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Aims Azacitidine (AZA), a pyrimidine analogue, is validated for high-risk myelodysplastic syndrome or low-blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure. Methods Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myelodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2-sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period. Results In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re-challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2). Conclusion This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease.

Isolated trisomy 8 (+8) is a frequent cytogenetic abnormality in the myelodysplastic syndromes (MDS), but its characteristics are poorly reported. We performed a retrospective study of 138 MDS patients with isolated +8, classified or reclassified as MDS (excluding MDS/myeloproliferative neoplasm). Myeloproliferative (MP) features were defined by the repeated presence of one of the following: white blood cell count >10 × 109 /l, myelemia (presence of circulating immature granulocytes with a predominance of more mature forms) >2%, palpable splenomegaly. Fifty-four patients (39·1%) had MP features: 28 at diagnosis, 26 were acquired during evolution. MP forms had more EZH2 (33·3% vs. 12·0% in non-MP, P = 0·047), ASXL1 (66·7% vs. 42·3%, P = 0·048) and STAG2 mutations (77·8% vs. 21·7%, P = 0·006). Median event-free survival (EFS) and overall survival (OS) were 25 and 27 months for patients with MP features at diagnosis, versus 28 (P = 0·15) and 39 months (P = 0·085) for those without MP features, respectively. Among the 57 patients who received hypomethylating agent (HMA), OS was lower in MP cases (13 months vs. 23 months in non-MP cases, P = 0.02). In conclusion, MP features are frequent in MDS with isolated +8. MP forms had more EZH2, ASXL1 and STAG2 mutations, responded poorly to HMA, and tended to have poorer survival than non-MP forms.

Background and aims: intensive chemotherapy (IC) has been used since the early 90's in the treatment of higher risk MDS, yielding 40 to 50% complete response (CR) but prolonged myelosuppression and 10 to 30% early deaths. IC is also recommended before allogeneic (allo) SCT when marrow blasts are increased (De Witte et al, Blood, 2017). CPX-351, a liposomal combination of cytarabine and daunorubicin, proved greater efficacy than classical IC with 3+7 in secondary-AML, including in patients with 20-30% marrow blasts and those who subsequently received allo SCT (Lancet et al, Lancet Haematol, 2021). We evaluated response to CPX-351 in a group of untreated higher risk MDS patients, most of whom were candidates for allo SCT. Methods: This prospective study, involving 12 GFM centers, included int-2 or high IPSS MDS, previously untreated with HMA or chemotherapy, and aged Results: 31 patients were included between July 2020 and January 2021. Median age was 62 years (range 31-69); WHO classification: 26 MDS-EB2, 5 CMML-2; IPSS: int-2: 84%, high: 16%; R-IPSS: intermediate: 29%, high: 55%, very high: 16%; karyotype: 2 very good, 22 good, 3 intermediate, 2 poor, 2 very poor. 27 patients received one induction cycle and 4 (in stable disease (SD) after the first cycle), a second induction cycle. Response rates, eventually evaluated a median of 53 days (range 28-112) from onset of induction, were with ELN 2017 criteria: CR: 52%, CRi: 13%, MLFS: 23%, SD: 13% and with IWG 2006 criteria : CR: 23%, mCR: 45%, mCR + HI-P: 6%, mCR + HI-P + HI-N: 6%, mCR + HI-N: 3%, PR: 3%, SD: 13%. Minimal residual disease assessment by NGS and flow cytometry will be presented at the meeting. 24/27 patients with baseline marrow blasts >10%, reached 20G/L and >50G/L were: 16 (range 0-55) days and 28 (range 8-51), respectively and to ANC >1G/L: 26 (range 2-60) days. Only one patient had grade ≥ 3 mucositis and 4 had grade ≥ 2 alopecia during induction treatment. No patient died during induction treatment or required management in the intensive care unit. With a median follow-up of 201 days (range 102-350), 22 of the 30 patients initially considered for allo SCT received transplant after no (10 pts), 1 (9 pts), 2 or 3 (3 pts) consolidation cycles and 5 are planned for allo SCT. Reasons for not being transplanted were, investigators' choice (n=1), relapse (1), no donor (1) and invasive fungal infection (n=1). None of the 4 non transplanted patients received consolidation cycles. Reasons for not receiving consolidation cycles were persistent cytopenia (n=5), cardiac toxicity (n=2), failure to achieve CR or PR (n=2). At the time of analysis (June 2021), 4 patients had relapsed, after 3 to 6 months of response. Conclusions : CPX-351 is effective in higher risk MDS/CMML, especially to achieve blast clearance, and as a bridge to allo SCT. Figure 1: waterfall plot according to IWG 2006 and ELN 2017 criteria Figure 1 Figure 1. Disclosures Fenaux: Novartis: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria; Takeda: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. OffLabel Disclosure: CPX-351 use off-label for myelodysplastic syndroms in a prospective trial

Background: Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mutant IDH1 approved in the US for adult patients with unfit or relapse/refractory AML with IDH1 mutation. Little is known on its efficacy in patients with IDH1 mutated MDS. Here we report interim results of a Phase 2 study evaluating safety and efficacy of IVO in three different cohorts of MDS patients: Higher risk MDS having failed azacytidine (AZA) (cohort A, n=29), untreated higher risk MDS without life threatening cytopenias (ie ANC < 500/mm3 or any recent severe infections and/or platelets below 30,000/mm3 and any bleeding symptom,) as a first line treatment (cohort B, with the addition of AZA in non-Responders after 3 cycles, n=29) and lower risk MDS having failed EPO (cohort C, n=10). (ClinicalTrials.gov NCT03503409). Methods: Subjects enrolled in cohort A, B or C received continuous 28-day cycles of IVO - 500 mg orally QD. In cohort B, AZA (75 mg/m2/d x 7 days, SC) was added to IVO after 3 cycles, only in the absence of IWG 2006 response (absence of CR, PR or HI). The primary endpoint was overall hematological response rate (ORR) at 3 and 6 months (including CR, PR, stable disease with HI according to IWG 2006). All responders allowed to continue treatment until loss of response. Secondary endpoints included safety, duration of response, EFS, overall survival and translational project evaluating the role of biomarkers on response. We report the preliminary results on the first 26 pts enrolled. Results: At data cut off (6/15/2021), 32 patients had been enrolled, including 26 who were evaluable for the primary endpoint. 13, 11 and 2 were enrolled in cohort A, B and C respectively. Median age was 76 years and 50% were female. WHO was MDS-MLD, MDS-EB1, MDS-EB2, CMML and low blast count AML in 2, 2, 12, 1 and 9 patients respectively. IPSS-R was low, intermediate, high and very high in 2, 6, 5 and 13 resp. IDH1 mutation was p.R132C in 15 patients, p.R132H in 7, p.R132G/S in 3 and not specified in 1. The ORR was 69% (18 patients) including 12 CR (46%), 1 PR and 5 HI. Most patients achieved response after 3 cycles (17/18). Response was achieved in 7 (54%), 10 (91%) and 1 (50%) in cohort A, B and C respectively. Moreover, CR was achieved in 3, 8 and 1 in cohort A, B and C respectively. In cohort B, AZA was added to IVO in one patient after 3 cycles, without additional response. With a median follow up of 9.1 months, the median duration of response of the 18 responders was 7.4 months, 9 of them lost their response, and two had died without loss of response (from bleeding and after HSCT, respectively). IPSS-R was the only prognostic factor of response after 6 cycles. At data cut off, 12 patients had progressed (9 in cohort A, 2 in cohort B and 1 in cohort C) and 11 (42%, 10 in cohort A and 1 in cohort C) patients had died, mostly of relapse/progression (n=5/11), infection in 1, suicide in 1, hemorrhage in 1 and other unrelated causes in 3. Median overall survival was 14 months in the whole cohort, 7.7 and not reached in cohort A and B resp. The most common treatment-related serious adverse event (SAE) was differentiation syndrome (4/5), one died and three resolved without sequelae. One patient had febrile neutropenia related to IVO, resolved without sequelae. Conclusion: IVO was well tolerated in MDS patients with significant responses in all the cohorts. With a response rate of 91%, IVO was particularly effective in treatment naïve higher risk MDS patients with IDH1 mutations (cohort B). These encouraging preliminary results have to be confirm in more patients. The IDIOME study is still ongoing, and molecular monitoring results of IDH1 mutations will be presented. Disclosures Sebert: BMS: Consultancy; Abbvie: Consultancy. Cluzeau: Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Agios: Honoraria; Amgen: Speakers Bureau; Takeda: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other: travel, accommodations, expenses. Stamatoulas Bastard: Pfizer: Other: Travel Support; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Ades: Abbvie: Honoraria; Takeda: Honoraria; Novartis: Honoraria; JAZZ: Honoraria; Celgene: Honoraria, Research Funding.

*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 Results From 2015 to 2019, a total of 79 patients were included at 29 trial sites in Germany, France and the Czech Republic. Patients' median age was 74 years (range 42-93), median baseline platelet count was 25.5 G/L (range 3-50 G/L) and they were stratified into cohort A (n=51) or B+C (n=28), respectively. The primary endpoint was met with 34 out of 79 (43%) patients responding (HI-P), with response being markedly higher in cohort A (49%, n=25) vs. cohort B and C (32%, n=9) (p=0.145). Ten (13%) and eight (10%) patients had additional neutrophil (HI-N) and erythroid (HI-E) responses, respectively. During treatment, six patients had transient increases in peripheral blasts to more than 10% and one patient progressed to AML after one month of ROM. Although a higher number of responders was observed in group A, neither TPO level at screening (p=0.21), nor number of pretreatment PTE (p=0.12) were significantly associated with response to ROM treatment. Thus, our findings do not confirm that baseline TPO levels and number of pretreatment PTE alone allow reliable prediction of response to ROM. With the aim to identify new molecular patterns correlating with response, we performed a targeted NGS analysis for somatic variants in 54 candidate genes in 75 patients at baseline and in 44 patients after 16 weeks of ROM. Responders (R) more frequently exhibited mutations like SRSF2 (R=39%, NR=17%), RUNX1 (R=24%, NR=14%) and TET2 (R=30%, NR=29%), whereas non-responders (NR) exhibited mutations like DNMT3A (R=12%, NR=21%), U2AF1(R=9%, NR=14%) or ASXL1 (R=6%, NR 17%) more frequent. The percentages of patients with a response to ROM were similar regardless of total number of baseline somatic mutations. Comparing responders vs. non-responders, we found no significant changes of variant allelic burden of variants detected pre- and post-ROM (Fig. 1). We identified the presence of a SRSF2 mutation as a significant predictor of response to ROM treatment (p=0.031, logistic regression). Mutated SRSF2 was significantly more frequent in responders (39%) compared to non-responders (17%) (p=0.036, Fisher's exact test) (Fig. 2A,B). We used logistic regression with stepwise backward selection to assess the influence of the presence of ASXL1, DNMT3A, RUNX1, TET2 and SRSF2 mutations on response. Our final regression model excludes the non-significant ASXL1, DNMT3A, RUNX1 and TET2 mutations and includes the significant SRSF2 mutation, resulting in an overall accuracy of 64.0% for a correct ROM response prediction in this patient cohort. Conclusion: This prospective study did not confirm a significant association between response to ROM, pretreatment PTE burden and endogenous TPO levels. Instead, patients with a mutated SRSF2 displayed a significantly higher response to ROM treatment. This may allow personalized treatment approaches in patients with LR-MDS and severe thrombocytopenia. In this study, extended treatment with ROM did not lead to a significant increase in AML cases. Disclosures Kubasch: Shire: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Research Funding. Cony-Makhoul:Novartis: Consultancy; Pfizer: Consultancy; Incyte Biosciences: Speakers Bureau; BMS: Consultancy; BMS: Speakers Bureau. Laribi:takeda: Research Funding; novartis: Honoraria, Research Funding; amgen: Research Funding; abbvie: Honoraria, Research Funding. Park:Takeda: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Metzeler:Astellas: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Schlenk:PharmaMar: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Roche: Research Funding; AstraZeneca: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Ades:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; novartis: Research Funding; Celgene/BMS: Research Funding; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Romiplostim is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP). Limitations of Use: Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.

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.

We performed a retrospective study to identify pretransplantation risk factors for steroid-refractory (SR) acute graft-versus host disease (aGVHD) after allogeneic stem cell transplantation from matched donors in 630 adult patients who underwent transplantation at our center between 2000 and 2012. The cumulative incidence (CI) of SR aGVHD was 11.3% ± 2.3%. The identified independent risk factors were matched unrelated donor (hazard ratio [HR], 2.52; P = .001), female donor for male recipient (HR, 1.84; P = .023) and absence of antithymocyte globulin (HR, 2.02; P = .005). Three risk groups were defined according to the presence of these risk factors. In the whole cohort, the CI of SR aGVHD was 3.5% ± 1.7% in the low-risk group (0 risk factor, n = 115), 9.3% ± 1.6% in the intermediate-risk group (1 risk factor, n = 323), and 19.3% ± 2.9% in the high-risk group (2 or 3 risk factors, n = 192). Our study suggests that pretransplantation characteristics might help identify patients at high risk for SR aGVHD. A risk adapted first-line treatment of aGVHD could be evaluated in those patients.

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 Results: From 2015 to 2018, a total of 68 patients were included in 20 trial sites in Germany, France and Czech Republic. Patients displayed a median age of 74 years and a median platelet count of 25 G/L (range 1-50 G/L) and were stratified into cohort A (n=47), B (n=17) or C (n=4), respectively. All patients received at least one cycle of romiplostim with a median weekly dose of 750μg and a median of 15 cycles of romiplostim until week 16. Reasons for premature study discontinuation before week 16 were investigator/patient decision (n=8), adverse events (n=5), disease progression (n=4) or death (n=1). There were 9 reported severe treatment-related adverse events in seven patients including pulmonary embolism (n=1), subacute stroke (n=1), mucocutaneous hemorrhage (n=1), asthenia (n=1), suspicion of anti-romiplostim antibodies (n=1), progression to AML (n=1) and varicella zoster infection (n=1). Two patients had transient increases in peripheral blasts to more than 10% and 1 patient progressed to AML after 1 month of treatment. HI-P was observed in 26 of 68 (38%) patients, while response was ongoing in 24 of them beyond week 16. Moreover, rate of HI-P lasting for at least 8 weeks was notably higher in cohort A (45%, n=21/47) compared to patients in cohort B and C (24%, n=5/21) (p=0.11). Median peak increase of PLT count in responding patients was 199 G/L in cohort A and 83 G/L in cohort B (p=0.25) and was observed in median after 7 weeks (range 3-16). In addition, responses occurred also in 2 patients in the neutrophil (HI-N) and in 7 patients in the erythroid (HI-E) lineage according to IWG 2006 criteria (Table 1). Explorative analysis showed a correlation between pretreatment platelet transfusion requirement and endogenous TPO-levels (spearman-test, p=0.034). Median pretreatment endogenous TPO-level was lower in responders compared to non-responders (82 vs. 103 pg/ml, p=0.15). Higher response rates occurred in patients with lower TPO-levels ( Conclusion: This prospective study confirms that romiplostim treatment is highly effective in a subgroup of LR-MDS patients, but neither baseline platelet transfusion requirements nor baseline TPO levels were significantly associated with clinical response to romiplostim. Further translational analyses are ongoing to elucidate potential biomarkers of response. Disclosures Platzbecker: Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Cony-Makhoul:Pfizer: Consultancy; Novartis: Consultancy; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Park:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thiede:Daiichi Sankyo: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AgenDix GmbH: Employment, Equity Ownership; Diaceutics: Membership on an entity's Board of Directors or advisory committees. Ades:Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. OffLabel Disclosure: Romiplostim is formally not licensed for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS).

e19564 Background: The aim of this single centre study was to assess the outcome of pts with MM following the relapse after ASCT, according to whether or not a RICALLO was performed. Methods: Recor...

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.

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.

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 Mutations were seen, for MP cases, in ASXL1 (64%), EZH2 (50%), TET2 (40%), RUNX1 (33%), SRSF2 (27%), DNMT3A (15%), JAK2 (14%), IDH2 (14%), NRAS (8%), SF3B1 (9%), U2AF1 (8%); for non MP cases in ASXL1 (33%), SRSF2 (27%), SF3B1 (27%), TET2 (20%), DNMT3A (13%), JAK2 (13%), RUNX1 (13%), EZH2 (7%), IDH2 (7%), ZRSR2 (7%), NRAS (0%). In spite of a trend for more mutations of ASXL1 (p=0.128), and EZH2 (p=0.053) in MP forms, the difference with non MP forms was not significant, possibly due to small patient numbers. 40 patients received an HMA (AZA in 36, DAC in 4) and 27.3% responded (4 CR, 1 PR, 1 marrow CR, 3 HI), including 11.7% of MP cases and 43.8% of non MP cases (p=0.057). 5 patients received intensive chemotherapy (with 2 CR). 42 (40.8%) received an ESA, with 60% responses, including 50% in MP and 73% in non MP patients (p= NS).10 (9.7%) received hydroxyurea. With a median follow up of 30 months, progression to AML was seen in 26% and 18.9% in MP and non MP patients, respectively (p= NS). Median survival was 35 months in the whole cohort, without difference between patients who, at diagnosis had MP features and no MP features (35 months for both). Conclusion Myeloproliferative (MP) features were found at diagnosis or during evolution in our experience in about 50% of MDS with isolated trisomy 8, a finding not previously reported, to our knowledge, and suggesting that some of those patients may have to be reclassified among MDS/MPN. The subset of patients with MP features tended to have a higher frequency of ASXL1 and EZH2 mutations (findings that will have to be confirmed on larger patient numbers), and seemed to respond poorly to HMA, although its survival was not lower than that of non MP forms in our experience. Disclosures Park: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Celgene: Research Funding. Fenaux:AMGEN: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding.