European Society For Blood And Marrow Transplantation Research Articles

Nutritional aspects in autoimmune diseases undergoing hematopoietic stem cell transplantation: overview and recommendations on behalf of the EBMT ADWP and Nurses Group

Autoimmune diseases (ADs) represent a heterogeneous group of conditions affecting 5–10% of the global population. In recent decades, hematopoietic stem cell transplant (HSCT), mainly autologous, has been successfully adopted to treat patients affected by severe/refractory ADs. In this context malnutrition has a detrimental impact on relapse, mortality, infection rate, engraftment, long-term survival, and prolongation of hospitalization. However, in this population, the management of nutrition should be improved since nutritional assessment is partially performed in routine clinical practice. A panel of nurses and physicians from the European Society for Blood and Marrow Transplantation (EBMT) reviewed all available evidence based on current literature and expert practices from centers with extensive experience in HSCT for ADs, on the nutritional management of ADs patients during HSCT procedure. In this context, adequate nutritional status predicts a better response to treatment and improves quality of life. Herein, a systematic and comprehensive monitoring of nutritional status before, during and after HSCT, with adequate nutritional support in the case of ADs patients, in addition to assessing the dietary requirements associated with HSCT has been covered. Moreover, given the singularity of each AD, the underlying disease should be considered for an appropriate approach. The management and evaluation of nutritional status must be carried out by a multidisciplinary team to assess the needs, monitor the effectiveness of each intervention, and prevent complications, especially in complex situations as patients affected by ADs.

Review of the 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT)

Review of the 50th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT)

Outcome of COVID-19 in patients with a history of acute leukemia; A Narrative Review

The chemotherapy and immunosuppressive medication may be associated with the suppressed immune system of a cancer patient making them susceptible to Coronavirus disease 2019 (COVID-19) with unclear mechanisms. We reviewed current studies on the clinical courses of leukemia patients with a risk of SARS-CoV-2 infection through searches in Pubmed databases and Google search engines. The criterion used for review includes their relevance to the defined review question, which is the outcome of COVID‐19 among leukemic patients and the relevant therapeutic interventions therewith. Patients with acute leukemia are among the most vulnerable groups of patients at risk of severe COVID-19 outcomes with several protocol management modifications proposed. The development of COVID-19 vaccines was an important milestone in reducing the risk of contracting and developing severe COVID-19 symptoms in leukemic patients after remission status. The European Society for Blood and Marrow Transplantation (EBMT), a collaborative network of centers and individuals working in the field of BMT and cellular therapy, has been updating its recommendations since the start of the COVID-19 pandemic.

Allogeneic hematopoietic cell transplantation for older patients with AML with active disease. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Older adults with acute myeloid leukemia (AML) refractory to initial or reinduction chemotherapy have a dismal prognosis if they do not undergo hematopoietic stem-cell transplantation (HCT). However, data assessing HCT outcomes from different donors are scarce. We evaluated results from a retrospective analysis on patients aged ≥70 years, with AML not in remission who received an allogeneic HCT from HLA-matched sibling donor (MSD), HLA-10/10 matched unrelated donor (MUD), or T-cell replete haploidentical (Haplo) donor, from 2010 to 2021, reported to the ALWP-EBMT database. A total of 360 patients (median age 72 years, range 70-79) were included in the analysis. Median follow-up for the entire population was 35.5 months. Donors were MSD (n = 58), 10/10 HLA-MUD (n = 228), and Haplo (n = 74). A total of 213 (59.2%) patients were primary induction failures, while 147 (40.8%) were in first or subsequent relapse. Graft source was peripheral blood in 92% of the patients. Patients transplanted from Haplo donors more frequently received marrow grafts (p < 0.01) and presented the combination female donor to male recipient (p < 0.01). The overall 2-year rates of overall survival (OS) and leukemia-free survival (LFS) were: 62.4% (95% CI 47.2-74.3) and 47.6% (95% CI 33.1-60.8) for MSD, 43% (95% CI 35.8-49.9), and 37.5% (95% CI 30.7-44.4) for MUD, and 25.9% (95% CI 15.8-37.2), and 26.5% (95% CI 16.3-37.8) for recipients of Haplo transplants. The 2-year cumulative incidence of relapse (RI) was slightly lower for Haplo recipients at 29.6% (95% CI 19-40.9), for MUD it was 30.2% (95% CI 23.9-36.7), and for MSD 34.9% (95% CI 22-48.2); counterbalanced by a higher incidence of non-relapse mortality (NRM) of 43.9% (95% CI 31.6-55.6) for Haplo recipients, 32.2% (95% CI 26-33.1) for MUD and 17.5% (95% CI 8.4-29.3) for MSD. Graft-versus-host disease (GVHD-free, relapse-free survival (GRFS) was 35.3% (95% CI 22.3-48.5) for MSD, 29.6% (95% CI 23.2-36.2) for MUD, and 19.2% (95% CI 10.7-29.6) for Haplo patients. In the multivariate model, compared to the referent group of MSD recipients, the risk of NRM was higher among patients transplanted from Haplo donors ([hazard ratio] HR 5.1, 95% CI 2.23-11.61, p < 0.001) and MUD (HR 3.21, 95% CI 1.48-0.6.94, p = 0.003). Furthermore, both Haplo and MUD were associated with inferior OS, (HR 3.6, 95% CI 1.98-0.6.56, p < 0.001, and HR 2.3, 95% CI 1.37-0.3.88, p = 0.002, respectively), and LFS (HR 2.24, 95% CI 1.31-0.3.84, p = 0.003, and HR 1.64, 95% CI 1.04-0.2.60, p = 0.034, respectively). Patients transplanted from Haplo donors were also associated with worse GFRS (HR 1.72, 95% CI 1.07-2.77, p:0.025) compared with MSD patients. Older adult AML patients with active disease transplanted from MSD experienced prolonged OS and LFS compared to 10/10 MUD and Haplo due to lower NRM. Prospective clinical trials are warranted.

PTCy versus ATG as graft-versus-host disease prophylaxis in mismatched unrelated stem cell transplantation

There is an increased risk of GVHD and of non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when mismatched unrelated donors (MMUD) are used. In Europe, it is standard practice to use rabbit anti-thymocyte globulin (rATG) to reduce the high NRM and GVHD risks after MMUD alloSCT. As an alternative to rATG, post-transplantation Cyclophosphamide (PTCy) is in increasing clinical use. It is currently impossible to give general recommendations regarding preference for one method over another since comparative evidence from larger data sets is lacking. To improve the evidence base, we analyzed the outcome of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies undergoing first peripheral blood alloSCT from MMUD (9/10 antigen match) between Jan 2018 and June 2021 in the database of the European Society for Blood and Marrow Transplantation (EBMT). We performed multivariate analyses using the Cox proportional-hazards regression model. We included 2123 patients in the final analyses (PTCy, n = 583; rATG, n = 1540). p values and hazard ratios (HR) presented here are multivariate outcomes. Two years after alloSCT we found a lower NRM in the PTCy group of 18% vs. 24.9% in the rATG group; p = 0.028, HR 0.74. Overall survival in the PTCy cohort was higher with 65.7% vs. 55.7% in the rATG cohort; p < 0.001, HR 0.77. Progression-free survival was also better in the PTCy patients with 59.1% vs. 48.8% when using rATG; p = 0.001, 0.78. The incidences of chronic GVHD and acute GVHD were not significantly different between the groups. We found significantly lower NRM as well as higher survival in recipients of peripheral blood alloSCTs from MMUD receiving PTCy as compared to rATG. The results of the current analysis suggest an added value of PTCy as GVHD prophylaxis in MMUD alloSCT.

Allogeneic haematopoietic cell transplantation for advanced systemic mastocytosis: Best practice recommendations on behalf of the EBMT Practice Harmonisation and Guidelines Committee.

Systemic Mastocytosis (SM) is a multifaceted clinically heterogeneous disease. Advanced SM (AdvSM) comprises three entities: aggressive SM (ASM), mast cell leukaemia (MCL) and SM with an associated hematologic neoplasm (SM-AHN), the latter accounting for 60-70% of all AdvSM cases. Detection of a disease-triggering mutation in the KIT gene (esp. KIT D816V) in >90% of the patients with ASM or SM-AHN has led to a significant improvement in therapeutic options by the implementation of two KIT-targeting kinase inhibitors: midostaurin and avapritinib. Although complete remissions have been reported, neither of these targeted agents is 'curative' in all patients and the duration of responses varies. The median overall survival, depending on the WHO subtype and scoring result, is approximately 1 to 4 years. Although the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM) consensus groups recommend allogeneic haematopoietic cell transplantation (allo-HCT) in drug-resistant and other high-risk patients, there is a relative lack of information to guide clinicians on which patients with AdvSM should be considered for transplant, and how KIT inhibitors may fit into the transplant algorithm, including their use pre- and post-transplant to optimise outcomes. Following the generation of an expert panel with a specialist interest in allo-HCT and mastocytosis, these best practice recommendations were generated according to the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonisation and guidelines and ECNM methodology. We aim to provide a practical, clinically relevant and up-to-date framework to guide allo-HCT in AdvsM in 2024 and beyond.

Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on behalf of the EBMT, ASTCT, CIBMTR, and APBMT.

Despite emergence of novel therapies to treat hematologic malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an essential treatment modality capable of curing these diseases. Allo-HCT has been also shown to be curative in benign hematologic disorders such as aplastic anemia, sickle cell disease, and thalassemia, among others. Recently, the American Society for Transplantation and Cellular Therapy (ASTCT) published standardized definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism. To attempt broader international consensus, a panel of adult and pediatric physician transplant experts was assembled from European Society for Blood and Marrow Transplantation (EBMT), ASTCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), and Asia-Pacific Blood and Marrow Transplantation (APBMT). Consensus was defined as ≥70% of voting members strongly agreeing or somewhat agreeing with a definition. With few exceptions, there was a consensus to endorse the prior ASTCT definitions. Importantly, we revised existing EBMT and CIBMTR data collection forms to align with these harmonized definitions that will facilitate research and international collaboration among transplant researchers and across transplant registries.

Umbilical Cord Blood Transplantation for Fanconi Anemia With a Special Focus on Late Complications: a Study on Behalf of Eurocord and SAAWP-EBMT

Hematopoietic cell transplantation (HCT) remains the sole available curative treatment for Fanconi anemia (FA), with particularly favorable outcomes reported after matched sibling donor (MSD) HCT. This study aimed to describe outcomes, with a special focus on late complications, of FA patients who underwent umbilical cord blood transplantation (UCBT). In this retrospective analysis of allogeneic UCBT for FA performed between 1988 and 2021 in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers, a total of 205 FA patients underwent UCBT (55 related and 150 unrelated) across 77 transplant centers. Indications for UCBT were bone marrow failure in 190 patients and acute leukemia/myelodysplasia in 15 patients. The median age at transplantation was 9 years (range, 1.2 to 43 years), with only 20 patients aged >18 years. Among the donor-recipient pairs, 56% (n = 116) had a 0 to 1/6 HLA mismatch. Limited-field radiotherapy was administered to 28% (n = 58) and 78% (n = 160) received a fludarabine (Flu)-based conditioning regimen. Serotherapy consisted of antithymocyte globulin (n = 159; 78%) or alemtuzumab (n = 12; 6%). The median follow-up was 10 years for related UCBT and 7 years for unrelated UCBT. Excellent outcomes were observed in the setting of related UCBT, including a 60-day cumulative incidence (CuI) of neutrophil recovery of 98.1% (95% confidence interval [CI], 93.9% to 100%), a 100-day CuI of grade II-IV acute graft-versus-host disease (GVHD) of 17.3% (95% CI, 9.5% to 31.6%), and a 5-year CuI of chronic GVHD (cGVHD) of 22.7% (95% CI, 13.3% to 38.7%; 13% extensive). Five-year overall survival (OS) was 88%. In multivariate analysis, none of the factors included in the model predicted a better OS. In unrelated UCBT, the 60-day CuI of neutrophil recovery was 78.7% (95% CI, 71.9% to 86.3%), the 100-day CuI of grade II-IV aGVHD was 31.4% (95% CI, 24.6% to 40.2%), and the 5-year CuI of cGVHD was 24.3% (95% CI, 17.8% to 32.2%; 12% extensive). Five-year OS was 44%. In multivariate analysis, negative recipient cytomegalovirus serology, Flu-based conditioning, age <9 years at UCBT, and 0 to 1/6 HLA mismatch were associated with improved OS. A total of 106 patients, including 5 with acute leukemia/myelodysplasia, survived for >2 years after UCBT. Nine of these patients developed subsequent neoplasms (SNs), including 1 donor-derived acute myelogenous leukemia and 8 solid tumors, at a median of 9.7 years (range, 2.3 to 21.8 years) post-UCBT (1 related and 8 unrelated UCBT). In a subset of 49 patients with available data, late nonmalignant complications affecting various organ systems were observed at a median of 8.7 years (range, 2.7 to 28.8 years) post-UCBT. UCB is a valid source of stem cells for transplantation in patients with FA, with the best results observed after related UCBT. After unrelated UCBT, improved survival was observed in patients who underwent transplantation at a younger age, with Flu-based conditioning, and with better HLA parity. The incidence of organ-specific complications and SNs was relatively low. The incidence of SNs, mostly squamous cell carcinoma, increases with time. Rigorous follow-up and lifelong screening are crucial in survivors of UCBT for FA.

Current challenges in cell and gene therapy: a joint view from the European Committee of the International Society for Cell & Gene Therapy (ISCT) and the European Society for Blood and Marrow Transplantation (EBMT)

Cell and gene therapy poses evolving challenges. The current article summarizes the discussions held by European Regional Committee of the International Society for Cell & Gene Therapy and the European Society for Blood and Marrow Transplantation (EBMT) on the current challenges in this field, focusing on the European setting. This article emphasizes the imperative assessment of real-world cell and gene therapy activity, advocating for expanded registries beyond hematopoietic transplantation and chimeric antigen receptor–T-cell therapy. Accreditation's role in ensuring standardized procedures, as exemplified by JACIE (The Joint Accreditation Committee of ISCT-Europe and EBMT), is crucial for safety. Access to commercial products and reimbursement variations among countries underscore the need for uniform access to advanced therapy medical products (ATMPs). Academic product development and point-of-care manufacturing face barriers to patient access. Hospital Exemption's potential, demonstrated by some initial experiences, may increase patient accessibility in individual situations. Regulatory challenges, including the ongoing European ATMPs legislation review, necessitate standardized criteria for Hospital Exemption and mandatory reporting within registries. Efforts to combat unproven therapies and fraud involve collaboration between scientific societies, regulatory bodies and patient groups. Finally, is important to highlight the vital role of education and workforce development in meeting the escalating demand for specialized professionals in the ATMP field. Collaboration among scientific societies, academic institutions, industry, regulatory bodies and patient groups is crucial for overcoming all these challenges to increase gene and cell therapy activity in Europe.

Analysis of laboratory parameters before the occurrence of hepatic sinusoidal obstruction syndrome in children, adolescents, and young adults after hematopoietic stem cell transplantation

PurposeHepatic sinusoidal obstruction syndrome (SOS) is a serious complication following hematopoietic stem cell transplantation (HSCT) in which early diagnosis improves patient outcome. The aim of our study was to detect laboratory parameters following HSCT that can predict the occurrence of SOS.MethodsThis retrospective study included 182 children, adolescents, and young adults who underwent allogeneic or autologous HSCT for the first time (median age 7.2 years). The diagnosis of SOS was based on the pediatric criteria of European Society for Blood and Marrow Transplantation (EBMT). We investigated 15 laboratory parameters after HSCT before the onset of SOS.ResultsThe overall incidence of SOS was 14.8%. SOS developed in 24 of 126 allogeneic (19.1%) and in 3 of 56 autologous (5.4%) HSCT patients at a median time of 13 days after HSCT. We observed a low SOS mortality rate of 11.1% within 100 days after HSCT. International normalized ratio (INR) ≥ 1.3, activated partial thromboplastin time (aPTT) ≥ 40 s, reptilase time ≥ 18.3 s, factor VIII ≤ 80%, antithrombin III ≤ 75%, protein C ≤ 48%, D-dimer ≥ 315 µg/L, bilirubin ≥ 9 µmol/L, and ferritin ≥ 3100 µg/L showed significant associations with the onset of SOS in the univariate analyses. In the multivariate analysis, INR ≥ 1.3 [odds ratio (OR) = 8.104, p = 0.006], aPTT ≥ 40 s (OR = 10.174, p = 0.001), protein C ≤ 48% (OR = 5.215, p = 0.014), and ferritin ≥ 3100 µg/L (OR = 7.472, p = 0.004) could be confirmed as independent risk factors after HSCT before SOS. If three of the four significant cut-off values were present, the probability of developing SOS was more than 70%. The probability of SOS was 96%, if all four laboratory parameters were changed according to the cut-off values. The values of factor XIII, von Willebrand factor (vWF), von Willebrand factor activity (vWF activity), protein S, fibrinogen, and alanine aminotransferase (ALT) were not relevant for the occurrence of SOS.ConclusionIn summary, the laboratory parameters INR, aPTT, protein C, and ferritin were very useful to predict the occurrence of SOS. In addition, this is the first report on a significant association between SOS and high values of INR and aPTT after HSCT before SOS.

Higher cyclosporine-A concentration increases the risk of relapse in AML following allogeneic stem cell transplantation from unrelated donors using anti-thymocyte globulin

Cyclosporine-A (CsA) is used to prevent acute graft-versus-host disease (aGvHD). European Society for Blood and Marrow transplantation (EBMT) recommends a CsA target serum concentration of 200–300 µg/L during the first month after allogeneic hematopoietic stem cell transplantation (HSCT). With this study, we investigated whether a median CsA concentration > 200 µg/L (CsAhigh) the first month after HSCT, compared to ≤ 200 µg/L (CsAlow), increased the relapse risk of acute myloid leukemia (AML), using unrelated donors (URD) and antithymocyte globulin (ATG). Data was collected from 157 patients with AML, transplanted 2010–2016. The cumulative incidence of relapse (CIR) at 60 months was 50% in the CsAhigh versus 32% in the CsAlow group (p = 0.016). In univariate analysis, CsAhigh versus CsAlow (p = 0.028), 10-unit increase of CsA as a continuous variable (p = 0.017) and high risk disease (p = 0.003) were associated with higher CIR. The results remained after adjusting for disease risk. Death following relapse occurred more frequently in the CsAhigh group (p = 0.0076). There were no significant differences in rates of aGvHD, chronic GvHD (cGvHD), EBV/CMV-infections or overall survival (OS) between the two groups. In conclusion, we found that a median CsA concentration > 200 µg/L, the first month after HSCT, results in higher CIR of AML when combined with ATG.

Graft-Versus-Host Disease (GvHD) and Steroid-Refractory GvHD after Allogeneic Hematopoietic Stem Cell Transplantation: A Large Real-World EBMT-Based Epidemiology and Treatment Pattern Study

Introduction: Graft-versus-host disease (GvHD) is a multi-systemic disorder affecting patients who undergo allogenic hematopoietic stem cell transplantation (allo-HSCT) and is associated with considerable morbidity and mortality both in its acute (a) and chronic (c) forms, particularly in patients with steroid-refractory (SR)-GvHD (Flinn AM and Gennery AR. Fac Rev 2023).Given the lack of real-life data on GvHD, this study was conducted using a large European database with the objective to provide evidence on the epidemiology and treatment patterns in patients with aGvHD, cGvHD, and SR-GvHD. Methods: This retrospective, observational cohort study was conducted between July 1, 2014 and December 31, 2020 in allo-HSCT patients registered to the European Society for Blood and Marrow Transplantation (EBMT) database. Male or female patients aged ≥12 years at index (≥18 years for SR-GvHD and ruxolitinib [RUX] cohorts) who had received ≥1 allo-HSCT during this study period (January 1, 2017 to July 1, 2019 for SR-GvHD and RUX cohorts) were included in the study population. The EBMT cohort included all allo-HSCT patients, irrespective of GvHD development post-transplant (Tx). The primary objective was to assess the cumulative incidence of aGvHD and cGvHD in patients from the EBMT cohort who met the inclusion criteria. Overall survival of patients up to 60 months was also assessed in the EBMT cohort. The SR-GvHD cohort comprised a sub-selection of GvHD patients (from selected EBMT centers) who were diagnosed with SR-aGvHD, SR-cGvHD, or both, some receiving RUX as treatment; from the SR-GvHD cohort, a sub-selection of patients who had been treated with RUX for aGvHD and/or cGvHD, irrespective of treatment line, were included in the RUX cohort. Results:In the EBMT database, 60,140 patients had received an allo-HSCT. Most patients (94.5%) underwent 1 allo-HSCT, the remaining had &amp;gt;1 procedure. The EBMT cohort included a higher proportion of male patients between 50 and 69 years (Table 1). The main indication for allo-HSCT was acute leukemia. At the time of Tx, most patients were in their early disease stage and had unrelated donors(Table 1). The cumulative incidence of aGvHD was 27.9% and 27.6%, 4 months after first and second Tx, respectively. The cumulative incidence of cGvHD was 37.4% and 29.7%, 60 months after first and second Tx, respectively. aGvHD was of grade 2-4 in 27.1% of patients, and the most affected organ was skin (33.6%, grade 2-4: 19.5%) followed by liver (4.0%, grade 2-4: 2.3%) and gut (4.6%, grade 2-4: 2.8%); however, organ involvement was not collected in many patients. The cGvHD was limited (13.6%), extensive (14.7%) or of unknown grade (3.1%). Graft failure occurred in 5.9% of patients. The overall survival of EBMT cohort patients at 60 months was 53.1% with a median follow-up time of 32.9 months. The most frequent cause of death was relapse/progression (30.6%) followed by infection (27.1%) and GvHD (19.1%). The EBMT registry contains more SR-GvHD patients but only for subset of 292 SR-GvHD patients, additional information was obtained, of which 37 (34.6%) patients were treated with RUX and 70 (65.4%) with other second-line (2L) treatment for SR-aGvHD. For SR-cGvHD, 59 (31.9%) received RUX and 126 (68.1%) other 2L treatment. Baseline characteristics were comparable between SR-GvHD and the EBMT cohort (Table 1). Within SR-GvHD treatment groups, overall, the baseline characteristics were comparable across RUX and other 2L, and consistent with the EBMT and SR-GvHD cohorts. Compared with other 2L treatment, a slightly higher proportion of RUX-treated patients were females in SR-aGvHD cohort and males in SR-cGvHD cohort. While the most common first-line treatment for aGvHD in both RUX and the other group was methylprednisolone, for SR-cGvHD, it was prednisone+cyclosporine in RUX and prednisone in the other group. Conclusion:This large retrospective real-world evidence study from the EBMT reports on patients with GvHD after allo-HSCT. The cumulative incidence of aGvHD at 4 months post-Tx and cGvHD at 60 months was similar after the first or the second Tx. Though this study provides valuable insights on the epidemiology and treatment patterns of SR-GvHD patients, interpretation of these data is limited due to the small sample size of RUX and other treatment groups compared with the EBMT cohort.

Hematopoietic Stem Cell Transplantation for DLBCL: 55,000 Cases from EBMT As a Comparator for CAR T-Cells

Introduction: Autologous (auto-HSCT) and allogeneic (allo-HSCT) stem cell transplantation represent established treatments for patients (pts) with diffuse large B-cell lymphomas (DLBCL). Transplant modalities and results substantially changed over time. Due to the favorable data reported for chimeric antigen receptor T-cell (CART) treatment and other more targeted drugs, the landscape of transplantation for DLBCL is rapidly changing. We provide long-term data for DLBCL transplants reported to the European Society for Blood and Marrow Transplantation (EBMT) over 30 years as a comparator to CAR T-cell therapies. Methods: We conducted a registry-based analysis of auto- and allo-HSCT activities in Europe and other countries reporting to EBMT in patients with DLBCL treated between 1990 and 2022. Patients meeting the following criteria were included: age≥18 years, diagnosis of DLBCL, auto-HSCT as first HSCT or allo-HSCT either as first HSCT or after auto-HSCT. For transplants reported between 1990-2019, information on modalities and outcomes were retrieved from the EBMT database. CART numbers from the first CART treatment reported to EBMT until 2022 were also collected. Results: In total, 50,776 patients received an auto-HSCT and 5,282 an allo-HSCT between 1990 and 2022. Numbers for auto-HSCT increased from 1,021 in 1990-1994 to a maximum of 2,385 in 2019; the number of allo-HSCT rose from 45 to 305 for these time periods. After 2019, transplant numbers experienced a sharp decline with only 1,548 auto- and 124 allo-HSCT performed in 2022, Conversely, the number of CART consistently increased since the first EBMT-recorded infusion in 2014, rising from 537 in 2019 to 809 in 2022. For detailed analyses, 38,979 auto-HSCT and 4,100 allo-HSCT pts (1,753 allo-HSCT as 1 st HSCT; 2,347 after auto-HSCT) between 1990 and 2019 were identified. Important trends for auto-HSCT were an increase of median age at HSCT [42.0yr (1990-1994) to 57.4yr (2015-2019), p&amp;lt;.0001] and better performance status ≥80% [91.3% (1990-1994) vs 93.0%(2015-2019), p=.006]. Peripheral blood (PB) became the dominant stem cell source for auto-HSCT in 1994; numbers of patients prepared with total body irradiation decreased [16.5% (1990-1994) to 0.4% (2015-2019), p&amp;lt;.0001]. For allo-HSCT pts, the following trends emerged: significant increase in median age [35.8yr (1990-1994) to 53.0yr (2015-2019), p&amp;lt;.0001], adoption of PB as the main stem cell source in 1998 and a substantial shift towards reduced intensity conditioning [0% (1990-1994) to 60.6% (2015-2019), p&amp;lt;.0001]. The proportion of unrelated donors and haploidentical donors significantly increased over time [0% (1990-1994) vs 51.2% (2015-2019), p&amp;lt;.0001 and 0% vs 16.2%, p&amp;lt;.0001]. With a median follow-up of 3.7yr (range 0-30.8yr) for autografted pts, 3-yr overall survival (OS) significantly improved over time [57% (1990-1994) to 71% (2015-2019), p&amp;lt;.001], the relapse rate (RI) declined [50% (1990-1994) to 36%(2015-2019), p&amp;lt;.001], but non-relapse mortality (NRM) remained at 4%. Auto-HSCT patients transplanted in first CR/PR between 2016 and 2019 showed superior outcomes compared to pts treated in second or later CR/PR [3-yr PFS: 69% vs 56%, p&amp;lt;.001; 3-yr OS: 79% vs 69%, p&amp;lt;.001]. For allo-HSCT recipients, with a median follow-up of 4.7yr (range 0-28.6yr), significant improvements were noted for 3-yr OS [35% (1990-1999) to 46% (2015-2019), p&amp;lt;.001)], 3-yr PFS ( p&amp;lt;.001) as well as 3-yr RI ( p&amp;lt;.005). However, 1-yr NRM only improved numerically [30% (1990-1994) to 20% (2015-2019), p=.21]. Conclusions: With more than 50,000 patients analyzed, we provide a comprehensive overview of changes in transplantation modalities and results over more than 30 years. We observed major changes in clinical characteristics and substantial improvements in all major outcome parameters. Patients became increasingly older and medically fit and were transplanted earlier in the course of disease. OS and PFS significantly increased, relapse incidence decreased, NRM did not show major evolution, all supposedly attributable to better patient selection and supportive care. With CART entering the clinical arena, the numbers of transplants for DLBCL sharply decreased. Auto- and allo-HSCT remain important modalities for pts failing CART or in countries where CART are not readily available. The outcomes reported here may serve as real-world benchmark data when new modalities like CART are considered.

Impact of Age on Outcome in Newly Diagnosed Multiple Myeloma Patients Undergoing Upfront Autologous Hematopoietic Cell Transplantation from the Worldwide Network for Blood and Marrow Transplantation Global Study

Background ： Induction therapy with proteasome inhibitors and immunomodulatory agents followed by autologous hematopoietic cell transplantation (HCT) is considered standard of care in front line multiple myeloma (MM) treatment. Utilization of autologous HCT is increasing worldwide in younger and older patients in light of improvements in supportive care and infrastructure. However, global perspectives on patterns of patient age and the impact of age on outcomes in this population are scarce. In the current analysis of global registry data, we focused on the age distribution and the association of age with outcomes after HCT worldwide. Methods: Data were provided by the Worldwide Network for Blood and Marrow Transplantation through the European Society for Blood and Marrow Transplantation (EBMT), the Center for International Blood and Marrow Transplantation (CIBMTR), the Australia and New Zealand Transplant and Cellular Therapy Registry (ANZTCTR), the Asian Pacific Blood and Marrow Transplant Group (APBMT), the Eastern Mediterranean Blood and Marrow Transplant Group (EMBMT), the Latin American Bone Marrow Transplant group (LABMT), and the Ottawa hospital myeloma registry. The study included newly diagnosed MM patients transplanted between 2013 and 2017. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS), incidence of relapse, and non-relapse mortality (NRM). The probability of OS and PFS was estimated based on the Kaplan-Meier method and differences were analyzed using the log-rank test. The incidences of relapse and NRM were modeled using the crude cumulative incidence estimator and compared between groups with Gray's test. Multivariate analyses were performed using Cox (cause-specific) proportional hazards models including a random effect for country. Age at HCT was modeled as a categorical variable (18-39, 40-64, 65-69, 70-74, and ≥75 years). Models further included patient sex, year of HCT, stage of disease at HCT, Karnofsky score, myeloma subclassification, conditioning dosage, interval between diagnosis and HCT, HCT comorbidity index, ISS at diagnosis, and cytogenetic risk score. Results: In total, 61,725 patients were included in this study; 37,459 (60.1%), 16,217 (26.3%), 3,164 (5.1%), 3,122 (5.1%), 543 (0.9%), 524 (0.8%), 339 (0.5%), 188 (0.3%), and 169 (0.3%) from EBMT, CIBMTR, ANZTCTR, Japan (APBMT), EMBMT, Taiwan (APBMT), LABMT, Ottawa, and Malaysia (APBMT), respectively. The median age at HCT was 60.8 (interquartile range: 54.6-65.8) years. The percentage of patients in the age groups 18-39, 40-64, 65-69, 70-74, and ≥75 years, varied considerably; 2%, 68.9%, 21.8%, 6.5%, and 0.8%, respectively (Table 1). The proportion of &amp;lt;40 years was higher in Malaysia, LABMT, and EMBMT (4-6%) compared to EBMT, CIBMTR, Japan, and ANZTCTR (2%). In contrast, the proportion of patients ≥65 years was higher in EBMT, CIBMTR, ANZTCTR, and Japan (&amp;gt;20%) compared to Malaysia, LABMT, and EMBMT (7-13%). The following patterns were observed in the age groups 18-39, 40-64, 65-69, 70-74, and ≥75 years, respectively. Melphalan 200 mg/m 2 for conditioning was used more frequently in younger patients (78.4%, 75.4%, 63.2%, 40.6%, and 28.3%, respectively). In 60.7% of the group ≥75 years, a lower dose of melphalan 140 mg/m 2 was chosen. OS was lower with older age (p&amp;lt;0.001) and was 86%, 83%, 81%, 78%, and 75% at 3 years, respectively (Figure and Table 1). PFS was similarly associated with older age (56%, 51%, 50%, 47%, and 45% at 3 years, respectively (p&amp;lt;0.001)). The cumulative incidence of relapse was not significantly different (15%, 16%, 15%, 16%, and 16% at 1 year, respectively (p=0.74)), but the cumulative incidence of NRM was higher with older age (p&amp;lt;0.001) and was 0%, 1%, 2%, 2%, and 4% at 1 year, respectively. On multivariate analysis, older age was associated with lower OS (overall p&amp;lt;0.0001), lower PFS (overall p=0.003), and higher NRM (overall p&amp;lt;0.0001), but not with the risk of relapse (overall p=0.79). Conclusions: There is considerable global variability in the age distribution of patients receiving HCT. Globally, 2% of patients receiving front line HCT for myeloma are aged &amp;lt;45 and 0.8% are &amp;gt;75 years. Advancing age was a significant risk factor for OS and PFS due to differences in NRM, but even in patients &amp;gt;75 years NRM was very low.

Outcomes and Late Complications after Umbilical Cord Blood Transplantation for Fanconi Anemia: A Study on Behalf of Eurocord and Severe Aplastic Anemia Working Party - EBMT

Fanconi Anemia (FA) remains a disease with poor prognosis for which hematopoïetic cell transplantation (HCT) offers the only available curative option, with particular good results observed after matched sibling donor transplants. This study aimed to assess transplant outcomes and describe late complications in a large cohort of patients with FA who underwent umbilical cord blood transplantation (UCBT) in the European Society for Blood and Marrow Transplantation (EBMT) affiliated centres. Methods: We retrospectively reviewed all cases of FA whoreceived UCBT as first allogeneic transplant between 1988 and 2021. Data on late effects were collected with a questionnaire completed by transplant centres for patients who survived &amp;gt;2 years (y) after UCBT. Results: A total of 205 patients with FA received UCBT (55 related and 150 unrelated) in 77 transplant centres. Indications for UCBT were bone marrow failure in 191 patients (BMF, 93%) and acute leukemia/myelodysplasia in 14 patients (AL/MDS, 7%). Median age at transplant was 8.8 y (1.2-43) and 90% (n=185) were children &amp;lt;18y old. Graft sources included single (n=164), double (n=23) or UCB co-infused with other cell sources (n=18). Recipients and UCB pairs had 0-1/6 HLA mismatches in 48% (n=99). Most patients (n=196, 97%) received reduced intensity conditioning. Flu Cy-based (n=116; 57%) and Bu Cy ± Flu (n=48, 23%) were the most frequently used regimens. Total body irradiation (TBI) or total lymphoid irradiation (TLI) were administered to 28% (n=58) of patients at doses &amp;lt; 8 Gy. Serotherapy consisted of anti-thymocyte globulin (ATG, n=159; 78%) or alemtuzumab (n=8; 4%). Graft- vs-host disease (GVHD) prophylaxis was mainly based on CSA ± steroids (65%) or MMF ± steroids (32%). Median follow-up was 88 months (3-345). The cumulative incidence (CI) of neutrophil recovery was 79% (67-79) at day 60,with a median time of 20 (7-62) days (d). The 100d CI of grades II-IV acute GVHD (aGVHD) was 29.8% (24-37). The 5y CI of chronic GVHD (cGVHD) was 30.4% (24-38) with 12% extensive forms. The 1y-CI of non-relapse mortality (NRM) was 37.4% (31-45). At 5y follow-up, event-free survival (EFS) was54% ± 3 and overall survival (OS) was 55% ± 3. In multivariate analysis, HLA matching 0-1/6 (HR 2.0, p=0.01) and related UCBT (HR 2.4; p=0.001) were predictive of better engraftment. None of the tested factors had statistical significant impact on incidence of aGVHD or cGVHD. Negative recipient CMV serology (HR 0.29, p=0.003) and transplant year ≥2013 (HR 0.29; p=0.004) were the only factors associated with improved OS. Both factors were also predictive of better NRM and EFS. Fifty-one recipients of UCBT (3 related and 48 unrelated) experienced primary graft failure (GF). Twenty-six patients underwent subsequent allogeneic HCT within a median of 1.8 months (0.8 -6.8) after first UCBT. Seven subsequent HCT recipients (1 related bone marrow (BM), 1 related peripheral blood, 1 unrelated BM, and 4 unrelated UCB) were alive at last follow-up. Second neoplasms developed in 8 patients (4%) within a median interval of 9.7 y post-UCBT (3.6-13.5) and included one donor derived-AML and 7 solidtumors (1 skin, 2 upper GI, 4 oral cavity) . A totalof93 patients (45%) died from transplant related toxicity (n=85, including 42 who died after GF), second neoplasms (n=6) or unknown cause (n=2). Survival &amp;gt;2y was observed in 106 patients, but comprehensive data for late transplant complications were available only in 45 long-term survivors. For these 45, median post transplant follow-up was 8.7y (2.7-28.8). Late organ impairments ( table 1) included: endocrine disorders (32%), lung (24%), eyes (20%), kidneys (20%), immune system (18%), liver (16%), musculoskeletal, and bone (16%) diseases. Other dysfunctions involved: oral mucosa (11%), neurologic system (7%), gastrointestinal (4%), genital (13%) and urinary tracts (4%). Cardiovascular complications were rare (1 case of chronic pericarditis). Conclusion: Improved outcomes have been observed in recent years in FA patients receiving unrelated UCBT likely due to improved conditioning regimens, effective post-transplant care and better HLA parity. With longer survival, late multi-organ complications are observed. Identification of risk factors and life-long screening for early management of organ impairments and second neoplasms are mandatory to improve quality of life of transplant survivors and decrease late mortality.

UM171 Expanded Cord Blood Transplantation Outcomes Compare Favorably to All Different Stem Cell Sources: An EBMT Registry Case-Control Analysis

Background: Cord blood (CB) transplantation (CBT) has several advantages compared with other graft sources, such as permissive human leucocyte antigen (HLA) mismatches, and low risk of chronic graft-versus-host disease (GVHD) and relapse. However, CBT has fallen into disfavor because of its high risk of non-relapse mortality (NRM) and prolonged hospitalization due to its low cell dose. Furthermore, the need for the rare large cord bloods (CBs) leads to selection of poorly HLA-matched CBs, known to further increase NRM. UM171 is a small molecule that expands hematopoietic stem cells. A phase I-II study of a single UM171-expanded, myeloablative and reduced intensity CBT for patients with high-risk hematologic malignancies who lacked a donor, demonstrated prompt neutrophil engraftment, the ability to use smaller, better HLA-matched CBs, and a low NRM of 5% (Cohen S et al. Lancet Haematol 2020). The aim of the current analysis was to compare outcomes after a UM171 CBT to real-world cohorts of 6 other stem cell sources identified in the European Society for Blood and Marrow Transplantation (EBMT) registry. Methods: This is a retrospective study comparing 22 adults who received a single UM171-expanded CBT in the phase I-II study between 2016-2018, to 6 cohorts of patients allografted from different stem cell sources and reported to the EBMT registry. Control patients were eligible if they had received a myeloablative or reduced intensity allogeneic transplant for a hematologic malignancy in Europe during 2010-2021, were between the ages of 18-65 years, and had a Karnofsky performance status (KPS) score ≥70. The different donor control cohorts were: 1) CB, single or double units, with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) for GVHD prophylaxis, 2) 10/10 HLA-matched unrelated donor (MUD) peripheral blood stem cells (PBSC) with a CNI and MMF or methotrexate (MTX), 3) 10/10 MUD bone marrow (BM) with a CNI and MMF or MTX, 4) 9/10 HLA-MUD BM or PBSC (9/10 UD), 5) T cell replete haploidentical donor (haplo) BM or PBSC, and 6) matched sibling donor (MSD) BM or PBSC. Exclusion criteria included in vitro manipulated grafts and CBT recipients who received anti-thymocyte globulin or alemtuzumab. Patients were directly matched for disease and status at transplant and propensity score matching was used for prior allograft, age, KPS, and conditioning regimen. Endpoints included engraftment, GVHD, NRM, relapse, progression-free survival (PFS), overall survival (OS), and GVHD-free relapse-free survival (GRFS). The EBMT attempted to identify 3 controls for each patient. If no control was identified for a UM171 patient, the latter was excluded from the analysis. Results: Between 17 and 21 UM171 CB patients were compared to 36 to 62 controls depending on the donor group as 1-3 controls could not be identified for each patient (Table 1). Median follow-up for the UM171 group was 36 months and generally longer for the controls. Neutrophil engraftment with UM171 CB was similar to all donor groups except slower for CB and MUD BM. Platelet engraftment was consistently slower for UM171 CB except when compared to conventional CB. The incidence of severe acute GVHD was similar across all donor groups. As there was no severe chronic GVHD in the UM171 group, the latter was associated with less extensive/severe chronic GVHD compared to MUD (PBSC and BM) and MSD. There was a trend towards lower NRM for UM171 CB compared to haplo and 9/10 UD but it did not reach statistical significance. PFS, OS and GRFS were all better with UM171 CB compared to haplo. Finally, GRFS was improved with UM171 CB when compared to MUD PBSC (Figue 1), 9/10 UD, and MSD. Conclusions: This registry matched case-control analysis demonstrated real-word evidence suggesting UM171-expanded CBT recipients have improved outcomes compared to other donor types. More specifically and due to the absence of severe chronic GVHD with UM171 CB, GRFS was better with UM171 CB when compared to other graft sources except for CB and MUD BM. Also, OS and PFS were superior with UM171 CB compared to haplo donors. Limitations of this study included the small number of UM171 patients, the inability to identify controls for each case, and certain missing data for the controls. UM171 expansion of CB appeared to achieve the desired outcome of maintaining benefits of CB while removing its disadvantages. Thus, prospective randomized studies are warranted to confirm these results.

Pre-Transplant Somatic Co-Occurring Mutations (by next generation sequencing) in Acute Myeloid Leukemia: Frequency and Impact on Clinical Outcomes after Allogeneic Hematopoietic Cell Transplantation - a Large Study on Behalf of the EBMT Acute Leukemia Working Party

Background: Acute myeloid leukemia (AML) is a very heterogeneous hematological malignancy, which includes numerous genetically defined subsets. The genomic classification of AML with the identification of mutations in transcription factors, epigenetic modifiers, spliceosome, cohesin complex, and signaling pathways has led to a more accurate risk stratification model. The main genetic aberrations included in the European LeukemiaNet (ELN) 2022 classification are NPM1 (risk group according to karyotype and FLT3-ITD status), FLT3-ITD (intermediate risk), bZIP in-frame mutated CEBPA (favorable risk), and RUNX1, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 and TP53 mutations (all belonging to the adverse risk group). In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), the frequency and prognostic value of different gene-gene interactions has not been studied and may differ from that of patients treated with chemotherapy alone. We aimed at evaluating, through the European Society for Blood and Marrow Transplantation (EBMT) database, the frequency and impact of different recurrent somatic mutations, either alone or in association, on prediction of relapse and survival in patients receiving allo-HSCT. Methods: This is a retrospective, registry-based, multicenter analysis from the EBMT with the approval of the EBMT Acute Leukemia Working Party. Adult patients aged more than 18 years with a diagnosis ofAML who received an allo-HSCT between 2013-2022, with an available genetic profile determined at diagnosis by next generation sequencing (NGS) were included. Results: We identified 836 allografted AML patients who had NGS performed at diagnosis. Most of these patients had de novo AML (88%), with a median age of 53 years (range: 18-78 years). Karyotype was favorable in 7%, intermediate in 69% and adverse in 24% of patients. At transplant, 74% of patients were in first remission (CR1) and 13% in CR2. The most frequent detectable mutations by frequency were DNMT3A (33%), FLT3 (29%), NPM1 (29%), TET2 (28%), NRAS (23%), RUNX1 (22%), WT1 (22%), BCOR (19%), ASXL1 (17%), IDH2 (17%), IDH1 (15%), SRSF2 (13%), STAG2 (12%), CEBPA (11%), TP53 (10%), KRAS (10%), and PTPN11 (10%) . By multiple correspondence analysis, two independent groups of co-occurring mutations were identified, the first group included DNMT3A, NPM1 and FLT3, the second group included ASXL1, SRSF2 and RUNX1. Outcome analysis was performed on the subset of 298 patients allografted in CR1 with available data for the aforementioned six genes ( DNMT3A, NPM1, FLT3, ASXL1, SRSF2 and RUNX1). Most of these patients had de novo AML (90%), with a median age of 53 years (range: 19-75 years). Patients received primarily reduced intensity conditioning (58%) and peripheral blood stem cells (93%) from matched sibling donors (35%), matched unrelated (28%), and haploidentical donors (21%). Seventy percent of these patients had intermediate-risk cytogenetics, while 27% were classified as adverse-risk. Median follow up calculated by the reverse Kaplan-Meier method was 2.5 years. Overall, the 2-year relapse incidence (RI), leukemia-free survival (LFS) and overall survival (OS) were 24%, 62% and 69%, respectively. When outcome analysis was performed according to the presence or absence of single mutations, none of the six mutations significantly affected RI or LFS. The 2-year OS was positively affected by the presence of NPM1 mutation (78% vs 66%; p=0.02) and FLT3 (79% vs 65%, p=0.01) but not significantly affected by the other 4 mutations. When mutations were investigated in groups, the 2-year RI, LFS and OS were 24%, 70% and 78%, respectively, for patients with NPM1 mutation regardless of other co-mutations, 35%, 56% and 69% for patients with FLT3-ITDand/or DNMT3A mutation, wild type NPM1, regardless of other co-mutations, 17%, 70% and 74% for patients with RUNX1 and/or ASXL1 and/or SRSF2 mutation without FLT3-ITD and with wild type NPM1 and wild type DNMT3A and 20%, 56% and 61% for patients with all six genes unmutated. Conclusion: NGS at diagnosis can be extremely useful in risk stratification of AML patients undergoing allo-HSCT, potentially allowing adequate post-transplant interventions. Notably, the 2-year LFS of 70% for patients harboring RUNX1 and/or ASXL1 and/or SRSF2 mutation indicates that allo-HSCT can overcome the adverse risk associated with these somatic mutations at diagnosis.

Practice Patterns of Transplant Centers Regarding Maintenance Treatment Post Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia: A Survey on Behalf of the EBMT Acute Leukemia Working Party

Introduction: Disease recurrence in acute myeloid leukemia (AML) remains the major reason of allogeneic hematopoietic cell transplantation (allo-HCT) failure. Strategies to reduce the risk of relapse such as prophylactic pharmacologic interventions post allo-HCT are more frequently applied by some transplant physicians, especially after the growing evidence of its efficacy and tolerability. Others are still being skeptical regarding its implementation due to difficulty proving efficacy by large randomized trials, or concerns of long-term toxicities. The aim of this study was to conduct a survey among the European Society for Blood and Marrow Transplantation (EBMT)-affiliated transplant centers to identify clinical practice patterns regarding maintenance treatment post-allo-HCT in AML. Methods: After the approval of the board of the Acute Leukemia Working Party (ALWP), EBMT-affiliated centers received by email a questionnaire-based survey between January and June 2023. The questionnaire consisted of 13 questions assessing clinical practices regarding maintenance treatment post allo-HCT in AML, specifically the indications of maintenance, the type, the drug used, and the duration of the treatment. Results: A total of 115 (out of 424) EBMT-affiliated centers from 31 countries responded to the survey with a response rate of 27.12%. Overall, 102 (88.8%) centers implement maintenance strategy whether pharmacological intervention or cellular therapy post allo-HCT in AML, most of the centers (N=67, 58.3%) use it based on a personalized decision, 17 (14.8%) use it routinely, and 18 (15.7%) use it exceptionally. Regarding the indication, the majority of the centers recommend maintenance treatment for AML patients in second remission or beyond (N=64, 62.7%) or in AML patients in first remission with high risk of relapse based on cytogenetic or molecular data (N=61, 59.8%), whereas 34 (33.3%) centers recommend it only for FLT3-mutant disease, and 11 (10.8%) centers in all patients regardless of the risk of disease. The majority of centers (N=77, 75.5%) use a combination of pharmacologic and cellular therapies, and 20 (19.6%) centers use only pharmacologic therapies. Among centers using pharmacologic therapies, 62 (63.9%) use hypomethylating agents (HMA) (azacitidine N=51 (82.3%), decitabine N=6 (9.6%), HMA with venetoclax N=23 (37%), HMA with donor lymphocyte infusion (DLI) N=38 (61%), or a combination of modalities in 42 (67.7%)). In general, most centers (N=35; 87.5%) do it pre-emptively either minimal residual disease (MRD) driven or chimerism driven, whereas 22 (55%) centers do it prophylactically. The majority of centers continue HMA for one-year duration (N=37, 59.7%), 15 (24.2%) for two years and only 10 (16.1%) continue until disease recurrence or toxicity. Out of 97 responding centers regarding the use of FLT3 inhibitors as maintenance, 93 (95.9%) are implementing this strategy. The most common choice was sorafenib in 82/93 (88.2%) centers, midostaurin in 28 (30%), and gilteritinib in 30 (32.2%). Among these, 56 (83.5%) centers use FLT3 inhibitors as prophylaxis whereas 28 (41.7%) use a pre-emptive approach. The preferred maintenance duration was for two years in 51 (54.8%) centers, followed by one-year duration in 30 (32.3%) centers, continuous until disease relapse or toxicity in 9 (9.7%) centers, and for five years in only 3 (3.2%) centers. Novel agents are used in 71 (70.2%) centers as maintenance either alone or in combination with HMA, of them 52 (73.2%) use venetoclax, and 13 (13.2%) use enasidenib. Finally, regarding practice patterns, 32 (29.6%) centers claim that maintenance treatment is part of their routine practice, 46 (42.6%) only for FLT3 mutant AML. Others are not routinely implementing maintenance because they are still skeptical and need more evidence by randomized clinical trials (N=8), whereas 5 centers are concerned regarding tolerability, and 16 (14.8%) cannot implement because of regulatory restrictions or lack of access. Conclusion: In this survey, the majority of responding EBMT-affiliated transplant centers is implementing post-transplant AML maintenance treatment, predominantly HMA and FLT3 inhibitors. Further studies are needed to clarify the appropriate strategy and duration of maintenance therapy. The study will help the EBMT to incorporate post-transplant strategies as a routine registry capture parameter.

Treosulfan-Based Reduced-Toxicity Conditioning for Elderly Patients with High-Risk Myelodysplastic and Myeloproliferative Disease for Allogeneic Hematopoietic Stem Cell Transplantation

Introduction Allogeneic hematopoietic stem cell transplantation (alloHCT) is the only potential curative treatment for patients (pts) with high-risk myeloid malignancies. Despite advances in the supportive care over the past decades, alloHCT is still associated with significant toxicity, especially in the elderly population. The choice of an adequate conditioning regimen has become essential in order to prevent treatment-related morbidity and mortality. Since myeloablative conditioning (MAC) is mostly restricted to the younger population due to the high toxicity, reduced-intensity conditioning (RIC) provides an alternative solution. However, especially for pts with high-risk disease, a potential increase in the incidence of relapse must be taken into account. The advent of reduced-toxicity conditioning regimens (RTC), mostly based on treosulfan in combination with fludarabine, offers a balance between a favorable toxicity profile and a strong anti-neoplastic effect. Considering the increasing rates of alloHCT among older pts in the past decades, finding the optimal conditioning regimen is still an unmet need for this collective. The objective of this study is to analyze the outcome of pts aged ≥60 years who underwent alloHCT for myelodysplastic or myeloproliferative disease and received a treosulfan-based conditioning. In order to maximize the anti-leukemic effect of the conditioning in this population we chose the myeloablative dose of treosulfan of 14g/m2 daily. Materials and methods We retrospectively analyzed the outcome of adult pts ≥60 years with myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or myelofibrosis (MF) who underwent their first allo-HCT from a matched or mismatched donor over a period of 10 years at the adult Bone Marrow Transplantation Unit of our institution. The conditioning consisted of a combination of treosulfan 14 g/m2/day on days -6 to -4, fludarabine, 30 mg/m2/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0) for MDS and treosulfan, 14 g/m2/day on days -6 to -4, fludarabine, 30 mg/m2/day on days -6 to -3 for CMML and MF. Endpoints of this analysis were engraftment rate (together with time to engraftment), relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM). Continuous variables were illustrated as median values. NRM, RFS and OS for the whole cohort were analyzed with the Kaplan-Meier method and presented as survival functions. Results Between 01/2012 and 12/2022 91 consecutive elderly pts were eligible for this analysis. Patient and transplant characteristics are listed in Table 1. The median follow-up after allo-HCT was 3.12 years (4 months-10.5 years). Median age was 65 years, 76% (n = 69) of patients had an EBMT (European Society for Blood and Marrow Transplantation) risk score of ≥ 4. In 20 of 91 pts (22%) a 9/10 matched unrelated donor was selected, due to the lack of a more suitable donor. The standard graft versus host disease (GVHD) prophylaxis was a combination of calcineurin inhibitors (CNI) +/- mycophenolate mofetil and Anti-T-lymphocyte globulin (ATG) (n= 85, 94%). Neutrophil engraftment was achieved in 98% (n= 89) of pts. The median time to engraftment was 13 days (12, 15). Fourteen of 91 pts (15%) developed severe (grade III-IV) acute GVHD, and 44% (n= 40) had chronic GVHD of any grade. Considering early toxicity, 2 patients of 91 (2%) died before day +30 after alloHCT due to transplant-related toxicity, overall 6 of 91 (7%) in the first 100 days after alloHCT. The 2-year OS was 55% (95% CI, 44.7-.66.2) (Figure 1) and RFS was 48.5% (95% CI, 38.9-60.5). The 2-year NRM was 37% (95% CI, 33.5-39.5). No significant differences have been observed in the outcome of the different disease entities. Main causes of death were infections (n= 15, 32%), GVHD (n=13, 27.7%) and disease relapse (n= 13, 27.7%). Conclusions Our retrospective analysis suggests that a treosulfan-based RTC with myeloablative potential in an elderly and frail population of pts with high-risk myeloid diseases is feasible, with an excellent engraftment rate and a limited early toxicity, and promotes disease control. We report a 2-year NRM of 37%, which was partially due to severe GvHD in a cohort of pts with a relatively high-proportion of mismatched donors (20%). The role of post-transplant cyclophosphamide as backbone of the GvHD prophylaxis of RTC regimes should be further evaluated, in prospective trials.

Clinical and Immunological Factors Associated with Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis Patients

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely recognized as the sole curative treatment for myelofibrosis (MF). However, patients with MF often experience graft function impairment despite successful engraftment and absence of relapse signs. Although it has been reported that poor graft function can have a negative impact on the outcomes of patients with MF after HSCT, the specific factors that can influence poor graft function are not yet clearly understood. In this background, we analyzed various clinical and immunological factors that may contribute to poor graft function after transplantation. The study included 93 patients who underwent HSCT for the treatment of MF at Seoul St. Mary's Hospital between the years 2000 and 2022. By cumulative incidence analysis of poor graft function (death, relapse, graft failure, and loss of chimerism as competing risks), we evaluated which pre-HSCT factors has significant impact on poor graft function after HSCT. The definition of poor graft function and graft failure in this study followed the criteria set by the European Society for Blood and Marrow Transplantation (EBMT). We measured the longitudinal diameter of spleen up to 2 months prior to HSCT, and classified the patients into pre-HSCT splenomegaly (≥ 14cm) or not. Next, we investigated the association of immune-related gene expression signature in bone marrow immune-microenvironment with the occurrence of poor graft function, by performing targeted gene expression profiling and gene set enrichment analysis using a custom NanoString panel composed of 579 immune-related genes in pre- and post-HSCT BM samples from patients with poor graft function and good graft function (total 24 samples). A median age of 93 patients was 57 years, and 55.9% were male. Secondary MF was observed in 30.1% of the cases. Fifty-three (57.0%) received graft from a matched sibling donor graft and 40 (43.0%) from a matched unrelated donor. Sixty-three (67.7%) patients were classified to the pre-HSCT splenomegaly group. In terms of ABO match, 45 (48.4%) patients were matched, 10 (10.8%) had bi-directional mismatch, 17 (18.3%) had major mismatch, and 19 (20.4%) had minor mismatch. The median infused CD34 (+) cell dose was 6.4 x 10^6/kg (Interquartile range 5.3 x 10^6/kg-8.3 x 10^6/kg). In our patients, cumulative incidence of poor graft function after 5 years from HSCT was 32.0% (95% CI: 23.4-42.7). Infused CD34 (+) cell dose, the presence of splenomegaly before HSCT were revealed to have an impact on the occurrence of poor graft function after HSCT. The other significant factor associated with poor graft function was ABO mismatch, in particular, with a substantial difference between matched patients and patients with bi-directional ABO mismatch. (Figure A). In NanoString panel analysis, although the expression of immune-related genes mostly upregulated after HSCT, genes related to processes such as complement system, inflammasomes, phagocytosis and degradation, and MHC class II antigen presentation pathways were significantly downregulated in PGF. Whereas, oxidative stress, inflammasomes, and autophagy pathways were downregulated in GGF (Figure B). In this study, we could observe that a significant proportion of MF patients undergoing HSCT experienced poor graft function. Factors that significantly associated with the occurrence of poor graft function included the CD34 (+) cell dose at the time of HSCT, the presence of splenomegaly before HSCT, and ABO mismatch. Interestingly, distinct gene expression signatures present in IME between pre- and post-SCT in both PGF and GGF. Further research is warranted to investigate the impact of poor graft function caused by these factors on outcomes such as transfusion requirements and quality of life.