ALBERT

Beschreibung: Introduction Isolated trisomy 8 is a frequent cytogenetic abnormality in MDS, but hematological characteristics of MDS with isolated trisomy 8 have not been reported in detail. Patients and Methods This was a retrospective analysis of cases of MDS with isolated trisomy 8 diagnosed in 6 French centers of the Groupe Francophone des Myélodysplasies (GFM) between 2003 and 2013. Only patients with isolated trisomy 8 diagnosed as MDS or MPN/MDS (other than CMML) according to WHO were eligible, excluding AML, well characterized MPN (PV, ET) and CMML. Myeloproliferative (MP) features were defined by repeated presence (in the absence of infection) of one of the following: WBC 〉 10G/L, circulating immature granulocytes (myelemia ) 〉 2%, or palpable splenomegaly. Results 103 patients with isolated trisomy 8 were identified, with a median age of 75 years, and M/F 1.7. At diagnosis, median WBC count was 4.1 G/L, with WBC ≥ 10 G/L in 13 patients (12.6 %), myelemia ≥ 2% in 27 patients (26.2 %), palpable splenomegaly in 9 patients (8.7 %). WHO diagnosis included 20 RA, 2 RARS, 22 RCMD, 1 RCMD-RS, 1 RCUD, 21 RAEB-1, 18 RAEB-2, 7 MDS-U, 10 MDS/MPN, 1 hypoplastic MDS. IPSS was intermediate 1 (72.2 %), intermediate 2 (19.6 %), high (8.2 %) ; IPSS-R was low (37.1 %), intermediate (29.9 %), high (22.7 %), very high (10.6 %). MP features were found in 50 patients (48.5 %): 31 at diagnosis, 19 during evolution (in patients without MP features at diagnosis). Bone marrow morphological features could be reviewed in 15 MP cases, showing hypercellular marrow in 60 % cases, granulocytic hyperplasia (E/G

Beschreibung: Introduction: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and peripheral cytopenia. In about half of patients with lower-risk (LR) MDS, thrombocytopenia is present at the time of diagnosis and associated with shortened survival and an increased risk of progression to acute myeloid leukemia (AML). The thrombopoietin receptor agonist (TPO-RA) romiplostim has shown safety and marked efficacy in a still poorly-defined subset of LR-MDS patients with thrombocytopenia. Methods: The EUROPE multicenter phase 2 trial within the EMSCO network investigated the impact of biomarkers like endogenous thrombopoietin (TPO) level and platelet transfusion events (PTE) on the efficacy of romiplostim (750µg SC qw) treatment in patients with LR-MDS (IPSS low/int-1). Patients were eligible if baseline bone marrow blast count was

Beschreibung: The female donor/male recipient combination (FM) increases the risks of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT), with a possible deleterious impact on overall survival (OS) [Gahrton G. Best Pract Res Clin Haematol. 2007 Jun;20(2):219-29]. Most patients in these studies received T-cell replete transplants. As a consequence, and because antithymocyte globulin (ATG) reduces the risk of GVHD, the impact of FM in the specific setting of allo-SCT with ATG remains poorly defined. To explore the impact of FM in the ATG setting, we undertook a retrospective analysis of male adult patients transplanted with rabbit ATG at our center between 01/01/2000 and 12/31/2012. Overall survival and disease-free survival (DFS) were calculated using the Kaplan-Meier estimate, with comparisons by the log-rank test. Cumulative incidences (CI) were used for NRM, relapse (REL), and GVHD in a competing risks setting, NRM being a competing event for REL, and death for GVHD. The Gray test was used to compare CI curves. For multivariate analysis, the variables with p value 〈 0.1 were entered into a Fine-Gray model where the least significant variables were excluded in sequential fashion until all remaining factors were significant at the p=0.05 level. The following variables were considered: recipient age (≥ vs 〈 56 years, median age), female donor (FD) vs male donor (MD), matched related (MRD) vs matched unrelated (MUD) donor, peripheral blood (PB) vs bone marrow (BM) graft, GVHD prophylaxis with cyclosporine (CsA)+metho vs others, myeloablative (MAC) vs reduced-intensity conditioning (RIC) regimen, CMV-seropositive vs seronegative recipient, early (CR1 or PR1 or chronic phase or untreated) vs advanced disease. Steroid-refractory (SR) acute (a) GVHD was defined as aGVHD progressing after 3 days of treatment, or unchanged after 7 days, or in incomplete response after 14 days. MUD were matched at the allele level for HLA-A, B, C, DRB1, DQB1. Two hundred and twelve male patients were identified and included in the present study. The median age was 56 years (18-67). Diseases were AML (n=61), ALL (n=16), NHL (n=36), Hodgkin's disease (n=10), myeloma (n=37), MDS (n=26), aplastic anemia (n=7), CLL (n=11), CML (n=1), and MPS (n=7). Status at transplant were CR1 or PR1 or chronic phase (n=74), 〉 CR1 or PR1 (n=83), refractory (n=34), or untreated (n=21). Conditioning regimens were RIC (n=195) or MAC (n=17). Donors were MRD (n=110) or MUD (n=102). Eighty-eight patients were transplanted with a FD. Source of stem cells were PB (n=193), BM (n=18), missing data (n=1). Prophylaxis of GVHD consisted of CsA+metho for 84 patients. The median follow-up was 42 months (5-149). In univariate analysis, the 3-year OS and DFS in FD vs MD groups were 48% ± 6% vs 56% ± 5% (p=0.3) and 42% ± 5% vs 50% ± 5% (p=0.4), respectively. The 3-year NRM and REL in the same groups were 25% ± 5% vs 19.6% ± 4% (p=0.4) and 30% ± 5% vs 31% ± 4% (p=0.9), respectively. The CI of aGVHD II-IV, aGVHD III-IV, SR aGVHD, and extensive chronic GVHD in FD vs MD groups were 37.5% ± 5% vs 33% ± 4% (p=0.5), 22.7% ± 4% vs 17% ± 3% (p=0.3), 17.2% ± 4% vs 8.3% ± 3% (p=0.049), and 20% ± 4% vs 22.5% ± 4% (p=0.9), respectively. Other variables considered in univariate analysis for SR aGVHD were recipient age (p=0.9), recipient CMV status (p=0.7), disease status (p=0.9), RIC vs MAC (p=0.16), MRD vs MUD (p=0.09), PB vs BM graft (p=0.4), and GVHD prophylaxis (p=0.2). In multivariate analysis, the risk factors for SR aGVHD were FD (HR=3.1, 95%CI: 1.2-7.9, p=0.01) and MUD (HR=2.9, 95%CI: 1.1-7.1, p=0.02). The CI of SR aGVHD were 32.3% ± 9.7% in the FD + MUD group (n=29), 9.7% ± 3.8% in the MD + MUD group (n=73), 10.7% ± 4.1% in the FD + MRD group (n=59), and 6.5% ± 3.7% in the MD + MRD group (n=51); p=0.004. We conclude that FD was an independent risk factor for SR aGVHD after allo-SCT with rabbit ATG in male adult patients mostly transplanted with PB after RIC. There was no impact of FD on aGVHD II-IV or III-IV, chronic GVHD, NRM, REL or survival. Finally, the absence of impact of FD on NRM and survival should be interpreted with caution given the retrospective design of the study and because we cannot exclude a possible limiting effect of an insufficient number of patients. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: The standard risk factors for acute graft-versus-host disease (aGVHD) after allogeneic stem cell transplantation (allo-SCT) from related or unrelated donors are well defined and include HLA mismatch or unrelated donor, older recipient age, and female donor for male recipient (FM). The steroid-refractory (SR) forms of aGVHD are important to consider because they often have a major deleterious impact on transplant outcome. Unfortunately, the specific risk factors for SR aGVHD are less clearly defined. To characterize these risk factors after allo-SCT from matched related or unrelated donors, we undertook a retrospective analysis of adult patients transplanted at our center between 01/01/2000 and 12/31/2012. Steroid-refractory aGVHD was defined as aGVHD progressing after 3 days of treatment, or unchanged after 7 days, or in incomplete response after 14 days. GVHD occurring after donor lymphocytes infusion were excluded. Overall survival (OS) was calculated using the Kaplan-Meier estimate. Cumulative incidences (CI) were used for SR aGVHD in a competing risk setting with death as a competing event. The Gray test was used to compare CI curves. For multivariate analysis, the variables with p value 〈 0.1 were entered into a Fine-Gray model and the least significant variables were excluded in sequential fashion until all remaining factors were significant at the p=0.05 level. The variables considered were recipient age (≥ vs 〈 50 years, median age), female vs male donor, FM vs other combinations, matched related (MRD) vs matched unrelated donor (MUD), peripheral blood (PB) vs bone marrow (BM) graft, GVHD prophylaxis with cyclosporine (CsA)+metho vs others, myeloablative (MAC) vs reduced-intensity conditioning (RIC) regimen, antithymocyte globulin (ATG) vs no ATG, number of CD34+ cells in the graft ≥ vs 〈 5.6 x 106/kg (median number), early (CR1, PR1, chronic phase, or untreated) vs advanced disease, CMV-seropositive vs seronegative recipient. Unrelated donors were matched at the allele level for HLA-A, B, C, DRB1, DQB1. Six hundred and thirty four patients were identified and included in the present study. The median age was 50 years (18-67). Diseases were AML (n=230), ALL (n=104), myeloma (n=80), NHL (n=74), Hodgkin's disease (n=18), MDS (n=47), CLL (n=29), CML (n=18), aplastic anemia (n=19), and MPS (n=15). Status at transplant were CR1 or PR1 or chronic phase (n=260), 〉 CR1 or PR1 (n=237), refractory (n=101), or untreated (n=36). Conditioning regimens were RIC (n=405) or MAC (n=229). Rabbit ATG was administered to 327 patients, of whom 298 received a RIC regimen. Donors were MRD (n=360) or MUD (n=274). Sources of stem cells were PB (n=452), BM (n=177), missing data (n=5). The prophylaxis of GVHD was CsA+metho for 339 patients. In the whole population, 71 patients presented a SR aGVHD at a median time of 29 days (8-137) after transplant, representing a CI of 11.2% ± 1.2%. Their OS at 1 year post-transplant was 27% ± 5%. In univariate analysis, the risk factors for SR aGVHD were MAC (p=0.02), MUD (p=0.02), no ATG (p=0.01), and a trend for FM (p=0.07). Other variables considered in univariate analysis were recipient age (p=0.6), female vs male donor (p=0.6), recipient CMV status (p=0.7), status at transplant (p=0.2), PB vs BM graft (p=0.9), number of CD34+ cells (p=0.4), and GVHD prophylaxis (p=0.6). In multivariate analysis, the risk factors for SR aGVHD were MUD (HR=2.5, 95%CI: 1.5-4.1, p=0.0003), FM (HR=2, 95%CI: 1.2-3.4, p=0.008), and no ATG (HR=2.1, 95%CI: 1.3-3.4, p=0.002). Patients were then divided into 3 groups. The CI of SR aGVHD was 2.7% ± 1.6% in the low-risk group (no MUD + no FM + ATG; n=112), 21.8% ± 3.4% in the high-risk group (MUD + FM +/- ATG, or MUD + no FM + no ATG; n=147), and 9.6% ± 1.5% in the intermediate-risk group (n=375); p=10-6. We conclude that MUD, FM, and no ATG were independent risk factors for SR aGVHD in adult patients after allo-SCT from MRD or MUD. These data support the prevalent roles of HLA and donor T cell alloreactivity in the pathogenesis of SR aGVHD and may help identify patients at high risk of SR aGVHD, candidates for experimental first-line therapies of aGVHD. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Background: MDS-RS are associated with a low risk of Acute Myeloid Leukemia (AML) progression and prolonged survival in most cases, but recurring anemia whose treatments, including Erythropoiesis Stimulating Agent (ESA), Lenalidomide, hypomethylating agents (HMAs), Luspatercept, and experimental drugs generally have transient effect and/or are not widely available. MDS-RS patients thus eventually have regular Red Blood Cells (RBC) transfusion dependency (TD) associated with mean low hemoglobin levels, and chronic anemia responsible for reduced quality of life, cardiovascular complications, and iron overload with organ dysfunction. We performed a retrospective observational study to describe transfusion characteristics and costs, along with clinical events, in a French population of RBC TD MDS-RS patients. Methods: Adult RBC-TD patients with MDS-RS from 12 hematology departments of the GFM were included. The number of RBC concentrates transfused was assessed over the last 6 months (during which no other treatment than transfusions was received), and patients categorized in low transfusion burden (LTB: 3 to 7 RBC/16 weeks) and high transfusion burden (HTB: ≥8 RBC concentrates /16 weeks). Data about iron chelation, full time hospitalization (differing from day care facility stays for programmed transfusions), causes of hospitalization, treatment of anemia before inclusion and transfusion costs was collected. Results: 100 patients MDS-RS were included, with a median time from diagnosis of 5 years (1 to 21 years). Median age was 78 years (57 to 99). Patients had received a median of 2 lines of treatment (including an ESA in 97% of them). 21% had LTB and 79% HTB. HTB patients had a longer disease duration, more frequent iron chelation (82% versus 50% in LTB patients, p=0.0052) and higher serum ferritin at inclusion (median 1958 µg/l versus 1176 µg/l, p=0.03). During the 6-month study period, 22% of the patients required full time hospitalization (in addition to day care facility for transfusions), including 25% of patients with HTB and 15% with LTB, and 43% during overall disease follow-up. Causes of full time hospitalization (figure) were symptomatic anemia (41%), general condition degradation (5%) or cardiac disease (8%), to both of which anemia potentially contributed, infection (23%), bleeding (8%), pulmonary (2%), 13% for other reasons. 15 HTB patients versus 1 LTB patient were hospitalized for symptomatic anemia. The 6-months average transfusion costs, including cost of the day care facility for RBC transfusion, transportation to and from the hospital, lab tests and iron chelation were $21459/patient, excluding costs of full-time hospitalization for complications. The average cost in HTB and LTB patients was $22829 and $7586/patient, respectively. Conclusion: Most MDS-RS patients currently become RBC-TD, often during several years, and most have high transfusion burden. The average cost of RBC transfusions and iron chelation was $21459/ 6 months. During this short observation time, 22% of the patients required full time hospitalization, due to complications of anemia in at least 50% of the cases, which also increased costs (comparison with rates of hospitalization in an age and sex matched general population will be presented). Poor quality of life associated with chronic anemia should also be taken into account in those RBC-TD patients. Widely available treatments, capable of avoiding RBC transfusion dependence and improving mean hemoglobin levels, are required in those MDS-RS patients. Disclosures Cony-Makhoul: BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Stamatoulas Bastard:Takeda: Consultancy; Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Park:Pfizer: Other: Travel expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.

Beschreibung: *UP, LA contributed equally Introduction A significant proportion of lower risk (LR)-MDS patients present with thrombocytopenia, being associated with shortened survival and higher risk of progression to acute myeloid leukemia (AML). Treatment options for patients with LR-MDS and severe thrombocytopenia remain limited apart from transfusion support. Romiplostim (ROM), a thrombopoietin receptor agonist (TPO-RA) has shown safety and efficacy dependent on endogenous TPO levels as well as platelet transfusion history in a poorly defined subset of LR-MDS patients (Giagounidis et al. Cancer 2014, Sekeres et al. BJH 2014). Methods The multicenter phase 2 EUROPE trial investigated potential biomarkers of response (e.g. TPO levels, molecular markers) to single agent ROM in LR-MDS patients with severe thrombocytopenia. Patients were eligible if platelet counts were ≤30 G/L or ≤50 G/L in case of bleeding history. The primary efficacy endpoint was the rate of hematologic improvement of platelets (HI-P, according to IWG 2006 criteria) lasting for at least 8 weeks after 16 weeks of ROM (750µg SC qw) treatment. At the time of screening, patients were assigned into 3 different cohorts based on their previous platelet transfusion events (PTE) as well as centrally assessed TPO serum levels (A: TPO