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Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT. ispartof: BLOOD vol:140 issue:14 pages:1635-1649 ispartof: location:United States status: published

Background: No adequate data exist on the impact of multiple myeloma (MM) with extramedullary disease (EMD) after autograft and maintenance therapy.Methods: We identified 808 patients with newly diagnosed MM who received first autograft, of whom 107 had EMD (83 paraskeletal and 24 organ involvement), and who had been reported to the EBMT registry December 2018. Distribution according to type of involvement was similar between the treatment groups (p = .69). For EMD, 46 (40%) received thalidomide, 59 (51%) lenalidomide, and 11 (10%) bortezomib.Results: The median follow-up from maintenance start was 44 months. Three-year progression-free survival (PFS) was 52% (48%-57%) for no EMD, 56% (44%-69%) for paraskeletal involvement, and 45% (22%-68%) for organ involvement (p = .146). Early PFS (within first year) appeared to be significantly worse for organ involvement (hazard ratio, 3.40), while no significant influence was found after first year from maintenance start. Three-year overall survival (OS) was 81% (77%-84%), 88% (80%-96%), and 68% (47%-89%; p = .064), respectively. With thalidomide as reference, lenalidomide was significantly associated with better PFS and OS, whereas bortezomib appeared to improve outcome specifically in EMD.Conclusion: Lenalidomide maintenance is standard of care for MM without EMD, whereas extramedullary organ involvement remains a significant risk factor for worse outcome, especially for early events after maintenance start.

Allogeneic transplantation (allo-HCT) is a curative treatment in CLL whose efficacy including the most severe forms had led to the 2006 EBMT recommendations. The advent after 2014 of targeted therapies has revolutionized CLL management, allowing prolonged control to patients who have failed immunochemotherapy and/or have TP53 alterations. We analysed the pre COVID pandemic 2009–2019 EBMT registry. The yearly number of allo-HCT raised to 458 in 2011 yet dropped from 2013 onwards to an apparent plateau above 100. Within the 10 countries who were under the EMA for drug approval and performed 83.5% of those procedures, large initial differences were found but the annual number converged to 2–3 per 10 million inhabitants during the 3 most recent years suggesting that allo-HCT remains applied in selected patients. Long-term follow-up on targeted therapies shows that most patients relapse, some early, with risk factors and resistance mechanisms being described. The treatment of patients exposed to both BCL2 and BTK inhibitors and especially those with double refractory disease will become a challenge in which allo-HCT remains a solid option in competition with emerging therapies that have yet to demonstrate their long-term effectiveness.

Contains fulltext : 293484.pdf (Publisher’s version ) (Open Access) From 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of quality-assuring the HSCT process and meeting FACT-JACIE accreditation requirements relating to 1-year survival outcomes. Informed by previous experience from Europe, North America and Australasia, the Clinical Outcomes Group (COG) established criteria for patient and Center selection, and a set of key clinical variables within a dedicated statistical model adapted to the capabilities of the EBMT Registry. The first phase of the project was launched in 2019 to test the acceptability of the benchmarking model through assessment of Centers' performance for 1-year data completeness and survival outcomes of autologous and allogeneic HSCT covering 2013-2016. A second phase was delivered in July 2021 covering 2015-2019 and including survival outcomes. Reports of individual Center performance were shared directly with local principal investigators and their responses were assimilated. The experience thus far has supported the feasibility, acceptability and reliability of the system as well as identifying its limitations. We provide a summary of experience and learning so far in this 'work in progress', as well as highlighting future challenges of delivering a modern, robust, data-complete, risk-adapted benchmarking program across new EBMT Registry systems. 01 juni 2023

To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients.

ispartof: BONE MARROW TRANSPLANTATION vol:57 issue:10 pages:1607-1611 ispartof: location:England status: published

Benchmarking is commonly used in many healthcare settings to monitor clinical performance, with the aim of increasing cost-effectiveness and safe care of patients. The funnel plot is a popular tool in visualizing the performance of a healthcare center in relation to other centers and to a target, taking into account statistical uncertainty. In this paper we develop methodology for constructing funnel plots for survival data. The method takes into account censoring and can deal with differences in censoring distributions across centers. Practical issues in implementing the methodology are discussed, particularly in the setting of benchmarking clinical outcomes for hematopoietic stem cell transplantation. A simulation study is performed to assess the performance of the funnel plots under several scenarios. Our methodology is illustrated using data from the EBMT benchmarking project., 24 pages, 4 figures, 1 table

Multiple myeloma (MM) accounts for 10% of haematological malignancies. Overall survival (OS) has improved in recent years due to increased use of autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed MM and the advent of novel agents, including proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. To assess trends in ASCT including patient selection, choice of induction regimen, depth of response and survival, we performed a retrospective analysis of all patients undergoing first ASCT for MM in European Society for Blood and Marrow Transplantation centres between 1995 and 2019. A total of 117 711 patients across 575 centres were included. The number of transplants performed increased sevenfold across the study period. The median age increased from 55 to 61 years, and the percentage of patients aged >65 years rose from 7% to 30%. Use of chemotherapy-based induction fell significantly, being largely replaced by bortezomib-based regimens. The two-year complete response rate increased from 22% to 42%. The five-year progression-free survival and OS rates increased from 28% to 31% and from 52% to 69%, respectively. Transplant mortality fell from 5.9% to 1.5%. Ongoing advances in MM treatment may challenge the future role of ASCT. However, at the current time, ASCT remains central to the MM treatment paradigm.

Hepatitis-associated aplastic anemia (HAAA) has been reported in 23% to 33% of patients who received orthotopic liver transplantation (LT) for acute liver disease of unknown origin (nonviral hepatitis). In this situation, hematopoietic stem cell transplantation (HSCT) might be a curative option. Here the authors report on 6 patients who received HSCT after LT for nonviral HAAA hepatitis. The outcomes were interpreted in the context of recently reported immune suppressive therapy (IST) outcomes in 8 patients with HAAA and to HSCT outcomes in patients with HAAA who recovered from hepatitis without undergoing LT. All patients transplanted by using HLA-identical sibling donors (3 of 6) were alive and had normal liver function and hematopoiesis without graft versus host disease. Both patients receiving bone marrow from a matched unrelated donor (MUD) experienced extensive graft versus host disease that was fatal for one patient. Thereby, the authors conclude that HSCT can be considered as a first-choice treatment for this category of patients when HLA-identical donors are available. When no HLA-identical donor is available, IST should be applied as HSCT with other donor sources might be reserved for IST nonresponders or poor responders.

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment >20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Introduction Young patients with idiopathic aplastic anemia (AA) respond better to immunosuppressive therapy (IST) but the long-term outcome is suboptimal with non-response in 30% of patients as well as significant risks of relapse, ciclosporine (CSA) dependence and clonal evolution. Excellent results of up-front unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) have been reported in a cohort of 29 children with idiopathic AA using an Alemtuzumab-based regimen, with low Graft versus Host Disease (GvHD) rates and only 1 death (Dufour C, BJH 2015). We took advantage of the SAAWP registry of the European Blood and Marrow Transplantation (EBMT) to analyze the outcomes of 65 young patients who received up-front UD HSCT in Europe. Methods : Patients who had received an UD HSCT for AA, between 2010 and 2018, registered in the SAAWP registry were included. Patients who had received IST (CSA or anti-thymocyte globulin (ATG)) before HSCT, cord blood, haplo-identical transplant were excluded as well as patients suffering from congenital bone marrow disorders. The primary endpoint was overall survival (OS) at 2 years. Secondary endpoints were GVHD-free/relapse-free survival (GRFS) - defined at 2 years as being alive, engrafted without acute GVHD grade III-IV, and extensive chronic GVHD during follow-up. Results : Sixty-five patients were included between 2010 and 2018; median age was 16 years old (9-26). Time to HSCT was 6.5 months (IQR 3.6-11.7). Thirty-nine patients were transplanted from a matched unrelated donor (at least 8/8 HLA matched), 11 patients had mismatched UD (HLA data missing for 14 patients). The two-year overall survival rate was 92% (95% CI, 85-99%) (figure 1,A) with a median follow-up of 32 months (25-43). Main cause of death was infection (2 out of 5 deaths). Failure occurred in 8% (1-15%) of the patients. Acute GVHD grade II-IV was observed in 13% (5-22%) of the patients and Grade III and IV happened for two patients (3%). Chronic GVHD at 2 years occurred for 12% (4-21%) of the patients, with no extensive case. GRFS was 87% (77-96%) at 2-years (Figure 1, B). In our cohort, 57 patients received in vivo T cell depletion using either ATG (n=33, 60%) or anti-lymphocyte globulin (n=4, 7%) or alemtuzumab (n=20, 30%). Due to low rate of events happening during outcome, no risk factor analysis could be driven. Conclusion: In this retrospective cohort of 65 patients with idiopathic aplastic anemia, up-front UD transplantation leads to promising results, confirming previous studies on a smaller cohort of patients. Moreover, we did not find any difference according to in vivo T-cell depletion type, suggesting excellent results are not exclusively related to alemtuzumab-based regimen. Because of obvious limitation related to retrospective studies, unreported events and information bias cannot be excluded. Prospective trials are on their way in the United States and in Europe to formally confirm upfront UD transplantation as standard of care for pediatric patients with idiopathic aplastic anemia. Disclosures Rambaldi: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; University of Milan: Current Employment; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Griškevičius:Novartis: Research Funding. Dalle:Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Bellicum: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Pfizer: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau. Peffault De Latour:Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients. (C) 2021 Published by Elsevier Inc. on behalf of The American Society for Transplantation and Cellular Therapy.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53–71%) for MMUD, versus 80% (66–95%) for HDs with only in vivo T cell depletion and 60% (47–73%) for HDs with in vivo and ex vivo T cell depletion (p =.22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73–99%) than for those transplanted from a MMUD 58% (48–68%) or those with graft manipulation 56% (42–69%) (p =.046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p =.005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts. © 2021 Wiley Periodicals LLC., The authors are particularly thankful to all centers from the Severe Aplastic Anemia Working Party and the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation, who kindly agreed to participate in this study (see Appendix S1). We would also like to thank Anne E. Lippinkhof, Study Coordinator, Severe Aplastic Anemia Working Party for her invaluable help.

The EBMT Chronic Malignancies Working Party performed a retrospective analysis of 215 patients who underwent a second allo-HCT for myeloma between 1994 and 2017, 159 for relapse and 56 for graft failure. In the relapse group, overall survival (OS) was 38% (30–46%) at 2 years and 25% (17–32%) at 5 years. Patients who had a HLA-identical sibling (HLAid-Sib) donor for their first and second transplants had superior OS (5 year OS: HLAid-Sib/HLAid-Sib: 35% (24–46%); Others 9% (0–17%), p p = 0.03). More as opposed to fewer than 2 years between transplants was associated with superior 5-yr OS (31% (21–40%) vs. 10% (1–20%), P = 0.005). On multivariate analysis, consecutive HLA-identical sibling donor transplants conferred a significant OS advantage (0.4 (0.24–0.67), p

Introduction Acute and chronic graft vs. host disease (a/cGVHD) are major causes of treatment failure and non-relapse mortality (NRM) in multiple myeloma (MM) patients (pts) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Use of post-transplant cyclophosphamide (PTCy) is now an established method for GVHD prophylaxis after HLA haplo-identical (haplo)-HCT. We previously reported data in MM pts undergoing haplo-HCT (EBMT/CIBMTR) and showed that PTCy was associated with promising overall survival (OS) (Sahebi et al., BBMT 2019). However, data using PTCy for GVHD prophylaxis in other donor types are very limited in MM. Methods We evaluated PTCy as GVHD prophylaxis in MM pts who underwent a first allo-HCT using matched related (MRD), matched unrelated (MUD), mismatched related or unrelated (MMRD/MMUD, one antigen), and haplo donors within EBMT centers. OS and progression free survival (PFS) were determined by means of the Kaplan-Meier estimator. Neutrophil and platelet engraftment, relapse and NRM, and a/cGVHD were analyzed individually in a competing risks framework with relapse and death as competing events. Cox proportional hazards regression was used in the multivariable analyses. All estimates include 95% confidence intervals. All included covariates are listed in the Table. Patient Characteristics Between 2012-2018, a total of 295 MM pts received PTCy as GVHD prophylaxis. Median age at transplant was 55 yrs. Allo-HCT was given at a median interval of 34.9 mo from MM diagnosis. The conditioning regimen included reduced intensity (RIC, 193, 65.4%) and myeloablative (MAC, 102, 34.6%). All pts except 10 (3.4%) had prior autologous HCT; all of these 10 pts received a haplo-HCT. GVHD prophylaxis included PTCy + cyclosporine A or tacrolimus +/- mycophenolate mofetil in the majority of patients (239, 81%), and this combination was used in nearly every patient with haplo-HCT. Overall, peripheral blood was used as the stem cell source in about 80% of pts, but bone marrow was used in nearly 40% of haplo-HCTs. Results (Median and 95% confidence interval are provided)1) Median time to neutrophil engraftment was 19 d (18-19 d) with no apparent difference among donor types.2) Median time to platelet engraftment was 23 d (21-26 d), whereas haplo-HCT engraftments were longer (27 d (25-33 d)).3) NRM at 1 yr was 18% (12-22%) and at 2 yrs was 19% (14-24%), with no significant difference among different donor types. Age < 50 yrs significantly decreased NRM to 9% (2-16%, p=0.027) at 2 yrs.4) Cumulative incidence of grade II-IV aGVHD at +100 d was 30% (25-36%), and 1 yr cGVHD was 27% (21-32%), with no apparent difference among donor types.5) OS was 63% (57-69%) at 1 yr and 51% (45-58%) at 2 yrs for the whole group, with no statistical difference among different donor types after a median follow-up of 26.1 mo. Disease status at transplant < PR significantly decreased OS to 35% (22-47%, p=0.005) at 2 yrs.6) PFS was 42% (36-49%) at 1 yr and 26% (20-32%) at 2 yrs for the whole group without apparent significant difference among donor types. Disease status at transplant < PR significantly decreased PFS to 16% (6-26%, p=0.028) at 2 yrs.7) However, in multivariable analyses, donor type using haplo, HR 1.65 (0.56-1.67, p=0.03), was associated with increased mortality in addition to disease status at allo-HCT < PR, HR 1.93 (1.25-2.97, p=0.003). Finally, MUD was associated with an improved PFS, HR=0.63 (0.4-0.99, p=0.04). Disease status < PR, HR=1.85 (1.24-2.74, p=0.002) was again associated with inferior PFS. Summary PTCy in MM patients undergoing allo-HCT throughout donor types resulted in a low incidence of aGVHD grade II-IV of 30% and cGVHD of 27%, with OS of 51% and PFS of 26% at 2 yr. Our first donor comparison using PTCy revealed improved survival in matched (MRD and MUD) versus haplo allo-HCT after adjusting for other risk factors. Disclosures Blaise: Jazz Pharmaceuticals: Honoraria. Tarella:TG-therapeutics: Research Funding; ImmunoGen: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDonald:venetoclax advisory board in South Africa (in CLL context): Consultancy; Alberts Cellular Therapy: Current Employment. Milpied:Roche: Honoraria, Other: Travel support; Astellas: Honoraria; Gilead Sciences: Other: consultancy or advisory role; Celgene: Other: Travel support; Sandoz: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Schonland:Janssen: Honoraria, Other: travel support to meetings, Research Funding; Prothena: Honoraria, Other: travel support to meetings, Research Funding; Takeda: Honoraria, Other: travel support to meetings, Research Funding.

Acute graft-versus-host disease (aGvHD) remains a major threat to successful outcome following allogeneic hematopoietic cell transplantation though advances in prophylaxis and supportive care have been made. The aim of this study is to test whether the incidence and mortality of aGvHD have decreased over time. 102,557 patients with a median age of 47.6 years and with malignancies after first allogeneic sibling or unrelated donor (URD) transplant were studied in the following periods: 1990-1995, 1996-2000, 2001-2005, 2006-2010 and 2011-2015. Findings: 100-day incidences of aGvHD grades II-IV decreased from 40% to 38%, 32%, 29% and 28%, respectively, over calendar time (P

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured.

Transplacental trafficking of maternal and fetal cells during pregnancy establishes long-term reciprocal microchimerism in both mother and child. Consequently, the maternal immune system may become sensitized to paternal histocompatibility antigens. It has been hypothesized that mother's "exposure" to paternal HLA haplotype antigens during pregnancy may affect the outcome of hematopoietic stem cell transplantation (HSCT) when the mother serves as a donor for the child. In T cell-depleted HLA-haploidentical HSCT, maternal donors have been associated with improved transplantation outcomes. The present retrospective multicenter study, conducted on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society of Blood and Marrow Transplantation, involved 409 patients (102 pediatric and 307 adult) with acute leukemia who underwent HLA-haploidentical HSCT. The goal of the study was to evaluate the role of maternal donors in a large cohort of haploidentical transplantation recipients. Transplantation from maternal donors was associated with a lower relapse incidence in T cell-depleted HSCTs (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.16 to 3.92; P = .018) as well as in a limited series of unmanipulated in vivo T cell-depleted HSCTs (HR, 4.15; 95% CI, 0.94 to 18.35; P= .06), along with better graft-versus-host disease/relapse-free survival (GRFS) in T cell-depleted HSCT (HR, 1.67; 95% CI, 1.02 to 2.73; P = .04). These results indicate that the mother is the preferred donor to provide better GRFS in T cell-depleted HLA-haploidentical HSCT for acute leukemia. (C) 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Graft-versus-host disease (GVHD) remains among the major causes of treatment failure in patients with multiple myeloma (MM) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). The use of post-transplantation cyclophosphamide (PT-Cy) is now a well-established and widely used method for GVHD prophylaxis after HLA haploidentical HCT. However, the rationale for using PT-Cy in the setting of matched donor transplantation is less apparent, given the lesser degree of bidirectional alloreactivity. In this retrospective study, we investigated the role of PT-Cy as GVHD prophylaxis in patients with multiple myeloma underoing allo-HCT, among different donor types, to determine cumulative incidence of acute and chronic GVHD and impact on engraftment, progression-free survival (PFS), GVHD-free/relapse- free survival (GRFS), overall survival (OS), and NRM A total of 295 patients with MM underwent allo-HCT using grafts from a matched related donor (MRD; n = 67), matched unrelated donor (MUD; n = 72), mismatched related or unrelated donor (MMRD/MMUD, 1 antigen; n = 27), or haploidentical donor (haplo; n = 129) using PT-Cy between 2012 and 2018. In addition to PT-Cy, agents used in GVHD prophylaxis included calcineurin inhibitors in 239 patients (81%), with mycophenolate mofetil in 184 of those 239 (77%). For grade II-IV acute GVHD, the cumulative incidence at day +100 was 30% (95% confidence interval [CI], 25% to 36%), 9% (95% CI, 5% to 12%) for grade III-IV acute GVHD, and 27% (95% CI, 21% to 32%) for chronic GVHD (limited, 21%; extensive, 6%), with no differences by donor type. The median time to neutrophil engraftment was 19d (95% CI, 18-19), with no significant difference by donor type. The median time to platelet engraftment was delayed in haploidentical donor graft recipients (27 days versus 21 days; P < .001). Two-year OS, PFS, GRFS, and NRM were 51% (95% CI, 45% to 58%), 26% (95% CI, 20% to 32%), 24% (95% CI, 18% to 30%), and 19% (95% CI, 14% to 24%), respectively, with no significant difference between different donor types. In multivariable analyses, compared with the haplo donors, the use of MRDs was associated with significantly better OS (hazard ratio [HR], 0.6; 95% CI, 0.38 to 0.95; P = .029), and the use of MUDs was associated with a significantly higher GRFS (HR, 0.63; 95% CI, 0.42 to 0.97; P = .034). There was a trend toward improved PFS with use of MUDs (HR, 0.69; 95% CI, 0.46 to 1.04; P = .08). Our data show that PT-Cy in MM patients undergoing allo-HCT resulted in low rates of acute and chronic GVHD and led to favorable survival, especially in the matched related donor setting. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

IPSS-R is a well established prognostic factor for transplant outcome in patients with MDS, irrespective whether it is assessed at diagnosis or at transplant. However it is unclear how a change in IPSS-R, e.g. by reducing bone marrow blasts through therapy, would potentially affect transplant results. In particular the decision to treat patients before transplant or perform an upfront allogeneic transplantation can so far not be based on evidence. We did a registry search based in the MDS quality initiative conducted by EBMT to identify transplanted patients with MDS and sufficient data to calculate IPSS-R at diagnosis and before transplant. The search was limited to patients reveiving a first allogeneic stem cell transplantation in the period 2005 -2018. 1482 patients were identified. Median age at alloHCT was 59 (interquartile range 51-64) years, 60% were male. Donors were related in 36%, graft source was PBSC in 85% of cases. Conditioning was standard dose in 33% and reduced intensity in 67%. IPSS-R both at diagnosis and at transplant had a significant impact on OS and RFS after alloHCT. To investigate the effect of a change in IPSS-R between diagnosis and transplant we constructed 3 subgroups: stable IPSS-R, improved IPSS-R, worsened IPSS-R. A change in IPSS-R was noted in 77.5% of patients with prior chemotherapy, 72% with prior HMA and 59.8% of untreated patients. Univariate analysis showed no significant difference in OS or RFS in patients with stable IPSS-R compared to improved or worsened IPSS-R. In patients treated with chemotherapy before transplant OS and RFS was significantly worse with worsened IPSS-R, while this effect was not found in patient treated with hypomethylating agents (HMA) or untreated patients. The same analysis was performed regarding the difference in bone marrow blasts and the cytogenetics score: OS and RFS after transplant were significantly worse with increased blasts (p=0.04 and p=0.001) and a worsened cytogenetic score before transplant (both p In this retrospective analysis from a large cohort of patients with MDS we found that worsening of IPSS-R, blast count or cytogenetic score had a negative prognostic impact in chemotherapy-treated patients, while only worsened blast count and cytogenetics were significant negative factors in HMA-treated or untreated patients. Conversely we did not find a positive effect of improved IPSS-R, decreased blasts or improved cytogenetics in any of the subgroups of treated or untreated patients. Thus for MDS patients receiving an allogeneic transplantation our results provide no clear signal that prior therapy is able to improve transplant outcome. Disclosures Scheid: Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria. Chevallier:Incyte Corporation: Honoraria. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria.

Background Survival after Allo-HSCT for severe idiopathic aplastic anemia (SAA) has improved over past 20 years, approaching 75% at 5 years. However, beyond survival, a SAA-adapted composite endpoint GVHD and relapse free survival (GRFS) may more accurately assess patient outcomes, becoming a meaningful study endpoint. We analyzed GRFS aiming to identify risk factors and specific causes of GRFS failure. Methods This retrospective analysis from the SAAWP Data Quality Initiative (DQI registry database) program of EBMT included patients with: diagnosis of idiopathic SAA; first Allo-HSCT from 2005 to 2016; and matched related (MRD) or unrelated donor (UD) (no cord blood). Relevant events for Kaplan-Meier calculation of GRFS were: relapse (including primary and secondary graft failure); grade 3-4 acute GVHD; extensive chronic GVHD; and death. In addition, we used a competing-risk model to analyze cumulative incidences of specific causes of GRFS failure. Results We analyzed 580 patients (385 adults and 195 younger than 18 years), with a median age of 23 years ( 6 months) and previous treatment before Allo-HSCT showed that age (HR=1.02, [1.01-1.03], p Among the 209 patients who underwent upfront Allo-HSCT from a MRD, 5-year GRFS was 77% (71-84). In multivariate analysis, time from diagnosis to Allo-HSCT (HR=2.64, [1.38-5.03], p=0.003) and age (HR=1.03, [1.00-1.05], p=0.039) independently influenced GRFS. When investigating the causes of GRFS failure in this subset of patients who underwent upfront MRD Allo-HSCT, time from diagnosis to Allo-HSCT was the only remaining factors significantly associated with the risk of death without prior failure (HR=0.29, [0.10-0.84], p=0.022). No factor was found specifically associated with any other causes of GRFS failure. Conclusions We observed 5-year GRFS of 69%, meaning that most of patients who underwent Allo-HSCT for idiopathic SAA are cured without experiencing severe forms of acute and chronic GVHD. In the context of upfront MRD Allo-HSCT, GRFS was even more promising (77%). In this particular setting, time from diagnosis to Allo-HSCT was the most important factor influencing GRFS, suggesting the need to proceed to Allo-HSCT as quick as possible when a MRD is available. Disclosures Ganser: Novartis: Consultancy; Celgene: Consultancy. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

This follow-up study of a randomized, prospective trial included 192 patients with newly diagnosed severe aplastic anemia receiving antithymoglobulin and cyclosporine, with or without granulocyte colony-stimulating factor (G-CSF). We aimed to evaluate the long-term effect of G-CSF on overall survival, event-free survival, probability of secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), clinical paroxysmal nocturnal hemoglobinuria, relapse, avascular osteonecrosis and chronic kidney disease. The median follow-up was 11.7 years (95% CI, 10.9- 12.5). The overall survival rate at 15 years was 57±12% in the group given GCSF and 63±12% in the group not given G-CSF (P=0.92); the corresponding event-free survival rates were 24±10% and 23±10%, respectively (P=0.36). In total, 9 patients developed MDS or AML, 10 only a clonal cytogenetic abnormality, 7 a solid cancer, 18 clinical paroxysmal nocturnal hemoglobinuria, 8 osteonecrosis, and 12 chronic kidney disease, without any difference between patients treated with or without G-CSF. The cumulative incidence of MDS, AML or isolated cytogenetic abnormality at 15 years was 8.5±3% for the G-CSF group and 8.2±3% for the non-G-CSF group (P=0.90). The cumulative incidence of any late event including myelodysplastic syndrome or acute myeloid leukemia, isolated cytogenetic abnormalities, solid cancer, clinical paroxysmal nocturnal hemoglobinuria, aseptic osteonecrosis, chronic kidney disease and relapse was 50±12% for the G-CSF group and 49±12% for the non-G-CSF group (P=0.65). Our results demonstrate that it is unlikely ABSTRACT A. Tichelli that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppressive therapy (NCT01163942). CA extern

Introduction. Chronic lymphocytic leukemia (CLL) has typically an indolent course but can undergo transformation into a more aggressive lymphoma so called Richter's syndrome. While the advent of novel targeted therapies is transforming the management of patients with CLL, these drugs failed to prevent the risk of RS. RS is associated with a very poor outcome and is thus becoming the main obstacle to long term CLL control. Autologous (auto-) and allogeneic (allo-) hematopoietic stem-cell transplantation (-SCT) have been recommended as the treatment of choice in eligible patients with clonally related RS (Rossi Blood 2018) but previous experience is still limited to less than 50 cases. We here aimed to investigate the safety and efficacy of both auto- and allo-SCT for patients with RS in a large cohort in a period overlapping the advent of novel agents. Methods. We report on a retrospective study of consecutive adult patients with RS who underwent auto- or allo-SCT between 2008 and 2018 in EBMT centers. Results. A total of 197 patients (M/F= 133/64) were included in the present study; 125 patients received allo-SCT and 72 auto-SCT. The main difference between these 2 cohorts was the median age at transplant that was lower in the allo- than in the auto-SCT group (median age 57 [18-71] vs 61 [39-74] years, p = 0.006). Regarding the allo-SCT cohort, median time from RS diagnosis to SCT was 10 months [1.1-322.8] and 54.2% had received >2 therapeutic lines for RS. At allo-SCT, 60 (48.4%) were in CR and 53 (42.7%) in PR or SD. Most patients received reduced intensity conditioning (RIC) regimen (n= 90, 72.6%) and peripheral blood (89.6%) as stem cell source. Donors were related (matched, n=40 (33%) or mismatched, n=4 (3%)) or unrelated (matched, n= 76 (61%) and mismatched, n=4 (3%). A total of 41 patients (33.6%) received total body irradiation (TBI). With a median follow-up of 48 months, 2-year OS was 46% (36-55%) and 2-year PFS 38% (28-48%). Two-year cumulative incidence of relapse (CIR) was 31% (22-40%) as was the 2-year NRM (Figure 1). Two-year CIR was significantly reduced in patients with ≤2 therapeutic lines for RS (12% (1-22%) vs 41% (26-55%); p=0.005). Performance status affected 2-y PFS (24% (7-42%) if Karnofsky index Regarding the auto-HSCT cohort, median time from RS diagnosis to HSCT was 7.8 months [2.6-102.7] and 66.7% had received >2 lines for RS. At auto-SCT, 36 (52.2%) were in CR and 36 (37.7%) in PR or SD. With a median follow-up of 18 months, 2-year OS was 69 % (56-82%) and 2-year PFS 47% (33-62%). Two-year cumulative incidence of relapse (CIR) was 46% (32-60%) and 2-year NRM was 7% (0-13%) (Figure 2). CR patients presented better PFS (69% (50-88%) vs 29% (9-50%); p=0.002) and OS (82% (66-97%) vs 56% (35-78%) ; p=0.03). Performance status affected 2-y PFS (25% (2-48%) if Karnofsky index 90%, p = 0.005) and 2-y OS (55% (29-82%) if Karnofsky index 90%, p = 0.04). Disclosures Guièze: Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Finke:Riemser: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Medac: Honoraria, Other: research support, Speakers Bureau. Chevallier:Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria.

We report on 499 patients with severe aplastic anemia aged >= 50 years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (n = 275, 55%) or HLA-matched (8/8) unrelated donors (n =187, 37%) between 2005 and 2016. The median age at HCT was 57.8 years; 16% of patients were 65 to 77 years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90% (hazard ratio HR], 1.41; 95% confidence interval [CI], 1.03 to 1.92; P= .03) and after unrelated donor transplantation (HR, 1.47; 95% CI,1 to 2.16; P = .05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66% (range, 57% to 75%) and 57% (range, 47% to 76%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57% (range, 48% to 67%) and 48% (range, 36% to 59%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65 years or older (subdistribution HR [sHR], 1.7; 95% confidence interval, 1.07 to 2.72; P= .026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI) + methotrexate (sHR, .52; 95% CI, .33 to .81; P= .004) and CNI alone or with other agents (sHR, .27; 95% CI, .14 to .53; P < .001) compared with CNI + mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes. (C) 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

ispartof: HAEMATOLOGICA vol:104 issue:8 pages:E335-E339 ispartof: location:Italy status: published

Background The best preparative regimen for the growing number of older acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients undergoing allogeneic hematopoietic cell transplantation (HCT) from matched related (MRD) or unrelated donors (MUD) remains undefined. A large randomized phase III trial (MC-FludT.14/L study: ClinicalTrials.gov Identifier: NCT00822393) recently demonstrated that myeloablative intravenous (IV) treosulfan (10 g/m² IV on days -4 to -2) in combination with fludarabine (TreoFlu) improves outcome in older and/or comorbid patients with AML in complete remission (CR) or MDS compared with the reference reduced intensity busulfan (0.8 mg/kg IV in 6-hour intervals on days -4 and -3) and fludarabine (30 mg/m² IV on days -6 to -2 in each study arm) regimen. The beneficial effect of the TreoFlu regimen resulted from a significantly reduced non-relapse mortality (NRM) and translated to improved event-free survival (EFS) and overall survival (OS) (Beelen DW et al The Lancet Haematology, 2019). These results raised the question, how this new regimen compares to broadly applied myeloablative regimens, namely busulfan (0.8 mg/kg IV in 6-hour intervals over 4 days) plus cyclophosphamide (120 mg/kg IV over 2 days) (BuCy) or melphalan (140 mg/m² IV over 1 day or 2 days) plus fludarabine (MelFlu) in older AML and MDS patients. To address this question, we performed a comparative analysis of MC-FludT.14/L study patients treated with the TreoFlu regimen and similar patients of the European Blood and Marrow Transplantation Society (EBMT) registry, who underwent HCT from MRD or MUD after the BuCy or MelFlu regimen between 2010 and 2016. Patients and Methods Inclusion criteria were essentially the same as for the MC-FludT.14/L-study (patient age 50 to 70 years [yrs], primary or secondary AML in CR or MDS, Karnofsky-index ≥ 60%, MRD or MUD, 1st HCT). The study objectives were to compare OS, relapse incidence (RI), and NRM at 2 yrs after HCT between the TreoFlu regimen and the BuCy or MelFlu regimen. A total of 1493 EBMT registry patients (median age 58 yrs, AML: n=1135 [76%], MDS: n=358 [24%]) were identified for the comparison with the 252 MC-FludT.14/L patients (median age 61 yrs, AML: n=174 [69%], MDS: n=78 [31%]). A 1:1 matching method based on propensity scores (PS) with 14 patient-, donor-, and disease-characteristics was used to reduce confounding due to differences between regimens and was performed separately for AML and MDS patients. With the exception of comparison between the TreoFlu and BuCy regimen in AML patients, a significantly higher proportion of patients in the TreoFlu regimen subsets had a HCT-comorbidity index > 2 compared to patient subsets treated with the BuCy or MelFlu regimen. Results For patients with AML, the 2-yrs OS estimate was significantly higher after the TreoFlu compared with the BuCy regimen (76.4%, 95%-confidence interval [95%-CI]: 66.8% - 85.9% vs 49.2%, 95%-CI: 36.4% - 62.1%, p Conclusion In older AML and MDS patients, the new TreoFlu regimen compares favorable to the broadly applied myeloablative BuCy and MelFlu regimens. The substantially lower 2-yrs NRM estimate supports its superior tolerability in this patient population. This large retrospective comparative analysis provides a basis for properly designed randomized trials of the new toxicity reduced myeloablative TreoFlu regimen in comparison with other myeloablative regimens in this target population. Table Disclosures Beelen: Medac GmbH Wedel Germany: Consultancy, Honoraria. Stoelzel:Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding; JAZZ Pharmaceuticals: Consultancy. Dreger:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Neovii, Riemser: Research Funding; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.

Introduction The only curative treatment approach for patients with myelodysplastic syndromes (MDS) is allogeneic hematopoietic stem cell transplantation (HSCT), but disease relapse after transplantation is a major concern. Predictors for disease outcome after HSCT are limited. However, unfavorable cytogenetic abnormalities have been shown to serve as predictors for MDS-relapse after transplantation. Similar to the data available in MDS-patients not undergoing HSCT (Schanz et al. J Clin Oncol 2012), there is evidence that the novel 5-group cytogenetic classification has a better predictive value for outcome after HSCT than standard IPSS cytogenetics (Deeg et al. Blood 2012). The aim of this large multicentric, international study was to retrospectively determine the impact of the new 5-group cytogenetic MDS classification on outcome after HSCT. Patients and Methods Patients were selected from the EBMT database who had received HSCT for the treatment of MDS between 1982 and 2010 and for whom sufficient cytogenetic information was available. In total, 903 patients were included into the study. At time of HSCT, 97 (10.7%) patients had untreated MDS, 218 (24.1%) patients had advanced MDS or AML evolving from MDS in complete remission, and 227 (25.1%) patients were not in remission after treatment (in 12.3% information on stage of the disease was not available). Median time between diagnosis and transplant was 6.6 months (range 0.2-359.3). Matched related donor HSCT was performed in 574 patients (63.6%), and matched unrelated donor HSCT in 329 patients (36.4%). Bone marrow (35.4%) or peripheral blood (64.6%) served as stem cell graft. Myeloablative preparative regimens were used in 582 patients (64.5%), and a non-myeloablative regimen was given to 320 patients (35.4%). Impact of cytogenetic classification was analyzed in uni- and multivariate models regarding overall survival (OS) and relapse free survival (RFS) after HSCT. Predictive performance of the 2 classifications was compared by means of the cross-validated log partial likelihood. Results Estimated 5-year RFS and OS were 32% and 36% respectively. According to the 5-group cytogenetic classification 19 (2.1%) patients had very good risk cytogenetics, 204 (22.6%) normal risk cytogenetics, 438 (48.5%) intermediate risk cytogenetics, 178 (19.7%) poor risk cytogenetics, and 64 (7.1%) very poor risk cytogenetics. Good, intermediate, and poor risk cytogenetics according to IPSS were found in 192 (38.0%), 500 (40.2%), and 211 (23.7%) patients, respectively. In univariate analysis 5-group cytogenetic information was found to be strongly associated with OS and RFS (OS: log-rank test P

Background Standard survival analysis fails to give insight into what happens to a patient after a first outcome event (like first relapse of a disease). Multi-state models are a useful tool for analyzing survival data when different treatments and results (intermediate events) can occur. Aim of this study was to implement a multi-state model on data of patients with rectal cancer to illustrate the advantages of multi-state analysis in comparison to standard survival analysis. Methods We re-analyzed data from the RCT FOGT-2 study by using a multi-state model. Based on the results we defined a high and low risk reference patient. Using dynamic prediction, we estimated how the survival probability changes as more information about the clinical history of the patient becomes available. Results A patient with stage UICC IIIc (vs UICC II) has a higher risk to develop distant metastasis (DM) or both DM and local recurrence (LR) if he/she discontinues chemotherapy within 6 months or between 6 and 12 months, as well as after the completion of 12 months CTx with HR 3.55 (p = 0.026), 5.33 (p = 0.001) and 3.37 (p

INTRODUCTION Diamond-Blackfan Anemia (DBA) is a congenital pure red cell aplasia, secondary to ribosomal protein genetic defects that usually presents within the first year of age and can be associated with congenital abnormalities and increased risk of cancer. Some patients are successfully treated with steroids but most of them remain transfusion-dependent. Stem Cell Transplantation (SCT) represents the only curative option for this disease, however data from literature is scarce and limited to a very small number of cases. In this retrospective study we describe the outcome of SCT in patients with DBA reported in the EBMT data base. PATIENTS AND METHODS The study was conducted on behalf of Severe Aplastic Anemia Working Party of the EBMT and was based on data of patients affected with DBA who underwent SCT and registered in the EBMT Data Base. Clinical information of the disease and details on transplant procedures and follow-up were collected by a specific form distributed to Centres participating in the study. RESULTS Between 1985-2016, 106 patients (60 males-46 females) aged 6.8 yo (range 1-32) underwent SCT from matched sibling donor (58, 57%), unrelated donor (37, 36%) or from other donors (7, 7%) using bone marrow (73, 69%), peripheral blood (21, 20%) or cord blood (12, 11%) as cell source. 91 patients (86%) received a myeloblative regimen which included Busulfan in 66 cases. 86% (80-93%) of patients engrafted by day 28. Median days to neutrophils and platelets engraftment were 18 and 36, respectively. EFS and OS at 36 months were 81% (74-89%) and 84% (77-91%), respectively. OS was significantly higher (p=0.01) in patients CONCLUSION To the best of our knowledge, this is the largest reported cohort of patients transplanted for DBA and having a long follow-up. The very good OS of patients undergoing transplant from both sibling and unrelated donors and the rather low rate of cGvHD confirms that this procedure can be considered an alternative option for transfusion-dependent patients Disclosures Bader: Riemser, Neovii: Research Funding; Medac: Patents & Royalties, Research Funding; Amgen (Brasil), Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy. Risitano:Alexion: Honoraria, Research Funding, Speakers Bureau; Achillion: Research Funding; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding, Speakers Bureau; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amyndas: Consultancy; Biocryst: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Research Funding; Ra Pharma: Research Funding; Alnylam: Research Funding; Alnylam: Research Funding; Achillion: Research Funding. Peffault de Latour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

Introduction The use of autologous haematopoietic cell transplantation (auto-HCT) in the treatment of myeloma (MM) has greatly increased over the last twenty-five years. There are, however, few large datasets detailing the overall trends in transplant use, patient selection, induction regimen, choice of mobilisation regimen, stem cell yield, response to transplant and survival. We performed a retrospective analysis of all patients who underwent first auto-HCT for MM in EBMT centres between 1993 and 2017 and analysed these trends over consecutive five-year cohorts: (1) 1993-1997, (2) 1998-2002, (3) 2003-2007, (4) 2008-2012 and (5) 2013-2017. Methods Data on patients with MM who underwent a first auto-HCT at EBMT centres between 1993 and 2017 were obtained from the EBMT registry. Med-A forms consist of registration and follow-up forms. More detailed information in captured in Med-B forms. Results A total of 103,032 patients in 568 centres in 54 countries were included in this analysis. The number of transplants increased seven-fold between the first and fifth cohorts: (1) 5,246, (2) 12,554, (3) 21,153, (4) 28,390 and (5) 35,689. The gender breakdown has been consistent over time: 58% Male, 42% Female. Over these years, the median patient age at transplant has increased significantly, as follows: (1) 54, (2) 57, (3) 58, (4) 59, and (5) 61 years. The percentage of patients >65 years at transplant has also increased: (1) 3%, (2) 9%, (3) 14%, (4) 14%, and (5) 22%. Between 1993 and 1997, IgG, IgA and Light Chain (LC) MM constituted 58%, 22% and 16%, respectively. The corresponding percentages between 2013 and 2017 were 52%, 18% and 27%, respectively. Data on the choice of first induction regimen was available in 19,882 (21%) cases (Med-B forms) though only cohorts 4 (2008-2012) and 5 (2013-2017) had specific data in more than 80% of cases. The trends in the percentage use of these regimens in the two cohorts since 2008 are as follows: VTD: 11% to 32%; VCD: 5% to 20%; CTD 15% to 10%; VD: 19% to 7%; PAD 5% to 4%; VRD 2% to 3%; VAD: 8% to 3%. The CR rates pre-ASCT have improved: (1) 16% (2) 14% (3) 13% (4) 20% and (5) 21%; >PR rates pre-ASCT also reveal deeper responses over time: (1) 65%, (2) 68%, (3) 70%, (4) 72%, and (5) 73%. Stem cell mobilisation regimen data was available in 19,882 (19%) cases. In these centres, the use of cyclophosphamide has steadily increased: (1) 31%, (2) 54%, (3) 63%, (4) 64%, and (5) 65%. Conversely, the use of single agent G-CSF has declined: (1) 69%, (2) 45%, (3) 36%, (4) 31%, and (5) 28%. G-CSF + Plerixafor was used in 3.5% of cases from 2008-2012 and 5% in 2013-2017. The median number of stem cells collected (CD34+cells x 10^6/kg) has gradually increased: (1) 5.1, (2) 5.2, (3) 6.3, (4) 6.6, and (5) 6.5, though the median cell dose infused has remained relatively constant: (1) 3.6, (2) 4.1, (3) 4.0, (4) 3.8, and (5) 3.8. Almost all (99%) patients received peripheral blood (PB) stem cells. The number of months from diagnosis to auto-HCT has been stable since 1998: (1) 8.9, (2) 7.7, (3) 7.4, (4) 7.4, and (5) 7.3. Finally, three-year overall survival (OS) post-transplant has risen from 65% to 81% and Progression-Free Survival (PFS) from 41% to 46% (Figure 1). Conclusions This very large dataset shows consistently increasing numbers of auto-HCT for MM in Europe over the last 25 years. Although it is still sometimes stated that 65 years is the upper age limit for auto-HCT in Europe, 22% of auto-HCT recipients in the most recent cohort were older. Analysis of MM subtypes shows an increasing rate of auto-HCT for patients with LC MM, possibly facilitated by the deeper responses which are now being achieved, overall CR rates having risen from 16% to 21% and >PR rates from 65% to 73%. Most patients (59%) in the most recent cohort (2013-2017) received bortezomib-based triplet induction regimens: VTD: 32%; VCD: 20%; PAD 4%; VRD 3%. Data from a subset of centres confirm the use of cyclophosphamide-based stem cell mobilisation in two-thirds; only 5% used G-CSF + Plerixafor. The median stem cell yield has increased by a quarter. As the median cell dose infused remains unchanged, this most likely reflects increasing rates of storage for subsequent transplants. Finally, serial cohort analysis reveals rising rates of OS and PFS over the 25 years, reflecting the deeper responses achieved pre-transplant and the increasing availability of novel agents, whether in the setting of consolidation or maintenance. Figure 1 Disclosures Hayden: Alnylam: Honoraria; Amgen: Honoraria. Goldschmidt:MSD: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Research Funding. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Benjamin:Gilead: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Eusapharm: Consultancy; Servier: Research Funding; Allogene: Research Funding; Pfizer: Research Funding. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Gribben:Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Beksac:Celgene: Consultancy; Amgen: Consultancy; Janssen&Janssen: Consultancy; Takeda: Consultancy. Schönland:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant.

Allogeneic hematopoietic stem cell transplantation (HCT) may result in long-term disease control in high-risk chronic lymphocytic leukemia (CLL). Recently, haploidentical HCT is gaining interest because of better outcomes with post-transplantation cyclophosphamide (PTCY). We analyzed patients with CLL who received an allogeneic HCT with a haploidentical donor and whose data were available in the EBMT registry. In total 117 patients (74% males) were included; 38% received PTCY as GVHD prophylaxis. For the whole study cohort OS at 2 and 5 yrs was 48 and 38%, respectively. PFS at 2 and 5 yrs was 38 and 31%, respectively. Cumulative incidence (CI) of NRM in the whole group at 2 and 5 years were 40 and 44%, respectively. CI of relapse at 2 and 5 yrs were 22 and 26%, respectively. All outcomes were not statistically different in patients who received PTCY compared to other types of GVHD prophylaxis. In conclusion, results of haploidentical HCT in CLL seem almost identical to those with HLA-matched donors. Thereby, haploidentical HCT is an appropriate alternative in high risk CLL patients with a transplant indication but no available HLA-matched donor. Despite the use of PTCY, the CI of relapse seems not higher than observed after HLA-matched HCT.

Introduction The prospective randomized study on treatment of 192 severe aplastic anemia (SAA) patients with ATG and Cyclosporine (CSA) with and without G-CSF showed that G-CSF added to ATG/CSA decreases the rate of early infection episodes and days of hospitalization in very SAA (vSAA) patients, but has no significant impact on overall survival (OS), event free survival (EFS), relapse, or death rates (Blood, 2011;17:4434). The number of secondary MDS/AML was low, however with a short observation time. Now, 16 years after initiation of the study, a follow-up was planned to evaluate long-term outcome, comparing patients with and without G-CSF. Patients and Methods A total of 192 patients with newly diagnosed SAA, not eligible for stem cell transplantation (SCT) were entered into this prospective randomized multi-center study to receive ATG/CSA with (49.5%) or without G-CSF (50.5%). In 2011, 44 of the 192 patients had died. For the present study the follow-up of the 148 patients alive at time of first publication were requested. There were 49% males (49% G-CSF; 48% no G-CSF), 36% with vSAA (32% G-CSF; 41% no G-CSF). The median age at randomization was 46 years (2-80), 47 (2-80) for the G-CSF and 44 (7-80) for the non-G-CSF group. The median follow-up using reverse KM method was 11.7 years (10.9-12.5). Results Among the 110 survivors (17 missing), 71 (65%) were in CR, 33 (30%) in PR and 6 not in remission (5%), without any difference between the G-CSF and non-G-CSF group (P=0.523). At last follow-up 65 (34%) of the patients have died. Causes of death were infection (26), bleeding (3), SAA unspecified (3), MDS/AML (4), solid cancer (3), transplant related mortality (8), cardiovascular/aging (7), or unspecified (11). There was no difference in the causes of death between patients treated with or without G-CSF. OS at 15 years was 57±12% for the G-CSF and 63±12% for the non-G-CSF group (P=0.927). EFS, including SCT, relapse, non-response at day 120, second MDS/AML, PNH or death as an event, was 24±10% for the G-CSF, and 23±10% for the non-G-CSF group (P=0.367). Nine patients developed florid or morphological signs of MDS/AML, 9 clonal cytogenetic anomaly only, 7 a solid cancer, 18 clinical PNH, 8 avascular osteonecrosis, and 12 chronic kidney disease (No difference between patients treated with or without G-CSF). Cumulative incidence (CI) at 15 years of MDS/AML (isolated cytogenetic anomalies not included) was 5.0±2% (G-CSF) and 7.3±3% (no G-CSF), respectively (P=0.693); for clinical PNH it was 10.1±5% and 13.3±7% (P=0.499), for relapse of responding patients at day 120, 29.8±22% and 25.1±17% (P=0.545), and for chronic kidney failure 16%±12% and 13%±12% (P=0.513), respectively. Forty patients needed a second line immunosuppressive therapy (IST) for relapse (17), refractory disease (8), cyclosporine dependence (6) or isolated cytopenia (9) (G-CSF 26; no G-CSF 16; P=0.291); 16 patients needed a third line IST for relapse (5), refractory disease (7), isolated cytopenia (4) (G-CSF 12; no G-CSF 4; P=0.647). Twenty-eight patients were treated with allogeneic SCT in second or subsequent line (G-CSF 12; no G-CSF 16). CI at 15 years of SCT (competing risk, death without SCT) was 14±8% (G-CSF) and 22%±10% (no G-CSF), respectively (P=0.380). OS at 10 years since SCT was 46±24%. The most important risk factors for patients treated with ATG/CSA with or without G-CSF were age and severity of the disease at randomization: OS at 15 years was 89±12% (60 years of age), respectively (P>0.001), and 64±5% and 52±7% for patients with SAA and vSAA, respectively (P=0.021). There was no difference between patients treated with or without G-CSF. Finally, the lack of neutrophil response by day 30, which was significant at first evaluation, is still associated with borderline lower survival (46.6±14% versus 67.1±9%; P=0.058). Conclusion: Long-term outcome of SAA patients treated with ATG/CSA was not influenced by supplementing G-CSF in term of OS, EFS, death rates, relapse, PNH, secondary MDS/AML, solid cancer and non-malignant late complications. Due to the pre-cancer nature of the disease and its long-lasting treatment, patients treated with IST are at risk for a number of malignant and non-malignant late complications. It is somewhat disappointing that in this careful followed cohort less than 25% of patients are alive and event-free 10-15 years after initial treatment. Disclosures Peffault De Latour: Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hoechsmann:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Schrezenmeier:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Bader:Neovii: Research Funding; Cellgene: Consultancy; Riemser: Research Funding; Medac: Patents & Royalties, Research Funding; Novartis: Consultancy, Speakers Bureau. Risitano:Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.