. For all patients, the 1 and 2-year overall survival (OS) rates were 59% [95% confidence interval (CI) 47–75] and 55% (95% CI 43–71), respectively. The most frequent reason we did not proceed to allo-SCT was disease progression or insufficient response after induction. For transplanted patients, the 1- and 2-year OS were 76% (95% CI 62–93) and 72.5% (95% CI 58–91), respectively. Toxicity-related mortality (TRM) 1 year after allo-SCT was only 8.2% (95% CI 0–18.5). The 2-year progression-free survival (PFS) rate of patients who did not proceed to allo-SCT (n = 20) was below 30%. The disease status at the time of transplantation was a strong predictive marker for both PFS and OS in transplant patients. Conclusions Upfront allo-SCT in PTCLs is feasible with low TRM, and it provides long-term disease control. However, one-third of patients remain chemo-refractory and, thus, new therapeutic approaches are warranted. The role of upfront allo-SCT compared with other therapeutic approaches in PTCLs requires investigation in randomized studies.

Background. The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukemia (AML) relies heavily on immune-mediated graft-versus-leukemia effects. Following bone marrow or peripheral blood stem cell transplantation, there is a strong association between occurrence of graft-versus-host disease (GVHD) and a lower risk of AML relapse. Here, we evaluated the kinetics of relapse rate in correlationto GVHD occurrence after UCBT. Methods. The study population included adult patients with de novo or secondary AML, receiving single or double UCBT between 2004 and 2014 at EBMT-affiliated centers.The kinetics of relapse rate over time in correrlation to occurence of GVHD was assessed by calculating the relapse rate per patient-year within sequential 90-day intervals (as previously reported by Inamoto et al., Blood 2011, 14 : 456-463). The smoothed rates were plotted as curves for each GVHD condition (no GVHD, acute GVHD or chronic GVHD). The impact of GVHD on relapse and overall mortality was also assessed with Cox models adjusted for patient age, status at transplantation, cytogenetics, total nucleated cells (TNC), and single versus double UCBT, modeling acute and chronic GVHD as time-dependent covariates. Results. The study included data from 1069 patients given single (n=567) or double (n=501) UCBT. Median patient age at transplantation was 45 (range, 18-73) years. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32% and overall survival was 32% as well. As shwon in the figure 1, relapse rates declined gradually over time during the first 30 months after transplantation and were lower in patients with chronic GVHD than in those without GVHD. Furthermore , in a multivariate Cox model, there was a suggestion for lower incidence of relapse in patients who experienced chronic GVHD (HR 0.6, P=0.1). In contrast, there was a significant increase in the risk of mortality in patients with grade III-IV acute (HR 2.4, P Conclusions. Although this study suggest that chronic GVHD might be associated with lower risk of AML recurrence after UCBT, grade III-IV acute and chronic GVHD each increased overall mortality. Figure 1 Rates of relapse and risk of early and late relapse according to GVHD status. Relapse rates were calculated within sequential 90-day intervals for patients without GVHD (shown in blue), for patients with grades II-IV acute GVHD (shown in green) or for patients with chronic GVHD (shown in red). Small symbols represent the actual relapse rates for each 90-day interval. The smoothed rates were plotted as curves for each condition. Figure 1. Rates of relapse and risk of early and late relapse according to GVHD status. Relapse rates were calculated within sequential 90-day intervals for patients without GVHD (shown in blue), for patients with grades II-IV acute GVHD (shown in green) or for patients with chronic GVHD (shown in red). Small symbols represent the actual relapse rates for each 90-day interval. The smoothed rates were plotted as curves for each condition. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria.

Outcome after reduced-intensity conditioning allogeneic SCT for AML in first complete remission: comparison of two regimens

Background Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for most patients with CN AML. It is now well established that some relevant molecular markers can allow for the definition of risk groups after conventional chemotherapy. However, the role of these markers among other factors influencing outcome after alloSCT remains to be defined. Hence, we conducted an EBMT registry-based analysis aiming to define the exact prognostic role of molecular subgroups in conjunction with other classical risk factors after alloSCT for CN-AML. Patients, Methods and Results 752 adults (375 males) fulfilled the inclusion criteria, i.e. first alloSCT for CN-AML between 2000 and 2011, matched sibling (MSD) or unrelated (MUD) donor, and known mutational status of FLT3-ITD and NPM1, the two most frequently observed molecular markers in CN-AML. Median age was 51y (range, 18-71), disease status at time of alloSCT was CR1 (n=554), CR2/3 (n=90), primary induction failure (PIF, n=39), relapsed disease (n=62) and unknown (n=7). Myeloablative and reduced-intensity conditioning regimens were used in 371 and 378 patients, respectively. 597 received allogeneic PBSCs. With a median follow-up of 27 months, The 2-year estimates of overall survival (OS) and leukemia-free survival (LFS) were respectively 68±2% and 61±6% after alloSCT in CR1, 63±2% and 53±6% in CR2/3, 36±7% and 33±8% in PIF, and 28±7% and 25±6% in relapsed disease. In 554 patients transplanted in CR1, OS, LFS, cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated according to molecular subgroups. Whereas NPM1mut had no influence on outcome, FLT3-ITD was associated with increased CIR (p . A multivariate Cox model of predefined risk factors including age, WBC at diagnosis, time to reach CR1, donor type, conditioning type (reduced vs. standard), and presence of NPM1mut and FLT3-ITD, was performed. Age >=50 years was the only risk factor for NRM (HR= 2.40, 95%CI: 1.32-4.37), while the presence of FLT3-ITD was the only risk factor for CIR (HR=2.85; 95%CI; 1.76-4.60). Both age >=50 years and FLT3-ITD were associated with inferior LFS (HR=1.65, 95%CI: 1.14-2.39, p=0.01 for age, HR=2.08, 95%CI: 1.43-3.01, p=0.001 for FLT3-ITD) and, most importantly, OS (HR=1,76; 95%CI: 1.19-2.61, p=0.005 for age, and HR=2.19; 95%CI: 1.48-3.26, p=0.0001 for FLT3-ITD). The latter data allowed to identify 3 prognostic groups with 2-years OS of 83±4% (younger age and FLT3-ITDneg), 70±4% (older age OR FLT3-ITD) and 48±5% (older age and FLT3-ITD), p Conclusion In the largest study on CN-AML performed thus far, we identified age >=50 years and FLT3-ITD as the major risk factors for OS after alloSCT in CR1, independently from other risk factors such as type of donor or conditioning. In patients harboring FLT3-ITD, a limited protective role for NPM1 mutation could be observed. These results underscore the importance of post-transplant strategies to prevent relapse in AML with FLT3-ITD. Encouraging results were observed after SCT in PIF, relapse or advanced CR. Disclosures: Schmid: Novartis: Honoraria, Research Funding, travel grant Other; Roche: travel grant, travel grant Other; MSD: Honoraria. Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

BACKGROUND: Primary graft dysfunction (PGD) occurs in approximately 5 to 15% and is associated with very poor outcome after allogeneic stem cell transplantation (allo-SCT) (Dominietto et al, BJH, 2001). Despite the lack of consensual diagnostic criteria, PGD is commonly defined as the primary failure of hematologic recovery, often reflected by thrombocytopenia, along with full donor chimerism and hypocellular marrow. Few studies, however, have addressed the prognostic impact of platelet recovery on post-transplant outcome. Furthermore, all published cohorts varied in terms of disease types and transplantation modalities. The aim of this retrospective study was to evaluate the prognostic impact of primary platelet recovery in a homogeneous cohort of patients receiving allo-SCT following myeloablative conditioning (MAC) from an HLA-matched sibling or unrelated donor (10/10) for myelodysplastic syndrome (MDS). METHODS: In this, multicenter study, we investigated the 5-year probabilities of overall survival (OS) and non-relapse mortality (NRM) of 155 MDS patients who underwent allo-SCT between January 1999 and December 2009. Variables were assessed at transplant and at d+100 post-transplant. Platelet recovery was defined as the first occurrence of a stable platelet count ≥ 20G/L before d+100, persisting for more than 7 days without transfusion. Twelve patients who relapsed before d+100 were excluded from the analysis. RESULTS: According to WHO classification, 56 patients (36%) presented with refractory anemia, 43 (28%) with refractory anemia with excess blast type 1 (RAEB-1), 56 (36%) with RAEB-2 and RAEB-t/AML. IPSS was at the time of diagnosis low/intermediate-1, intermediate-2/high in 53 (34%) and 57 patients (37%), respectively (missing data for 45 patients). Progression to a more advanced disease before transplant was observed in 47 patients (30%). The IPSS cytogenetic risk was good/intermediate in 102 patients (66%), poor in 36 patients (23%). Cytogenetic data were missing in 17 cases. Stem cell source was bone marrow in 96 patients (62%) and peripheral blood stem cells in 59 patients (38%). Median age was 46 and marrow blasts was ≥ 10% in 49 patients (32%). Primary failure of platelet recovery was observed in 27 patients (17%) and grade III/IV acute GVHD in 39 patients (25%). In univariate analysis primary failure of platelet recovery (7% versus 50%, p < 0.001), grade III/IV acute GVHD (49% versus 25%, p < 0.001), previous progression (51% versus 28%, p = 0.02), marrow blasts ≥ 10% (50% versus 30%, p = 0.02) significantly impacted OS. After adjustment for significant covariates, absence of platelet recovery retained its adverse impact on outcome for both OS (HR = 6.72, CI = 3.70 - 12.2, p < 0.001) and NRM (HR = 6.57, HR = 3.10 - 13.90, p < 0.001). Importantly, grade III/IV acute GVHD was not an independent prognostic factor in multivariate analysis. CONCLUSION: Primary failure of platelet recovery after allo-SCT following MAC was the only factor influencing both NRM and OS, offsetting the prognostic significance of grade III/IV acute GVHD. Our results emphasize the need to perform prospective trials to investigate therapeutic approaches to reverse graft dysfunction, such as mesenchymal stem cell infusion, and thrombopoietin agonists. Disclosures No relevant conflicts of interest to declare.

International audience; BACKGROUND AND OBJECTIVES: High-dose chemotherapy with allogeneic stem cell transplantation (SCT) has proven to be a successful treatment for low-grade lymphoma (LGL), but is associated with considerable transplant-related mortality (TRM). In an effort to reduce toxic mortality while maintaining the graft-versus-leukemia effect, allogeneic SCT has been combined with a reduced-intensity conditioning (RIC) regimen. The aim of this study was to determine the outcome of patients with LGL treated with RIC allogeneic SCT. DESIGN AND METHODS: This retrospective multicenter study included 73 patients with relapsed or refractory LGL allografted after a RIC regimen between 1998 and 2005 whose data were recorded in a French registry. RESULTS: Patients received a median of three lines of therapy prior to RIC allogeneic SCT. The most widely used conditioning regimens were fludarabine + busulfan + antithymocyte globulin (n=43) and fludarabine + total body irradiation (n=21). Prior to allografting, patients were in complete response (CR; n=21), partial response (PR; n=33) or had chemoresistant disease (n=19). The median follow-up was 37 months (range, 16 to 77 months). In patients in CR, PR and chemoresistant disease, the 3-year overall survival rates were 66%, 64% and 32%, respectively, while the 3-year event-free survival rates were 66%, 52% and 32%, respectively. The 3-year cumulative incidences of TRM were 32%, 28% and 63%, respectively. The incidence of relapse was 9.6%. INTERPRETATION AND CONCLUSIONS: Although associated with significant TRM, RIC allogeneic SCT in advanced chemosensitive disease leads to long-term survival.

In the sight of unpublished french diplomatic archives who detail the political situation inYemen, this article analyses the impact of italo–ottoman conflict on local political actors in Yemen who is occupied by ottoman forces and highly–coveted by some imperialist european countries. The war, who opposed italian and ottoman forces between 1911 and 1912, urge the others actors to position themselves facing with events from their own stakes or interests. Alliances and political strategies will deeply modified and the results of the armed conflict will be felt until the begining of the first war world, À la lueur d'archives françaises inédites détaillant la situation politique au Yémen à des fins diplomatiques, cet article s'efforce d'analyser l'impact du conflit italo–ottoman sur les acteurs politiques locaux dans un Yémen occupé par les forces ottomanes et convoité par des puissances impérialistes européennes. La guerre qui oppose forces italiennes et ottomanes de 1911 à 1912 incite rapidement d'autres acteurs à se positionner face aux événements, voire à les utiliser au profit de leurs propres enjeux ou intérêts. Alliances et stratégies politiques en seront profondément modifiées et les conséquences du conflit se feront sentir jusqu'au déclenchement de la première guerre mondiale.

Politique intérieureJanvier-Février1er janvier Vingt-cinq nouveaux juges sont désignés à la Cour suprême afin de résoudre les problèmes de corruption. 13 janvier Les locaux du journal en ligne al-Mu’tamar (dorénavant CPG, Congrès Populaire Général), ont été attaqués à la grenade pendant la nuit. Le cheikh ‘Abdul Mâjîd al-Zindânî est soupçonné. 30 janvierLes autorités yéménites interdisent aux Iraquiens résidant au Yémen de voter lors du scrutin destiné à élire les membres de l'Assemblée na...

The occurrence of late events [i.e. secondary malignancies (SM)] after therapy is of special relevance in patients with Hodgkin«s lymphoma (HL) as the median age of this population is quite low and first line therapy is curative in a high proportion of them. Autologous stem cell transplantation (ASCT) is the standard of care for patients with HL in first relapse and chemosensitive disease and for those patients who demonstrate to be primary refractory. The administration of chemotherapy +/- radiotherapy is a risk factor for the development of SM and, high dose chemoradiotherapy given as conditioning regimen before stem cell infusion can further increase this risk. In this retrospective study we have analyzed the incidence of SM as well as of the different subtypes [acute leukemias (AL) / myelodisplastic syndromes – myeloproliferative disorders (MDS-MPD), lymphomas and solid tumors (ST)] in more than 2000 HL patients undergoing an ASCT with a very long follow up after transplantation. 2261 patients with HL being treated with an ASCT between January/1985 and December/1995 and reported to the Lymphoma Database of the EBMT have been included in this analysis. There were 871 (38.5%) females and 1390 (61.5%) males with a median age at diagnosis of 26.8 years and at transplantation of 30.2 years. Median follow up for surviving patients was 9.1 years. Median time from diagnosis to ASCT was 26.6 months and 1989 patients (88% of the series) received at least 2 lines of chemotherapy before undergoing the autologous procedure. 694 patients were autografted in complete remission (CR) and the remaining 1567 with visible disease (amongst them, 279 patients had primary refractory disease, 458 patients sensitive relapse and 216, refractory relapse). Total body irradiation (TBI)-containing regimens only represented 4.2% of all conditioning protocols. 1300 patients were conditioned with BEAM / BEAM like protocols, 670 with CBV and 197 with other combinations. As expected because of the year of transplantation, bone marrow was used as the source of stem cells in 1407 patients (62.2%). After a median follow up of 10.5 years for all patients, 978 (45.4%) are alive and 1178 (54.6%) have died, 959 patients (43.7%) have relapsed after ASCT and 378 (17.5%) have died of non-relapse mortality (NRM). Relapse rate (RR) of the whole population of patients was 43.5%, 46.2% and 47% at 5, 10 and 15 years, respectively. NRM ranged from 14.6% to 19.8% at 5 and 15 years after ASCT, respectively. Disease free survival (DFS) was 41.9%, 36.5% and 33.2% at 5, 10 and 15%, respectively and finally, overall survival (OS) at 5, 10 and 15 years was 53.1%, 44.4% and 38.8%, respectively. 122 patients (5.4% of the series) developed a SM after ASCT. The most frequent ones were ST (49 patients – 40.2% of the series) followed by AL / MDS-MPD (26 patients – 21.3% / 23 patients – 18.8%), lymphomas (17 patients – 11.5%) and others (9 patients – 7.4%). 95 patients (78%) were in CR at the time of developing the SM and 27 patients (22%) had already relapsed after ASCT and being treated with additional chemotherapy. 30 patients with SM died of this late effect after ASCT (3% of NRM for the whole population of patients). In conclusion, the development of a SM after an ASCT represents a significant late effect in this big population of HL patients with a very long follow up, the most frequent ones being the ST that, as expected seem to develop later after transplantation than AL / MDS – MPD and lymphomas. The impact of prior therapy as well as other well know prognostic factors in the development of SM after ASCT is still unclear and needs to be better defined.SMSTAL / MDS - MPDLymphomas5-year CI2.4%0.3%1.7%0.1%10-year CI4.8%1.4%2.2%0.3%15-year CI7.7%3.2%2.5%0.4%20-year CI11.7%5.9%2.7%1.5%CI. Cumulative Incidence Disclosures: No relevant conflicts of interest to declare.

Background: ATRA combined to anthracycline based chemotherapy (CT) is the reference treatment of newly diagnosed APL. ATRA has also demonstrated a role during maintenance treatment in randomized studies (Fenaux, Blood 99; Talmann, NEJM 1997), and may even be useful during consolidation courses (Sanz, Blood, 2008, although this was not a randomized study). During induction treatment, the optimal duration of ATRA treatment, however, is unknown. We tried to assess this point using long-term results of APL 93 and APL 2000 trials, conducted by the European APL group in newly diagnosed APL between 1993 and 2004. Methods: APL 93 and 2000 trials combined ATRA plus 3 courses of daunorubicin (DNR) based CT and included a total of 902 pts with different randomizations (for date of introduction of CT, use or not of AraC and of maintenance treatment). Only treatment arms that proved “optimal” (ie with early addition of the first course of CT to ATRA, AraC in combination to DNR for the 3 CT courses, and combined maintenance with intermittent ATRA and low dose continuous CT) (Fenaux, Leukemia 2000;Ades JCO 2006) and adult pts who had achieved CR in those arms, ie 414 pts, were considered for this analysis of the influence of duration of ATRA during induction treatment on the cumulative incidence of relapse (CIR) and survival. Per protocol, ATRA (45 mg/m2/d, rounded to a daily dose of 8 pills of 10 mg per day, ie 80 mg/day in most pts) was to be administered “until CR”, and to be transiently discontinued only in case of severe ATRA syndrome. No dose reduction was allowed except in children, who were therefore excluded from this analysis. Results: In the 414 pts, who Included 263 (64%) pts with WBC < 10G/L and 151(36%) pts with WBC >10G/L, the median cumulative dose of ATRA administered during Induction treatment was 2160 mg (corresponding to 27 days at 80 mg/d) Early ATRA Interruptions, Ie before recovery from aplasia and patient discharge, were made almost exclusively for ATRA syndrome or unexplained fever, and were followed or not by restart of the drug. Final discontinuation of ATRA for induction treatment was made a median of 27 days after onset of ATRA treatment. Although both trials stated that ATRA should be continued “until CR”, ATRA discontinuation was more often made at the end of the period of aplasia and patient discharge, than at the time of documented CR on bone marrow examination, especially as marrow abnormal promyelocytes are known to disappear slowly in APL. No difference in 5 y CIR or survival were found in pts who had received more or less than 2160 mg of ATRA during induction in the whole population and in pts with baseline WBC less or greater than 10 G/L. 89/414 (21%) pts had received less than 1500 mg of ATRA during Induction (corresponding to less than 19 days at 80 mg/day), their 5 y CIR and survival were similar to those of pts who had received more than 1500 mg of ATRA during induction in the whole population, and in pts with baseline WBC > 10 G/L. However, in pts with baseline WBC Conclusion: Although ATRA duration for induction treatment was not randomized in APL 93 and 2000 trials, our results suggest that, in newly diagnosed APL pts with WBC < 10 G/L, short duration of ATRA during induction treatment may be associated with a higher risk of relapse. This, along with Spanish PETHEMA results supporting a possible role for ATRA during consolidation courses, suggests that sufficiently prolonged exposure to ATRA during the first months of treatment (and not only during maintenance) may be important for disease cure in APL.

The aim of this retrospective multicentric study was to assess the results of 112 consecutive umbilical cord blood transplantations (UCBT) following nonmyeloablative conditioning (NMA) performed in 20 French centres, between October 2003 and March 2007.Characteristics of the patients : Underlying disease: acute leukaemia: myeloid 60, lymphoblastic 17, lymphoma: 15, myelodysplasia: 5, myeloma: 4, Hodgkin: 4, chronic leukaemia: myeloid 3 and lymphoid 3 and 1 solid tumor. Median age at transplantation: 44 y (16–69), median weight: 62 kg (42–125), male: 49 (43%), CMV seropositivity: 64% ; 32 pts had received previous autologous and 3 allogeneic transplantation. The time between diagnosis and transplant was 19 months (3–174). Disease status at transplantation was early (31%), intermediate (37%) and advanced (32%). Median follow-up was 7 months (2–38). The original Minneapolis conditioning regimen was used in 106 (96%) pts and modified in 6 (4 or 6 Gy TBI: 4 pts; ATG: 2). Characteristics of the grafts: A single unit was infused in 77 pts (69%), two in 35 (31%). HLA compatibility was 6/6 in 6 pts, 5/6 in 36, 4/6 in 60, ≤ 3/6 in 6 ; 43 pts were ABO matched. Infused nucleated cells (NC) was 3.1×107/kg (1–9): 2.9 × 107/kg in single units and 3.7 × 107/kg in double units. Results: Neutrophils recovery was 85±4% at a median of 19 days (0–48) ; 14% pts experienced autologous recovery; 14% had mixed and 72% full donor chimerism at D+100. Univariate analysis indicated the low weight, previous transplantation, double units and HLA compatibility as significant factors for neutrophil recovery; however multivariate analysis did not find any significant factor. Acute GVHD was observed in 34±5% of pts: 21, 12 and 5 pts had grade II, III or IV aGVHD respectively and chronic GVHD in 16%. Non relapse mortality was 12±3% at 6 months ; relapse: 22±5% ; overall survival: 72±5%. Causes of death were relapse in 17 pts, GVHD in 2 pts, venocclusive disease and multiorgan failure in 5, infections in 4 and other toxicity in 3. DFS at 6 and 24 months were 68±5% and 65±5%, respectively. By univariate analysis, risk factors for DFS were age (>44y), weight, previous transplant, HLA disparity (0+1 vs 2+3), and NC dose (

Despite progress in their primary therapy, nearly half of patients (PTS) with DLCL will either relapse or fail to archieve a remission. Autologous transplantation may salvage those PTS with chemosensitive disease. However, PTS with high-risk disease or relapsing after autologous transplantation have a particularly poor prognosis. AlloSCT with RIC offers the advantage of a decreased transplant-related mortality combined with a Graft-versus-Lymphoma effect explaining its increasing use in PTS who fail standard therapy. We retrospectively analyzed all PTS with DLCL reported to the SFGM-TC registry, who underwent alloSCT after RIC. 51 PTS (median age 42 years, range 22 to 64 years) were transplanted from Oct. 2002 to Oct. 2004. 23% of PTS had received > 2 lines of prior therapy and 78% had relapsed after autologous transplantation. For 22% of PTS, alloSCT was the first graft. Median time from diagnosis to alloSCT was 33 months (6–126). Disease status at time of alloSCT was: complete remission (CR) n=22, partial remission (PR) n=18, stable disease (SD) n=2, progressive disease (PD) n=7. RIC consisted of fludarabine + busulfan in 27 PTS, fludarabine + total body irradiation in 10, fludarabine + cyclophosphamide in 7 and miscellaneous combinations in 7. GVHD prophylaxis consisted of cyclosporin A (CyA) alone in 18 PTS, CyA/methotrexate in 14 PTS, CyA/mycophenolate mofetil in 14 PTS and other immunosuppressive drugs in 5 PTS. 31 PTS received antithymocyte globulin. Stem cell source was peripheral blood stem cells in 43 PTS and bone marrow in 8. 47 donors were HLA-matched siblings, 4 were unrelated (3 donors HLA-matched and 1 donor with 1 HLA antigen mismatch). Median follow-up after alloSCT was 12 months (0–72). All PTS engrafted except one who died early after transplantation. Grade II to IV acute GVHD occurred in 16 PTS and extensive chronic GVHD in 8/43 valuable PTS. Non relapse mortality was 21% (multi-organ failure : 3, acute GVHD : 1, chronic GvHD : 1, interstitial pneumonia : 1, infection : 4, neurological complication : 1, unknown origin : 1). 20 PTS progressed after a median follow-up of 4.5 months (0–29) and 10 PTS died of progressive DLCL. 23 PTS remain alive and disease-free at a median follow-up of 17 months (1–72). Overall survival is 48% at 22 months. We observe a trend for better survival without statistical significance in PTS who received alloSCT as first graft compared to >1 graft. In PTS in CR or PR prior to transplantation, Kaplan-Meier analysis demonstrates a nearly significant trend for better survival compared to non-responders (55 vs. 28%, p=0,09), but it has to be noted that 3 of 7 PTS transplanted with PD are still alive. RIC followed by alloSCT seems to be feasible even in heavily pretreated PTS and offers the perspective of long lasting remission. Further prospective studies with RIC and alloSCT earlier in the disease course or in defined high-risk PTS in first relapse as an alternative to autologous transplantation should be undertaken.

The results of autologous stem cell transplantation following high dose chemotherapy for transformed low grade, high grade refractory or relapsing early (

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.

A l'occasion du tricentenaire de relations et d'échanges entre le Yémen et la France, cet ouvrage iconographique retrace les grandes lignes de cette histoire. Il reprend la trame d'une exposition de photographies, de dessins et de documents d'archives réalisée en 2004 à Sanaa par le CEFAS, l'Ambassade de France à Sanaa, le Centre culturel français et le Centre National des Archives yéménites.