Abstract: Isocitrate dehydrogenase (IDH) 1 and 2 mutations occur in 20% of acute myeloid leukemia (AML). Patients with AML carrying IDH1-2 mutations have a similar prognosis compared to patients without these mutations (DiNardo et al, AM J H, 2015). However, the impact of IDH1-2 mutations on patients with AML undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) is not well known. In this study, we investigate the prognostic impact of IDH1-2 mutational status on AML patients undergoing alloHCT in complete remission (CR). In this retrospective registry-based analysis, we identified 710 consecutive adult patients (46.2% female; median age: 58.5 years [range, 18-78]) with AML undergoing allo-HCT in CR between 2015 and 2019 at 85 EBMT participating centers. Cord blood, ex-vivo graft manipulated transplants, and patients with favorable cytogenetics were excluded. Median follow-up was 15 months [95% CI 13.4-16.6] . Patients were categorized based on IDH1-2 mutational status, with 300 (42%) mutated and 410 (58%) wild type. Six hundred and fifty-two (92%) and 58 (8%) patients had de novo and secondary AML, respectively, and 141 (20%) patients had poor-risk cytogenetics. IDH1-2 mutation was positively correlated with NPM1 mutation (40% in IDH1-2 mutated vs 27% in wild type, p=0.0001) and more frequently encountered in middle-aged patients (p=0.01). No correlation was noted between IDH1-2 and FLT3 mutation or other patient characteristics. Minimal residual disease (MRD) data was available for 344 patients, 53% of which were MRD-negative at transplant in both groups. Six hundred and twenty-three (88%) and 87 (12%) patients were in first and second CR at time of transplant, respectively. Patients received grafts from a matched sibling (24%), unrelated (62%), or haploidentical (14%) donor, and myeloablative conditioning (MAC) was used in 42%. Ninety-three percent of the patients received peripheral blood as the stem cell source. At day 180, the cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was significantly lower in IDH1-2 mutated compared to wild-type patients (22% vs 33%, p=0.002). No differences in chronic GVHD rates were noted between the 2 groups (39% vs 40%, p=0.87). The 2-year cumulative relapse incidence (RI) was significantly lower and the GVHD-free, relapse-free survival (GRFS) was also improved in IDH1-2 mutated compared to wild-type patients (14.4% vs 27%, p=0.001 and 47% vs 39%, p=0.006, respectively). This led to an improved leukemia-free survival (LFS) in IDH1-2 patients (69% vs 59%, p=0.01), however, it did not translate into an overall survival (OS) difference. No significant difference was noted in non-relapse mortality (NRM) between the 2 groups (17% vs 14.2%, p=0.26). These findings were confirmed in multivariate analysis. In fact, IDH1-2 mutation was associated with significant improvement in RI (hazard ratio [HR]=0.4 [95%CI 0.25-0.64] , p=0.0001), LFS (HR=0.7 [95%CI 0.51-0.95] , p=0.022), aGVHD II-IV (HR=0.63 [95%CI 0.45-0.87], p=0.005) and GRFS (HR=0.69 [95%CI 0.54-0.89] , p=0.004). Conversely, the presence of adverse cytogenetics and undergoing allo-SCT in second CR increased the RI (HR=2.29 [95%CI 1.46-3.61], p=0.0003 and HR=2.84 [95%CI 1.64-4.91] , p=0.0002, respectively) and were associated with a shorter LFS (HR=1.67 [95%CI 1.18-2.36], p=0.004 and HR=1.61 [95%CI 1.06-2.44] , p=0.025) while reduced intensity (RIC) conditioning had a worse impact on OS compared to MAC (HR=1.56 [95%CI 1.07-2.29], p=0.022). Additionally, in the subgroup of patients with available MRD data, MRD positivity at transplant significantly increased RI (HR=2.15 [95%CI 1.09-4.23] , p=0.027) with no impact on survival. In conclusion, our data suggest that the presence of IDH1-2 mutations acts as an independent prognostic factor and is associated with improved outcome in patients with AML in CR undergoing allo-HCT. Indeed, patients with IDH1-2 mutations had significantly lower rates of RI and aGVHD, which translated into improved LFS and GRFS. Nevertheless, patients with MRD positivity at time of transplant had significantly increased RI. Further studies investigating allo-HCT outcomes in IDH1-2 mutated patients with AML in the era of IDH inhibitors (both in the pre- and post-transplant setting) would help to further define the impact of these mutations in this setting and thus optimize an individualized treatment approach. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Esteve: Abbvie: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; Novartis: Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Jazz: Consultancy. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Ganser: Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees.

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin's lymphoma (HL), in particular those having failed a previous autologous SCT (ASCT). When an HLA-matched donor is lacking, a graft from a haploidentical donor (HAPLO), a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective, registry-based study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from a HAPLO, MMUD or CB graft. After detailed review of our database, we found 98 consecutive patients with HL who underwent a NMA/RIC allo-SCT from an alternative HLA-mismatched donor at 24 French and Belgian centers between January 2009 and December 2014. Probabilities of overall survival (OS), event-free survival (EFS) and graft-versus-host disease (GVHD)-free Relapse-free Survival (GRFS) were determined using the Kaplan-Meier method. The cumulative incidences of relapse (CIR), non-relapse mortality (NRM) and cGVHD were studied using a competing risk methodology. We defined GRFS as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD (all grades included). Regarding conditioning regimens and intensity, patients in the HAPLO group (n = 34) received a T-cell replete allo-SCT after a NMA (as described by the Baltimore group in Luznik et al, Biology of Blood and Bone Marrow Transplantation, 2008, n = 31, 91%) or a RIC (n = 3, 9%) followed by post-transplant cyclophosphamide (PT CY). Patients in the MMUD group (n = 27) received a variety of NMA (n = 7, 26%) and RIC (n = 20, 74%). All patients in the CB group received a RIC (n = 37, 37%). All but one patient (n = 33) in the HAPLO group received the following GVHD prophylaxis: Cy 50 mg/kg on day +3 and day +4, tacrolimus or CsA and mycophenolate mofetil started on day +5. One patient received only one day of PT CY 50mg/kg at day +3 and also received ATG on day -2 and day -1 for a total dose of 5mg/kg. GVHD prophylaxis for MMUD consisted of CsA or tacrolimus, started on day -3 or day -1 in all patients according to local practice with either mycophenolate mofetil (n = 25, 89%) or methotrexate 15 mg/m2 at day +1, 10 mg/m2 at day+3 and day +6 (n = 3, 11%). GVHD prophylaxis consisted of CsA and mycophenolate mofetil starting on day -3 for all CB patients. Median age at allo-SCT was 28 (range: 16-68). The median number of treatments before allo-SCT was 4 (range: 3-6). An ASCT had been performed prior to allo-SCT in 77% (n = 26), 100% (n = 28%) and 100% (n = 37) of cases in the HAPLO, MMUD and CB group, respectively. Disease status at allo-SCT per Cheson 1999 criteria was complete remission in 51% (n = 51), partial response in 32% (n = 31), stable or progressive disease in 11% (n = 11), while no data was available in 5% (n = 5). Positron emission tomography was positive at allo-SCT in 45% (n = 44), negative in 43% (n = 43) while no data was available in 12% (n = 12). Median follow-up was 31 months (range: 3 - 79). In univariate analysis we observed a significantly higher probability of GRFS in patients who received a HAPLO allo-SCT (52% versus 22% and 31% at three years in the HAPLO, CB and MMUD groups, respectively, p = 0.02, Logrank test). Higher GRFS was also observed in patients receiving a NMA conditioning compared to a RIC (50% versus 27% at three years, p = 0.009, Logrank test). We did not observe significant differences in OS, EFS or NRM, according to donor type. Disease status at allo-SCT significantly impacted OS (p 〈 0.001, Logrank test), CIR (p = 0.02, Gray's test), EFS (p 〈 0.001, Logrank test) and GRFS (p = 0.002, Logrank test). After adjustment for significant covariates, MMUD and CB remained associated with significantly lower GRFS (HR = 2.02, p = 0.03 and HR = 2.43, p = 0.009, respectively, Cox model) compared to HAPLO donors. In conclusion, significantly higher GRFS was observed in HL patients receiving a haploidentical NMA/RIC T-cell replete allo-SCT with PT CY. How this separation of the GVH from the graft-versus-lymphoma effect occurs requires further investigations. Haploidentical NMA/RIC T-cell replete allo-SCT with PT CY for advanced HL should now be compared with NMA/RIC allo-SCT from related and unrelated HLA-compatible donors, ideally within prospective trials. 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. Peffault De La Tour:ALEXION: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding.

Abstract: Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin 〈 2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan–Meier–estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan–Meier–estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.

Abstract: Introduction: De novo Ph+ acute myeloid leukemia (AML) has recently been described as a distinct AML subtype with a specific genome signature compared to chronic myeloid leukemia (CML). Although Allo-SCT is often proposed as the curative option, the outcome of Ph+ AML treated with Allo-SCT remains unknown in the literature. Methods: Between 2000 and 2012, 19 patients with Ph+ AML who received Allo-SCT were identified in France and compared to 21 patients with Ph+ biphenotypic acute leukemia (BAL) and 52 patients with myeloid blast crisis CML (MBC-CML). Clinical data were prospectively collected though ProMISe (Project Manager Internet Server), an internet-based system shared by all centers of The French Society of Bone Marrow Transplantation and Cell Therapies. The study was approved by local ethical committee. Results: For AML, BAL and MBC-CML patients, the median age per group was respectively 46 (18-67), 36 (18-52) and 36 (18-63) years. Median follow-up was 24 months. Additional cytogenetic abnormality was not different between the 3 groups. The MBC-CML group had a lower rate of induction therapy before Allo-SCT compared to the 2 other groups and a lower rate of remission status before transplant (p 〈 0.0001). However tyrosine-kinase inhibitor (TKI) exposure during induction was similar in each arm. A myelo-ablative conditioning regimen was used in 72% of cases without difference in each group. However the Ph+ BAL group received significantly more TBI-cyclophosphamide conditioning regimen compared to the Ph+ AML and MBC-CML groups (p 〈 0.03). No difference was observed between the 3 groups concerning graft source or the use of antithymocyte globulin (ATG). Acute graft-versus-host disease (aGVHD) with a grade≥2 was observed respectively in 37%, 19% and 32% of the Ph+ AML, BAL and MBC-CML groups. Chronic GVHD incidence was 42%, 24% and 27% in the 3 groups. Relapse I ncidence was 28%, 29% and 49% in the 3 groups. Two-year overall survival probability for Ph+ AML, BAL and MBC-CML was 65.5% (45.4-79.7), 58.3% (32.7-71.4), 38.3% (95% CI: 26.2-50.3), respectively (p=0.016, log-rank test, Figure 1). Two-year cumulative incidence of non-relapse mortality (NRM) was 17.7% (0.07-0.4) for Ph+ AML, 25.96 % (0.12-0.49) for Ph+ BAL and 33.2% (0.21-0.49) for the MBC-CML group. In univariate analysis, remission status and type of disease (Ph+ AML) were predictive factors for a better survival rate. The onset of GVHD was also predictive of a better overall survival (HR 0.43 [0.23-0.78] , p=0.006). Conclusion: Limited data are available on de novo Ph+ AML. This study showed a promising 65% two-years overall survival in Ph+ AML subtype in comparison with others Ph+ acute leukemia. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: Cellular composition of grafts is believed to be one of the significant determinants of outcomes of reduced-intensity conditioning (RIC) allogenic hematopoietic cell transplantation (allo-HCT). However, inconsistent results of the influence of CD34+ cells dose on the incidence of graft-versus-host disease (GVHD), disease control and survival have been reported in studies published thus far. Allo-HCT remains the only potentially curative treatment modality for eligible patients with myelofibrosis (MF). As patients with this diagnosis were underrepresented or not included in the above mentioned analyses, this EBMT registry study aimed to determine impact of CD34+ cell counts on allo-HCT results in this population. Methods: Six hundred and fifty seven patients with primary or secondary MF transplanted with use of peripheral blood (PB) as a source of stem cells after RIC regimen (Fludarabine/Melphalan, N=536 (82%); Fludarabine/Busulphan, N=121 (18%)) between 2000 and 2016 were included. Stem cell donor type was HLA-identical sibling (MSD; N=249, 38%) or unrelated (UD; N=408, 62%). Use of ex vivo T-cell depletion and post-transplant cyclophosphamide to prevent GVHD were the exclusion criteria. Median patient age was 58 (range, 22-76) years. In-vivo T-cell depletion was used in 526 (80%) of cases. Median transplanted CD34+ dose was 6.6 (2-29) x 10^6 per kg of recipient body weight. Median follow-up was 46 (2-194) months. Patient and transplant characteristics are summarized in Table 1. Results: We did not observe any impact of CD34+ cells dose on outcome variables in the whole study group. However, in an analysis adjusted for donor type, among patients transplanted from a MSD, the 2yr overall survival (OS) probability was 77% for those transplanted with higher doses of CD34+ cells (defined as 〉 7.0 x 10^6/kg) compared to 60% for lower CD34+ counts (below 7.0 x 10^6/kg), P=0.007 (Figure 1). The corresponding probabilities of 2yr non-relapse mortality (NRM) were 16% and 29% (P=0.04), respectively (Figure 2). In multivariate analysis, for patients transplanted from a MSD, higher CD34+ dose was an independent predictor for better survival (HR 0.56; P=0.01) and lower risk of NRM (HR 0.54; P=0.02). We did not find any association between CD34+ counts with probability of engraftment, the incidence of acute (aGVHD) and chronic (cGVHD) nor disease relapse. The effect of cell dose was not seen in the UD cohort. Factors associated independently with an unfavorable outcome in the whole study group were: older patient age and transplantation from CMV seronegative donors to seropositive recipients for OS and NRM and use of an UD and female donor for NRM. Allo-HCT from UD was also an independent predictor for higher incidence of aGVHD and lower probability of engraftment. Use of in vivo T-cell depletion was a protective factor for aGVHD. It was in turn associated with higher risk of relapse. Conclusions: Our analysis suggests a potential survival benefit for MF patients treated with RIC PB-allo-HCT from MSD with higher doses of CD34+ cells (threshold 〉 7.0 x 10^6/kg). We suggest that this factor should be taken into consideration when planning and performing hematopoietic cell apheresis. Disclosures Kröger: Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Robin:Novartis Neovii: Research Funding. Chevallier:Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria. Mielke:Bellicum: Consultancy, Honoraria, Other: Travel (via institution); EBMT/EHA: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; IACH: Other: Travel support; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; ISCT: Other: Travel support; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; DGHO: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau. Snowden:Janssen: Honoraria; Mallinckrodt: Honoraria; Kiadis: Membership on an entity's Board of Directors or advisory committees; IDMC: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Blaise:Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria.