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Background: Access to allogeneic haematopoietic stem-cell transplantation (HSCT) remains challenging for older patients (aged >60 years) with acute myeloid leukaemia. We aimed to evaluate the efficacy of venetoclax plus decitabine as first-line therapy and bridge to transplantation in this patient population., Methods: This multicentre, single-arm, phase 2 trial was conducted in 20 Gruppo Italiano Trapianto Midollo Osseo (GITMO) centres in Italy. Patients aged ≥60 and <75 years, with newly diagnosed acute myeloid leukaemia categorised as intermediate or high risk according to 2016 WHO and 2017 European LeukemiaNet, an ECOG performance status of less than 2, and considered fit for allogeneic HSCT were included. Patients received oral venetoclax with a 3-day ramp-up: 100 mg on day 1, 200 mg on day 2, and 400 mg once per day from day 3 of cycle one, and then every 28 days of each cycle (two to four in total). Decitabine was administered intravenously at a dose of 20 mg/m 2 from days 1 to 5 every 28 days. At cycle one, patients were admitted to hospital for a minimum of 24 h, whereas subsequent cycles could be administered on an outpatient basis. Two additional cycles were allowed while waiting for allogeneic HSCT or for those with no response or partial response after cycle two. The primary endpoint was the proportion of patients who had allogeneic HSCT performed during first complete remission, assessed in all patients who received at least one dose of the study medication. This study was registered with ClinicalTrials.gov (NCT04476199, ongoing) and EudraCT (2020-002297-26)., Findings: Between June 1, 2021, and Dec 30, 2022, 93 patients were enrolled and started venetoclax plus decitabine induction (44 [47%] at intermediate risk and 49 [53%] at high risk). The median age was 68·5 (IQR 60·3-74·7). All 93 participants were White, of whom 43 (46%) were female and 50 (54%) were male. The median follow-up was 236 days (IQR 121-506). 64 (69%) of 93 patients reached complete remission and 53 (57%) underwent allogeneic HSCT in complete remission. 53 (83%) of 64 with a complete remission underwent allogeneic HSCT. Five (8%) of 64 patients in complete remission relapsed before transplantation and four died as a consequence. Adverse events (grade ≥3) occurred in 49 (53%) of 93 patients. The most common adverse events were infections (including pneumonia, bacterial sepsis, and SARS-CoV-2 causing seven deaths among 28 [57%] of 49 patients), neutropenia (17 [35%]), thrombocytopenia (two [4%], including one fatal CNS bleeding), and cardiac events (four [8%], including one fatal heart failure). No treatment-related deaths were observed., Interpretation: Venetoclax plus decitabine induction can significantly enhance the feasibility of allogeneic HSCT in older patients with acute myeloid leukaemia who are deemed fit for transplantation., Funding: AbbVie and Johnson & Johnson., Competing Interests: Declaration of interests DR received consulting fees from Medac; honoraria and travel grants from Jazz Pharma, Novartis, MSD, Kite Gilead, and Medac; and has participated in data safety monitoring and advisory board meetings for Novartis, MSD, Kite Gilead, Medac, AbbVie, and Janssen. EB received consulting fees from AbbVie; travel grants from Amgen, Novartis, and AbbVie; and has participated in data safety monitoring and advisory board meetings for Otsuka and Amgen. FO received honoraria from Takeda, Medac, and Kyowa; and travel grants from Roche, Janssen, Kyowa, Takeda, Jazz Pharma, and Medac. RS received a travel grant from Takeda. MaM received honoraria from Novartis, MSD, Astellas Pharma, AbbVie, Takeda, Pfizer, Sanofi, Jazz Pharma, Janssen Cilag, Kite Gilead, Medac, and Bristol Myers Squibb; travel grants from Kite Gilead, Roche, and Janssen Cilag; has participated in data safety monitoring and advisory board meetings for Novartis, Takeda, Kite Gilead, Pfizer, Bristol Myers Squibb, and Janssen Cilag; and served as president of GITMO. CA received honoraria from AbbVie and Jazz Pharma; and has participated in data safety monitoring and advisory board meetings for AbbVie, Jazz Pharma, and Amgen. GB received travel grants from Janssen Cilag and Amgen. AC received honoraria from AbbVie, Menarini (Stemline), Pfizer, Jazz Pharma, and Servier; a travel grant from Jazz Pharma; and has participated in data safety monitoring and advisory board meetings for AbbVie and Menarini (Stemline). CG received consulting fees from AbbVie, Jazz Pharma, Incyte, Bristol Myers Squibb, and Astellas; and a travel grant from Jazz Pharma. PM received honoraria and travel grants from AbbVie and Johnson & Johnson. LG received honoraria from Novartis, MSD, Gilead, AbbVie, Sanofi, and Bristol Myers Squibb; and travel grants from Janssen and AbbVie. CS received honoraria from Jazz Pharma and Kite Pharma; and a travel grant from Jazz Pharma. VR received travel grants from Neovii, Medac, and Jazz Pharma. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is more effective than conventional immunosuppressive therapies (CIT) in improving the outcome of patients with rapidly progressive diffuse cutaneous systemic sclerosis (dcSSc). So far, there is still a paucity of data comparing AHSCT with rituximab (RTX). Aim of the study is to retrospectively compare, in patients with dcSSc, the effectiveness of AHSCT with that of RTX and CIT., Methods: Thirty-five dcSSc AHSCT-treated patients were compared with 29 and 36 matched cases treated with RTX and CIT, respectively. The patients were followed up for 5 years by assessing selected outcome measures every year. Overall survival, modified Rodnan skin score (mRSS), lung function tests (FVC and DLCO), and the revised EUSTAR Activity Index (REAI) were the outcome measures chosen to evaluate the therapy efficacy., Results: AHSCT was significantly more effective than RTX and CIT in prolonging survival, inducing a rapid reduction of the mRSS and REAI and maintaining the baseline level of lung function tests for a longer time. RTX therapy was also superior to CIT in reducing REAI, mRSS and in saving lung function., Conclusion: AHSCT is more effective than both RTX and CIT in prolonging survival and inducing prolonged remission in patients with rapidly progressive dcSSc., (© 2024. The Author(s).)

Abstract: It has been reported in prospective randomized trials that antithymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis has benefits in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with unrelated donors (UDs). However, the optimal GVHD prophylaxis strategy has been challenged recently by the increasing use of posttransplant cyclophosphamide (PTCY). We report from the European Society for Blood and Marrow Transplantation registry the outcomes of 960 patients with myelodysplastic neoplasms who underwent allo-HSCT from UD with PTCY or ATG as GVHD prophylaxis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). The disease characteristics were similar in both groups. Day 28 neutrophil engraftment was significantly better with ATG (93% vs 85%). Over a median follow-up of 4.4 years, the 5-year OS was 58% with PTCY, and 49% in the ATG group. The 5-year PFS was higher for PTCY at 53% vs 44% for ATG. Grade 2 to 4 acute GVHD incidence was lower when PTCY was used (23%), whereas there was no difference in the incidence of chronic GVHD at 5 years. Multivariable analyses confirmed better OS and PFS with PTCY with a hazard ratio (HR) for ATG of 1.32 (1-1.74) and a better PFS for PTCY with a HR for ATG of 1.33. This study suggests that GVHD prophylaxis using PTCY instead of ATG in this setting remains a valid option. Further prospective randomized studies would be essential to confirm these results., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In 2023, the EBMT Practice harmonization and Guidelines Committee partnered with the EBMT Infection Diseases Working Party (IDWP) to undertake the task of delivering best practice recommendations, aiming to harmonize by expert consensus, the already existing definitions and future epidemiological and clinical studies among centers of the EBMT network. To attain this objective, a group of experts in the field was convened. The workgroup identified and discussed some critical aspects in definitions of community-acquired respiratory viruses (CARV) and adenovirus (ADV) infections in recipient of hematopoietic cell transplant (HCT). The methodology involved literature review and expert consensus. For CARV, expert consensus focused on defining infection severity, infection duration, and establishing criteria for lower respiratory tract disease (LRTD). For ADV, the expert consensus focused on surveillance methods and the definitions of ADV infection, certainty levels of disease, response to treatment, and attributable mortality. This consensus workshop provided indications to EBMT community aimed at facilitating data collection and consistency in the EBMT registry for respiratory viral infectious complications., Competing Interests: Declaration of competing interest DA: No conflict of interest to declare. AB: No conflict of interest to declare. SC: No conflict of interest to declare. RdC: Participation in advisory boards for Astra-Zeneca, Astella, Moderna and MSD. Speaker for MSD, Gilead. None of these conflicts were related to this manuscript. RG: speaking honoraria from Biotest, Pfizer, Medac, Neovii and Magenta; none of the mentioned conflicts of interest were related to financing of the content of this manuscript. For non-profit organization, she is a co-chair of the EBMT PH & G committee. PL: Participation in advisory boards for Astra-Zeneca and Moderna. Speaker for MSD. None of these conflicts were related to this manuscript. MM: No conflict of interest to declare. DN: No conflict of interest to declare. FO: Declares no conflict of interest related to this work. For non-profit organization, he is a co-chair of the EBMT PH & G committee. JLP: Declares no conflict of interest related to this work. PV: Participation in advisory boards and speaking honoraria for Gilead Sciences, Pfizer, Mundipharma, F2G and Shionogi. Honoraria were paid to my institute. None of these conflicts were related to this manuscript. ISO: Declares no conflict of interest related to this work. For non-profit organization, she is the current secretary of the EBMT PH & G committee. JS: Declares no conflict of interest related to this work. IYA: Declares no conflict of interest related to this work. For non-profit organization, he is the current chair of the EBMT PH & G committee., (Copyright © 2024. Published by Elsevier Masson SAS.)

Abstract: In patients with myelodysplastic syndrome (MDS), higher revised International Prognostic Scoring System (IPSS-R) scores at transplant are associated with worse transplant outcome and, thus, lowering IPSS-R scores by therapeutic intervention before transplantation may seem beneficial. However, there is no evidence, to date, to support this approach. In a retrospective analysis, a total of 1482 patients with MDS with sufficient data to calculate IPSS-R score at diagnosis and at time of transplantation were selected from the European Society for Blood and Marrow Transplantation transplant registry and analyzed for transplant outcome in a multivariable Cox model including IPSS-R score at diagnosis, treatment intervention, change in IPSS-R score before transplant, and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R score change in untreated patients and moderately superior in patients treated with chemotherapy with improved IPSS-R score at transplant. Improved IPSS-R score after hypomethylating agents (HMAs) or other therapies showed no beneficial effect. However, when IPSS-R score progressed after chemotherapy, HMAs, or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit of IPSS-R score downstaging or reduction of BM blasts after chemotherapy and no benefit for HMAs or other treatments and thus question the role of prior therapy in patients with MDS scheduled for transplantation. The model-based survival estimates should help inform decision-making for both doctors and patients., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Since the early description of three patients with relapsed leukaemia after allogeneic haematopoietic cell transplantation (HCT) who obtained complete remission after donor lymphocyte infusions (DLIs), the added value of this procedure to induce or maintain graft-versus-leukaemia immunity has been undisputed. For more than 30 years, DLIs have become common practice as prophylactic, pre-emptive, or therapeutic immunotherapy. However, as with many aspects of allogeneic HCT, centres have developed their own routines and practices, and many questions related to the optimal applications and toxicity, or to the immunobiology of DLI induced tumour-immunity, remain. As a part of the Practice Harmonization and Guidelines Committee and the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation effort, a panel of experts with clinical and translational knowledge in transplantation immunology and cellular therapy met during a 2-day workshop in September, 2023, in Lille, France, and developed a set of consensus-based recommendations for the application of unmanipulated DLI after allogeneic HCT for haematological malignancies. Given the absence of prospective data in the majority of publications, these recommendations are mostly based on retrospective studies and expert consensus., Competing Interests: Declaration of interests SP has received travel expenses or honoraria for participation in advisory boards, symposia, or other scientific events from Alexion, Novartis, Jazz Pharmaceutical, Therakos, OneLamda, and Sobi; and received research funding from Janssen Horizon. CS has received travel expenses or honoraria for participation in advisory boards, symposia, or other scientific events from Novartis, Jazz Pharmaceutical, Neovii, Janssen, and Kite Pharma. JK has received grants from Novartis, Miltenyi Biotech, and Gadeta; is a Gadeta shareholder; and holds patent licenses with Gadeta and Miltenyi Biotech. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Allogeneic haematopoietic cell transplantation (allo-HCT) remains an option for tyrosine kinase inhibitor-resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high-risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry-based study of 1686 CML patients undergoing first allo-HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo-HCT was 46 years (IQR 36-55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse-free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non-relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft-versus-host disease (GvHD)-free/relapse-free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Abstract: Chronic myelomonocytic leukemia (CMML) is a heterogeneous disease presenting with either myeloproliferative or myelodysplastic features. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative option, but the inherent toxicity of this procedure makes the decision to proceed to allo-HCT challenging, particularly because patients with CMML are mostly older and comorbid. Therefore, the decision between a nonintensive treatment approach and allo-HCT represents a delicate balance, especially because prospective randomized studies are lacking and retrospective data in the literature are conflicting. International consensus on the selection of patients and the ideal timing of allo-HCT, specifically in CMML, could not be reached in international recommendations published 6 years ago. Since then, new, CMML-specific data have been published. The European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee assembled a panel of experts in the field to provide the first best practice recommendations on the role of allo-HCT specifically in CMML. Recommendations were based on the results of an international survey, a comprehensive review of the literature, and expert opinions on the subject, after structured discussion and circulation of recommendations. Algorithms for patient selection, timing of allo-HCT during the course of the disease, pretransplant strategies, allo-HCT modality, as well as posttransplant management for patients with CMML were outlined. The keynote message is, that once a patient has been identified as a transplant candidate, upfront transplantation without prior disease-modifying treatment is preferred to maximize chances of reaching allo-HCT whenever possible, irrespective of bone marrow blast counts., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

We retrospectively compared outcomes of 404 MDS patients undergoing 1st matched sibling donor allo-HCT receiving either PTCy-based (n = 66) or other "conventional prophylaxis" (n = 338; mostly calcineurin inhibitor + methotrexate or MMF). Baseline characteristics were balanced, except for higher use of myeloablative regimens in the PTCy group (52.3% vs. 38.2%, p = 0.047). Incidences of neutrophil (Day +28: 89% vs. 97%, p = 0.011) and platelet (Day +100: 89% vs. 97%, p < 0.001) engraftment were lower for PTCy-based. Day +100 cumulative incidences of grade II-IV and III-IV aGVHD, and 5-year CI of extensive cGVHD were 32%, 18% and 18% for PTCy-based and 25% (p = 0.3), 13% (p = 0.4) and 31% (p = 0.09) for the conventional cohort. Five-year OS (51% vs. 52%, p = 0.6) and GRFS (33% vs. 25%, p = 0.6) were similar between groups. Patients receiving PTCy had a trend to a lower cumulative incidence of relapse (20% vs. 33%, p = 0.06), not confirmed on multivariable analysis (p = 0.3). Although higher NRM rates were observed in patients receiving PTCy (32% vs. 21%, p = 0.02) on univariate analysis, this was not confirmed on multivariate analysis (HR 1.46, p = 0.18), and there was no resultant effect on OS (HR 1.20, p = 0.5). Based on these data, PTCy prophylaxis appears to be an attractive option for patients with MDS undergoing MSD allo-HCT., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Although CMML since long has been separated from MDS, many studies continue to evaluate the outcomes of both diseases after hematopoietic cell transplantation (allo-HCT) together. Data evaluating outcomes of a large CMML cohort after allo-HCT compared to MDS are limited. We aim to compare outcomes of CMML to MDS patients who underwent allo-HCT between 2010 and 2018. Patients ≥18 years with CMML and MDS undergoing allo-HCT reported to the EBMT registry were analyzed. Progression to AML before allo-HCT was an exclusion criterion. Overall survival (OS), progression/relapse-free survival (PFS), relapse incidence (including progression) (REL), and non-relapse mortality (NRM) were evaluated in univariable and multivariable (MVA) Cox proportional hazard models including interaction terms between disease and confounders. In total, 10832 patients who underwent allo-HCT were included in the study, there were a total of 1466 CMML, and 9366 MDS. The median age at time of allo-HCT in CMML (median 60.5, IQR 54.3-65.2 years) was significantly higher than in the MDS cohort (median 58.8, IQR 50.2-64.5 years; p < .001). A significantly higher percentage of CMML patients were male (69.4%) compared to MDS (61.2%; p < .001). There were no clinically meaningful differences in the distribution of Karnofsky score, Sorror HCT-CI score at allo-HCT, and donor type, between the CMML and MDS patients. RIC platforms were utilized in 63.9% of CMML allo-HCT, and in 61.4% of MDS patients (p = .08). In univariable analyses, we found that OS, PFS, and REL were significantly worse in CMML when compared with MDS (all p < .0001), whereas no significant difference was observed in NRM (p = .77). In multivariable analyses, the HR comparing MDS versus CMML for OS was 0.81 (95% CI, 0.74-0.88, p < .001), PFS 0.76 (95% CI 0.70-0.82, p < .001), relapse 0.66 (95% CI 0.59-0.74, p < .001), and NRM 0.87 (95% CI 0.78-0.98, p = .02), respectively. The association between baseline variables and outcome was found to be similar in MDS and CMML (all interaction p > .05) except for a decreasing trend over time of the risk of relapse in CMML (HR allo-HCT per year later 0.94, 95% CI 0.90-0.98), whereas no such trend was observed in MDS (HR 1.00, 95% CI 0.98-1.02). The poor outcome observed for CMML could be related to variables not measured in this study or to factors inherent to the disease itself. This study demonstrates that outcomes of CMML patients after allo-HCT are significantly worse compared to MDS. The results of this study may contribute to future recommendations for allo-HCT in CMML patients., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The recent application of whole exome or whole genome sequencing unveiled a plethora of germline variants predisposing to myeloid disorders, particularly myelodysplastic neoplasms. The presence of such variants in patients with myelodysplastic syndromes has important clinical repercussions for haematopoietic stem-cell transplantation, from donor selection and conditioning regimen to graft-versus-host disease prophylaxis and genetic counselling for relatives. No international guidelines exist to harmonise management approaches to this particular clinical scenario. Moreover, the application of germline testing, and how this informs clinical decisions, differs according to the expertise of individual clinical practices and according to different countries, health-care systems, and legislations. Leveraging the global span of the European Society for Blood and Marrow Transplantation (EBMT) network, we took a snapshot of the current European situation on these matters by disseminating an electronic survey to EBMT centres experienced in myelodysplastic syndromes transplantation. An international group of haematologists, transplantation physicians, paediatricians, nurses, and experts in molecular biology and constitutional genetics with experience in myelodysplastic syndromes contributed to this Position Paper. The panel met during multiple online meetings to discuss the results of the EBMT survey and to establish suggested harmonised guidelines for such clinical situations, which are presented here., Competing Interests: Declaration of interests YC has received consulting fees for advisory board from MSD, Novartis, Incyte, BMS, Pfizer, Abbvie, Roche, Jazz, Gilead, Amgen, Astra-Zeneca, and Servier and travel support from MSD, Roche, Gilead, Amgen, Incyte, Abbvie, Janssen, Astra-Zeneca, Jazz, and Sanofi all to his institution. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hematological toxicity is the most common adverse event after chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound and long-lasting and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regard to current practice patterns. Here, we sought to build consensus on the grading and management of immune effector cell-associated hematotoxicity (ICAHT) after CAR T-cell therapy. For this purpose, a joint effort between the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR T-cell experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late (after day +30) cytopenia. Detailed recommendations on risk factors, available preinfusion scoring systems (eg, CAR-HEMATOTOX score), and diagnostic workup are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic stem cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category after immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic workup and short- and long-term management., (© 2023 by The American Society of Hematology.)

For hematopoietic cell transplantation (HCT) and cellular therapy (CT), clinical patient care is localized, and practices may differ between countries and from center to center even within the same country. Historically, international guidelines were not always adapted to the changing daily clinical practice and practical topics there were not always addressed. In the absence of well-established guidelines, centers tended to develop local procedures/policies, frequently with limited communication with other centers. To try to harmonize localized clinical practices for malignant and non-malignant hematological disorders within EBMT scope, the practice harmonization and guidelines (PH&G) committee of the EBMT will co-ordinate workshops with topic-specific experts from interested centers. Each workshop will discuss a specific issue and write guidelines/recommendations that practically addresses the topic under review. To provide clear, practical and user-friendly guidelines when international consensus is lacking, the EBMT PH&G committee plans to develop European guidelines by HCT and CT physicians for peers' use. Here, we define how workshops will be conducted and guidelines/recommendations produced, approved and published. Ultimately, there is an aspiration for some topics, where there is sufficient evidence base to be considered for systematic reviews, which are a more robust and future-proofed basis for guidelines/recommendations than consensus opinion., (© 2023. The Author(s).)

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., (© 2022 by The American Society of Hematology.)

We performed a registry study on therapy-related myeloid neoplasm (t-MN), both therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) following treatment for breast cancer who underwent a first allogeneic hematopoietic cell transplant (allo-HCT). Of 252 identified female patients (median age 57 years), 77% were transplanted for t-AML and 23% for t-MDS, with a median time from breast cancer diagnosis to the diagnosis of tMN and subsequent allo-HCT of 3.7 and 4.6 years, respectively. At transplant, 191 patients were in remission for breast cancer, while 4 were not (57 missing). T-MN was in a complete remission at the time of transplant in 67% of patients. 2-year overall survival, relapse free-survival, relapse incidence and non-relapse mortality were 50%, 45%, 33%, and 22%, respectively. Multivariable analysis revealed that if the t-MN was not in CR pre-transplant, this was associated with lower OS, RFS, and a higher relapse incidence. Seventeen cases of breast cancer recurrence were recorded after a median of 2.4 years post-transplant, and relapse of primary breast cancer accounted for 7% of deaths. This study indicates that allo-HCT for t-MN following treatment for breast cancer shows encouraging transplant outcomes. The incidence of breast cancer relapse post-transplant remains a cause for concern., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Recently a new three-group clinical classification was reported by an International Consortium to stratify CMML patients with regard to prognosis. The groups were defined as follows: (1) Myelodysplastic (MD)-CMML: WBC ≤ 10 × 10 9 /l, circulating immature myeloid cells (IMC) = 0, no splenomegaly; (2) MD/MP (overlap)-CMML: WBC 10-20 × 10 9 /l or WBC ≤ 10 × 10 9 /l but IMC > 0 and/or splenomegaly; (3) Myeloproliferative (MP)-CMML: WBC > 20 × 10 9 /l. By analysing EBMT Registry patients who underwent allo-HCT for CMML between 1997 and 2016, we aimed to determine the impact of this classification on transplantation outcome and to make a comparison with the conventional WHO classification (CMML-0/CMML-1/CMML-2). Patient grouping was based on the data registered at time of transplantation, with IMC replaced by peripheral blasts. Among 151 patients included in the analysis, 38% were classified as MD-CMML, 42% as MD/MP-CMML and 20% as MP-CMML. With a median survival of 17 months in the whole series, MD-CMML patients were distinguished as a low-risk group with higher CR rate at transplant and a longer post-transplant 2-year progression-free survival in comparison to others (44.5% vs 33.5%, respectively), whereas the WHO classification was superior in identifying high-risk patients (CMML-2) with inferior survival outcomes., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The outcome of refractory/relapsed (R/R) acute leukemias is still dismal and their treatment represents an unmet clinical need. However, allogeneic transplantation (allo-HSCT) remains the only potentially curative approach in this setting. A prospective study (GANDALF-01, NCT01814488; EUDRACT:2012-004008-37) on transplantation with alternative donors had been run by GITMO using a homogeneous myeloablative conditioning regimen with busulfan, thiotepa and fludarabine while GVHD prophylaxis was stratified by donor type. The study enrolled 101 patients; 90 found an alternative donor and 87 ultimately underwent allo-HSCT. Two-year overall survival of the entire and of the transplant population (primary endpoint) were 19% and 22%, without significant differences according to disease, donor type and disease history (relapsed vs refractory patients). Two-year progression-free survival was 19% and 17% respectively. The cumulative incidences of relapse and non-relapse mortality were 49% and 33% at two years. Acute grade II-IV and chronic GVHD occurred in 23 and 10 patients. Dose intensification with a myeloablative two-alkylating regimen as sole strategy for transplanting R/R acute leukemia does seem neither to improve the outcome nor to control disease relapse. A pre-planned relapse prevention should be included in the transplant strategy in this patient population., (© 2022. The Author(s).)

Today, allogeneic stem cell transplantation (allo-SCT) can be offered to patients up to age 70 to 72 years and represents one of the most effective curative treatments for many hematologic malignancies. The primary objective of the study was to collect data from the allo-SCTs performed in Italy between 2000 and 2017 in patients aged ≥60 years to evaluate the changes in safety and efficacy outcomes, as well as their distribution and characteristics over time. The Italian Group for Bone Marrow Transplantation, Hematopoietic Stem Cells and Cell Therapy (GITMO) AlloEld study (ClinicalTrials.gov identifier NCT04469985) is a retrospective analysis of allo-SCTs performed at 30 Italian transplantation centers in older patients (age ≥60 years) between 2000 and 2017 (n = 1996). For the purpose of this analysis, patients were grouped into 3 time periods: time A, 2000 to 2005 (n = 256; 12%); time B, 2006 to 2011 (n = 584; 29%); and time C, 2012 to 2017 (n = 1156; 59%). After a median follow-up of 5.6 years, the 5-year nonrelapse mortality (NRM) remained stable (time A, 32.8%; time B, 36.2%; and time C, 35.0%; P = .5), overall survival improved (time A, 28.4%; time B, 31.8%; and time C, 37.3%; P = .012), and the cumulative incidence of relapse was reduced (time A, 45.3%; time B, 38.2%; time C, 30.0%; P < .0001). The 2-year incidence of extensive chronic graft-versus-host disease was reduced significantly (time A, 17.2%; time B, 15.8%; time C, 12.2%; P = .004). Considering times A and B together (2000 to 2011), the 2-year NRM was positively correlated with the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score; NRM was 25.2% in patients with an HCT-CI score of 0, 33.9% in those with a score of 1 or 2, and 36.1% in those with a score of 3 (P < .001). However, after 2012, the HCT-CI score was not significantly predictive of NRM. This study shows that the transplantation procedure in elderly patients became more effective over time. Relapse incidence remains the major problem, and strategies to prevent it are currently under investigation (eg, post-transplantation maintenance). The selection of patients aged ≥60 could be improved by combining HCT-CI and frailty assessment to better predict NRM., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option in advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS). This study presents an updated analysis of the initial experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT) describing the outcomes after allo-HSCT for MF and SS, with special emphasis on the impact of the use of unrelated donors (URD)., Methods and Patients: Eligible for this study were patients with advanced-stage MF or SS who underwent a first allo-HSCT from matched HLA-identical related or URD between January/1997 and December/2011. Sixty patients have been previously reported., Results: 113 patients were included [77 MF (68%)]; 61 (54%) were in complete or partial remission, 86 (76%) received reduced-intensity protocols and 44 (39%) an URD allo-HSCT. With a median follow up for surviving patients of 73 months, allo-HSCT resulted in an estimated overall survival (OS) of 38% at 5 years, and a progression-free survival (PFS) of 26% at 5 years. Multivariate analysis demonstrated that advanced-phase disease (complete remission/partial remission >3, primary refractory or relapse/progression in patients that had received 3 or more lines of systemic treatment prior to transplant or the number of treatment lines was not known), a short interval between diagnosis and transplant (<18 months) were independent adverse prognostic factors for PFS; advanced-phase disease and the use of URDs were independent adverse prognostic factors for OS., Conclusions: This extended series supports that allo-HSCT is able to effectively rescue over one third of the population of patients with advanced-stage MF/SS. High relapse rate is still the major cause of failure and needs to be improved with better strategies before and after transplant. The negative impact of URD is a matter of concern and needs to be further elucidated in future studies.

Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.

In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft- versus -host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Annaloro, Serpenti, Saporiti, Galassi, Cavallaro, Grifoni, Goldaniga, Baldini and Onida.)

Refractory/early relapsed and 17p deletion/p53 mutation (del(17p)/TP53mut)-positive chronic lymphocytic leukemia (CLL) has been conventionally considered a high-risk disease, potentially eligible for treatment with allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of patients with high-risk CLL treated with alloSCT, a B-cell receptor pathway inhibitor (BCRi), and both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced-intensity conditioning alloSCT, and 19 received alloSCT with a BCRi before and/or after transplantation. Inverse probability of treatment weighting analyses were performed to compare the alloSCT and no-alloSCT groups; in the 2 groups, 5-year OS, PFS, and cumulative incidence of nonrelapse mortality (NRM) and relapse were 40% versus 60% (P = .096), 34% versus 17% (P = .638), 28% versus 5% (P = .016), and 38% versus 83% (P = .005), respectively. Patients treated with alloSCT plus BCRi had a 3-year OS of 83%. The 3-year OS and NRM by year of alloSCT, including patients treated with BCRi, were 53% and 17% in 2000 to 2007, 55% and 30% in 2008 to 2012, and 72% and 18% in 2013 to 2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We have treated 69 patients with steroid refractory acute graft versus host disease (SR-aGvHD), with an anti-CD26 monoclonal antibody (Begelomab): 28 patients in two prospective studies (EudraCT No. 2007-005809-21; EudraCT No. 2012-001353-19), and 41 patients on a compassionate use study. The median age of patients was 42 and 44 years; the severity of GvHD was as follows: grade II in 8 patients, grade III in 33, and grade IV in 28 patients. There were no adverse events directly attributable to the antibody. Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. In conclusion, Begelomab induces over 60% responses in SR-aGvHD, including patients with severe gut and liver GvHD, having failed one or more lines of treatment.

Background: Atypical hemolytic uremic syndrome (aHUS) is life-threatening condition particularly when complicating allograft hematopoietic stem cell transplant (HSCT). In the past, the outcome was very poor with the majority of patients reaching end-stage renal disease or dying with little or no chances of kidney transplant (KTx) due to the high risk of relapse. The availability of C5 inhibition has opened up significant therapeutic opportunities and has improved the outcome particularly if complement dysregulation (CD) is the underlying pathogenetic mechanism., Methods: We describe a peculiar case of a girl with aHUS complicating HSCT and her subsequent successful KTx received from the same donor thus performed without immunosuppression but anti-C5 inhibition., Results: Soon after HSCT performed for acute lymphoblastic leukemia, the patient developed a TMA due to CD and reached end-stage renal disease. After 2 years on dialysis, the patient received a KTx from her father who was already the HSCT donor. Given the full chimerism, no immunosuppressive agent was prescribed except a short (2 days) course of steroids and eculizumab to prevent aHUS relapse. Nine months after the KTx, the patient is well with normal renal function, no immunosuppression and continues eculizumab prevention of aHUS (1 infusion every 21 days)., Conclusions: All patients with transplant-associated thrombotic microangiopathy should be screened for the causes of CD. C5 inhibition with eculizumab is an important therapeutic resource to manage this complication. When KTx is necessary, immunosuppression can be safely withhold in case of same donor for both grafts and documented full chimerism.

Available studies on metabolic syndrome (MS) after hematopoietic stem cell transplantation (HSCT) are retrospective with heterogeneous inclusion criteria, and little is known about the early post-transplant phase. In our prospective study, clinical and laboratory data were collected in 100 HSCT recipients, 48 allogeneic and 52 autologous, at baseline, at + 30, + 100 and + 360 days. At baseline, MS was observed in 24 patients, significantly associated with insulin resistance and leptin on multivariate analysis. At + 30, the diagnosis of MS was confirmed in 43 patients, significantly related to insulin resistance and allogeneic transplants. If the whole series was considered, patients with MS had significantly higher mortality from any cause. The baseline presence of any MS feature was a predictor of + 30 MS. Isolated occurrences of MS features were related to hyperleptinemia and hyperinsulinemia, except in the case of low HDL cholesterol, linked to adiponectin and resistin. Our data confirm that patients undergoing HSCT have a high prevalence of MS, with hyperleptinemia playing a major role. The early peak of new MS cases is primarily attributable to insulin resistance, notably but not exclusively immunosuppression-induced; the subsequent long-term increase in MS cases may be an effect of persistent adipokine imbalance.

Background and Aims: Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for patients with severe, treatment-refractory Crohn's disease [CD]. The evidence base for AHSCT for CD is limited, with one randomised trial [ASTIC] suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe, outside the ASTIC trial., Methods: We identified 99 patients in the European Society for Blood and Marrow Transplantation [EBMT] registry, who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in seven countries., Results: Median patient age was 30 years [range 20-65]. Patients had failed or been intolerant to a median of six lines of drug therapy; 61/82 [74%] had had surgery. Following AHSCT, 53/78 [68%] experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months [range 6-174]; 22/82 [27%] required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at latest follow-up, 57% [24/42] achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at 1 year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% confidence interval [CI] 1.14-4.83, p = 0.02). One patient died due to infectious complications [cytomegalovirus disease] at Day +56., Conclusions: In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted., (© The Author(s) 2018. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Despite the major recent progress in the treatment of Crohn's disease [CD], there is a subset of patients in whom the disease runs an aggressive course with progressive tissue damage requiring early and repeated surgical management. Increasing evidence supports sustained and profound improvement in gastrointestinal parameters and quality of life following high-dose immunosuppressive therapy and autologous haematopoietic stem cell transplantation [AHSCT] compared to standard therapy in this context. In addition, international transplant registry data reflect the use of AHSCT in CD outside of trials in selected patients. However, AHSCT may be associated with significant treatment-related complications with risk of transplant-related mortality. In a joint initiative, the European Crohn's and Colitis Organisation [ECCO] and the European Society for Blood and Marrow Transplantation [EBMT] have produced a state-of-the-art review of the rationale, evaluation, patient selection, stem cell mobilization and transplant procedures and long-term follow up. Given the unique spectrum of issues, we recommend that AHSCT should only be performed in experienced centres with expertise in both haematological and gastroenterological aspects of the procedure. Where possible, patients should be enrolled on clinical trials and data registered centrally. Future development should be coordinated at both national and international levels.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.

Introduction: Novel targeted therapies and monoclonal antibodies can be combined with allogeneic stem cell transplantation (allo-SCT) at different time-points: 1) before the transplant to reduce tumour burden, 2) as part of the conditioning in place of or in addition to conventional agents 3) after the transplant to allow long-term disease control. Areas covered: This review focuses on the current integration of new drugs with allo-SCT for the treatment of major hematological malignancies for which allo-SCT has been a widely-adopted therapy. Expert opinion: After having been used as single agent salvage treatments in relapsed patients after allo-SCT or in combination with donor lymphocyte infusions, many new drugs have also been safely employed before allo-SCT as a bridge to transplantation or after it as planned consolidation/maintenance. This era of new drugs has opened new important opportunities to 'smartly' combine 'targeted drugs and cell therapies' in new treatment paradigms that may lead to higher cure rates or longer disease control in patients with hematological malignancies.

The treatment of patients with refractory/relapsed B cell non-Hodgkin lymphoma (NHL) is evolving because of the availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and mortality remain a matter of concern. We conducted a multicenter prospective phase II trial to evaluate the benefit of including only 1 dose of rituximab in the conditioning regimen before alloSCT. The primary endpoint was progression-free survival. The study enrolled 121 patients with relapsed/refractory B cell lymphomas. The conditioning regimen consisted of thiotepa, cyclophosphamide, fludarabine, and rituximab (500 mg/m 2 ). Rabbit antithymocyte globulin was administered only in case of unrelated donors. Sixty-seven (55%) and 54 (45%) patients received grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of nonrelapse mortality (NRM) was 21% at 3 years. The CCIs of chronic graft-verus-host disease (GVHD) at 3 years were 54% and 31% in recipients of matched sibling and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-year progression-free and overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite endpoint of GVHD-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a prospective trial of lymphoma patients: the 1-year and 3-year GRFS were 40% and 34%, respectively. AlloSCT can cure a fraction of patients with rather low NRM and an encouraging PFS and GRFS., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Atypical chronic myeloid leukaemia (aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who underwent allo-HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen (HLA)-identical siblings in 64% and matched unrelated (MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T-cell depletion was applied in 87% and 26% of transplants from MUD and HLA-identical siblings, respectively. According to the EBMT risk-score, 45% of patients were 'low-risk', 31% 'intermediate-risk' and 24% 'high-risk'. Following allo-HSCT, 87% of patients achieved complete remission. At 5 years, relapse-free survival was 36% and non-relapse mortality (NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse-free survival was higher in MUD than in HLA-identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo-HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates., (© 2017 John Wiley & Sons Ltd.)

An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with ≥10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DLI strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT., (© 2017 by The American Society of Hematology.)

We retrospectively evaluated the efficacy of autologous hematopoietic stem cell transplantation (AHSCT) in 18 patients with rapidly progressive diffuse cutaneous systemic sclerosis (rp-dcSSc), and compared their disease outcomes with those of 36 demographically- and clinically-matched patients treated with conventional therapies. Cutaneous involvement, by performing modified Rodnan skin score (mRss), lung diffusion capacity, by measuring diffusing capacity of lung for carbon monoxide (DLCO), and disease activity, by applying the European Scleroderma Study Group (ESSG) scoring system, were the outcome variables measured at the baseline time and then every 12 months for the following 60 months in both the AHSCT-treated patients and the control group. In the AHSCT group, treatment-related mortality was 5.6%. In this group, both mRss and ESSG scores showed a significant reduction 1 year after AHSCT (P<0.002); and these results were maintained until the end of follow-up. Conversely, DLCO values remained stable during the whole period of follow-up. Survival rate of AHSCT group was much higher than that observed in the whole control group (P=0.0005). The probability that the ESSG score and mRss would remain at a high level, and DLCO could decrease, was significantly higher in the control group as a whole and in the subgroup of control patients treated with cyclophosphamide than in the AHSCT group. This study confirms that the AHSCT is effective in prolonging survival, as well as in inducing a rapid reduction of skin involvement and disease activity, and preserving lung function in patients with rp-dcSSc.

Importance: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease., Objective: To evaluate the effect of autologous HSCT on refractory Crohn disease., Design, Setting, and Participants: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids., Interventions: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed., Main Outcomes and Measures: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) <150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging., Results: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; P = .60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P = .01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died., Conclusions and Relevance: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease., Trial Registration: clinicaltrials.gov Identifier: NCT00297193.

Myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and a variable propensity for leukemic transformation. In recent years there has been an explosion of information on the molecular genetic changes underlying these disorders. This information has substantial prognostic implications, and the influence on therapeutic approaches and the treatment of patients is evolving. Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only known cure for these diseases, but appropriate patient selection is of utmost importance from a risk-benefit perspective. This review focuses on the factors influencing risk stratification in MDS and optimal choice of front-line therapy in the current era, including the interplay of clinical factors and molecular genetic factors, and factors that determine eligibility for alloSCT. The myelodysplastic/myeloproliferative diseases also will be discussed, including the increasing effort to understand the molecular genetics and natural history of these disorders and treatment approaches.

Acquired chromosomal abnormalities are important prognostic factors in patients with myelodysplastic syndromes treated with supportive care and with disease-modifying therapeutic interventions, including allogeneic hematopoietic stem cell transplantation. To assess the prognostic impact of cytogenetic characteristics after hematopoietic stem cell transplantation accurately, we investigated a homogeneous group of 523 patients with primary myelodysplastic syndromes who have received stem cells from human leukocyte antigen-identical siblings. Overall survival at five years from transplantation in good, intermediate, and poor cytogenetic risk groups according to the International Prognostic Scoring System was 48%, 45% and 30%, respectively (P<0.01). Both the disease status (complete remission vs. not in complete remission) and the morphological classification at transplant in the untreated patients were significantly associated with probability of overall survival and relapse-free survival (P<0.01). The cytogenetic risk groups have no prognostic impact in untreated patients with refractory anemia ± ringed sideroblasts (P=0.90). However, combining the good and intermediate cytogenetic risk groups and comparing them to the poor-risk group showed within the other three disease-status-at-transplant groups a hazard ratio of 1.86 (95%CI: 1.41-2.45). In conclusion, this study shows that, in a large series of patients with primary myelodysplastic syndromes, poor-risk cytogenetics as defined by the standard International Prognostic Scoring System is associated with a relatively poor survival after allogeneic stem cell transplantation from human leukocyte antigen-identical siblings except in patients who are transplanted in refractory anemia/refractory anemia with ringed sideroblasts stage before progression to higher myelodysplastic syndrome stages., (Copyright© Ferrata Storti Foundation.)

Cytomegalovirus (CMV) replication after allogeneic hematopoietic stem cell transplantation (HSCT) was historically associated with increased nonrelapse mortality (NRM). More recently, different groups have reported an association between CMV replication and reduced risk of acute myeloid leukemia (AML) relapse. Given the conflicting results, we evaluated the impact of CMV replication and other covariates on the outcome of a retrospective cohort of 265 adults with B cell lymphoma receiving allogeneic HSCT from HLA-identical siblings or alternative donors. In time-dependent multivariate analysis, CMV replication, evaluated by pp65 antigenemia, had no independent effect on the risk of relapse (hazard ratio [HR], 1.0; 95% confidence interval [CI], .6 to 1.6; P = .9), although it was associated with a reduced overall survival (HR, 2.0; 95% CI, 1.3 to 3.2; P = .001) and an increased NRM (HR, 2.5; 95% CI, 1.1 to 5.3; P = .01). Consistently, donor and/or recipient CMV seropositivity were not associated with a different outcome relative to CMV double-negative serostatus. In multivariate models, a diagnosis of follicular lymphoma (P < .0001) and pretransplantation complete remission status (P < .0001) were the main independent predictors for improved relapse-free survival. In summary, contrary to what is observed in patients with AML, this report identifies no independent role for CMV replication or serostatus on the relapse of patients with B cell lymphomas undergoing allogeneic HSCT., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP-IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP-IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Approximately one-third of patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (HSCT) are cured by this treatment. Treatment failure may be due to transplant complications or relapse. To identify predictive factors for transplantation outcome, we studied 519 patients with MDS or oligoblastic acute myeloid leukemia (AML, <30% marrow blasts) who received an allogeneic HSCT and were reported to the Gruppo Italiano Trapianto di Midollo Osseo registry between 2000 and 2011. Univariate and multivariate survival analyses were performed using Cox proportional hazards regression. High-risk category, as defined by the revised International Prognostic Scoring System (IPSS-R), and monosomal karyotype were independently associated with relapse and lower overall survival after transplantation. On the other hand, older recipient age and high hematopoietic cell transplantation-comorbidity index (HCT-CI) were independent predictors of nonrelapse mortality. Accounting for various combinations of patient's age, IPSS-R category, monosomal karyotype, and HCT-CI, the 5-year probability of survival after allogeneic HSCT ranged from 0% to 94%. This study indicates that IPSS-R risk category and monosomal karyotype are important factors predicting transplantation failure both in MDS and oligoblastic AML. In addition, it reinforces the concept that allogeneic HSCT offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages.

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages., (Copyright © 2013 Wiley Periodicals, Inc.)