Tomasz Czerw

Myelodysplastic/myeloproliferative neoplasms (excluding CMML) are rare and heterogenous malignancies with recurrent and overlapping clinicopathological abnormalities. Classification and characterization continue to evolve, but outcomes remain unsatisfactory and allo-HCT is currently the only curative therapy. Experience with these diseases is limited by rarity, accounting for <1% of allo-HCT procedures in Europe annually. Transplant indications have recently been described by this group, however response assessment, post-transplant surveillance and management of poor graft function, splenomegaly and relapse are not well established. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization & Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) collaborated to develop a practical and expert consensus-based guideline. Criteria for remission confirmation are proposed, including timing/thresholds for morphological, molecular, cytogenetic and chimerism analysis, aiming to harmonize comparisons in registry data and between international series. Suggestions for managing poor graft function and splenomegaly are designed to broadly align with those for myelofibrosis and related disorders. Relapse post-transplant remains a frequent challenge and the lack of robust evidence, in both the pre-transplant/post-transplant setting, underpins a need for collaborative clinical trials. This document serves as a framework to model post-transplant care, guide future research and address unresolved questions.

Outcomes in myelofibrosis (MF) patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) appear unaffected by the intensity of the preparative regimen, defined traditionally as myeloablative (MAC) or reduced intensity conditioning (RIC). The Transplant Conditioning Intensity (TCI) index is an objective tool offering a precise measure of conditioning intensity. We explored the potential association between TCI score and overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) in 2454 MF patients undergoing allo-HCT between 2012 and 2021, selected from the EBMT registry. Patients receiving TCI-intermediate/high regimens had similar OS (HR 1.12, 95% CI 0.97–1.30) and PFS (HR 1.00, 95% CI 0.88–1.14) compared to TCI-low regimens. However, TCI-intermediate/high regimens were associated with lower risk of relapse (HR 0.74, 95% CI 0.61–0.91, p = 0.008) and higher risk of NRM (HR 1.24, 95% CI 1.04–1.48, p = 0.02). Our findings suggest that the TCI score provides a more clinically relevant stratification of conditioning intensity than the conventional MAC/RIC classification. While higher intensity TCI regimens are associated with lower RI, this benefit is offset by increased NRM, resulting in no survival advantage. However, the TCI index may enable a more personalized approach to conditioning regimen selection by balancing relapse risk with patient frailty.

Selecting the optimal donor is crucial for optimizing results of allogeneic hematopoietic cell transplantation (allo‐HCT). We analyzed outcomes based on donor type in 2809 myelofibrosis (MF) patients undergoing first allo‐HCT between 2015 and 2021 at EBMT centers. Study outcomes included overall survival (OS), progression‐free survival (PFS), relapse, non‐relapse mortality (NRM), engraftment, and graft‐versus‐host disease (GvHD). Four groups were compared: matched sibling donor (MSD, n = 742), matched unrelated donor (MUD, n = 1401), mismatched unrelated donor (MMUD, n = 379) and haploidentical donor (HD, n = 287). After a median follow‐up of 33.5 months, 3‐year OS rates were 65.8%, 61.5%, 53.2%, and 57.7% for MSD, MUD, MMUD, and HD, respectively. Multivariable analyses (MSD as reference) showed that donor type significantly correlated with OS (HR: 1.63 for MMUD, HR: 1.42 for HD), PFS (HR: 1.38 for MMUD), NRM (HR: 1.73 for MMUD, HR: 1.47 for HD), engraftment (HR: 0.72 for MMUD, HR: 0.40 for HD), grade 2–4 acute GvHD (HR: 1.53 for MUD, HR: 1.69 for MMUD, HR: 1.49 for HD), and extensive chronic GvHD (HR: 0.77 for MUD, HR: 0.65 for HD). Donor type was not associated with relapse risk. In patients over 60 years, correlations between donor type and outcomes were consistent with those in the overall study population. In summary, with current practices, MF patients receiving MSD or MUD grafts achieve comparable outcomes. In contrast, MMUD and HD transplants have worse OS due to increased NRM. MMUD transplants have a higher risk of GvHD than HD transplants, but this difference seems to disappear with post‐transplant cyclophosphamide.

With the incorporation of effective therapies for myelofibrosis (MF), accurately predicting outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) is crucial for determining the optimal timing for this procedure. Using data from 5183 patients with MF who underwent first allo-HCT between 2005 and 2020 at European Society for Blood and Marrow Transplantation centers, we examined different machine learning (ML) models to predict overall survival after transplant. The cohort was divided into a training set (75%) and a test set (25%) for model validation. A random survival forests (RSF) model was developed based on 10 variables: patient age, comorbidity index, performance status, blood blasts, hemoglobin, leukocytes, platelets, donor type, conditioning intensity, and graft-versus-host disease prophylaxis. Its performance was compared with a 4-level Cox regression–based score and other ML-based models derived from the same data set, and with the Center for International Blood and Marrow Transplant Research score. The RSF outperformed all comparators, achieving better concordance indices across both primary and postessential thrombocythemia/polycythemia vera MF subgroups. The robustness and generalizability of the RSF model was confirmed by Akaike information criterion and time-dependent receiver operating characteristic area under the curve metrics in both sets. Although all models were prognostic for nonrelapse mortality, the RSF provided better curve separation, effectively identifying a high-risk group comprising 25% of patients. In conclusion, ML enhances risk stratification in patients with MF undergoing allo-HCT, paving the way for personalized medicine. A web application (https://gemfin.click/ebmt) based on the RSF model offers a practical tool to identify patients at high risk for poor transplantation outcomes, supporting informed treatment decisions and advancing individualized care.

“Nonclassical” myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.

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.

Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT.

Adult acute lymphoblastic leukemia (ALL) is associated with poor outcomes. ALL is initiated by primary aberrations, but secondary genetic lesions are necessary for overt ALL. In this study, we reassessed the value of primary and secondary aberrations in intensively treated ALL patients in relation to mutator enzyme expression. RT-PCR, genomic PCR, and sequencing were applied to evaluate primary aberrations, while qPCR was used to measure the expression of RAG and AID mutator enzymes in 166 adult ALL patients. Secondary copy number alterations (CNA) were studied in 94 cases by MLPA assay. Primary aberrations alone stratified 30% of the patients (27% high-risk, 3% low-risk cases). The remaining 70% intermediate-risk patients included BCR::ABL1^pos subgroup and ALL lacking identified genetic markers (NEG ALL). We identified three CNA profiles: high-risk bad-CNA (CNA^high/IKZF1^pos), low-risk good-CNA (all other CNAs), and intermediate-risk CNA^neg. Furthermore, based on RAG/AID expression, we report possible mechanisms underlying the CNA profiles associated with poor outcome: AID stratified outcome in CNA^neg, which accompanied most likely a particular profile of single nucleotide variations, while RAG in CNA^pos increased the odds for CNA^high/IKZF1^pos development. Finally, we integrated primary genetic aberrations with CNA to propose a revised risk stratification code, which allowed us to stratify 75% of BCR::ABL1^pos and NEG patients.

To develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age >50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels <100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P < .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P < .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes.