Raynier Devillier

Post-transplant cyclophosphamide (PTCy) has transformed graft-versus-host disease (GVHD) prophylaxis but its role in matched-donor reduced-intensity allogeneic hematopoietic cell transplantation (allo-HCT) remains uncertain. We retrospectively analyzed adults with AML or MDS reported to the French–Belgian–Swiss EBMT/SFGM-TC registry who received a first allo-HCT from a matched related (MRD) or matched unrelated donor (MUD) after reduced-intensity conditioning (RIC) with peripheral blood stem cells between 2014 and 2022. Among 3624 patients, GVHD prophylaxis comprised immunosuppressive agents without in vivo T cell depletion (NONE, n = 213), PTCy±immunosuppression (PTCy, n = 97), ATG±immunosuppression (ATG, n = 3 286), or PTCy+ATG±immunosuppression (PTCy+ATG, n = 28). In multivariable competing-risk models, PTCy was associated with a significant reduction of grade III-IV aGVHD compared to ATG (HR 0.44, p = 0.026). Both PTCy and ATG were associated with a lower incidence of extensive cGVHD vs NONE, without affecting NRM or relapse risk. With a median follow up of 16.6 months, the probability of 1-year OS, PFS and GRFS were 69.92%, 62.46% and 48.39%, regardless of donor type or GVHD prophylaxis group. These large, homogeneous registry data support PTCy as an effective alternative to ATG for GVHD prophylaxis in RIC MRD/MUD allo-HCT for AML/MDS, and provide a benchmark while ongoing randomized trials mature.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for secondary acute myeloid leukemia (sAML). Post-transplant cyclophosphamide has improved graft-versus-host disease (GVHD) prophylaxis, enabling the broader use of alternative donors. For patients lacking a human leukocyte antigen (HLA)-matched donor, haploidentical donor (Haplo) or 9/10 HLA mismatched unrelated donor (MMUD) HSCTs are widely used, yet their relative effectiveness in sAML is uncertain. We retrospectively compared outcomes after Haplo versus MMUD HSCT in adults with sAML in first complete remission transplanted between 2010 and 2022. Among 711 patients, 602 received Haplo and 109 MMUD grafts. Patient and transplant characteristics differed between cohorts, including donor age, conditioning intensity, graft source, and transplant year. Neutrophil recovery was faster after MMUD transplantation, while platelet recovery was comparable. Rates of acute and chronic GVHD, relapse incidence, non-relapse mortality, overall survival, leukemia-free survival, and GVHD-free/relapse-free survival were similar. Reduced intensity conditioning lowered acute GVHD risk, while peripheral blood grafts increased chronic GVHD. Lower Karnofsky score, older age and adverse-risk cytogenetics were adverse prognostic factors. Haplo and MMUD transplantation demonstrated comparable efficacy and safety with post-transplant cyclophosphamide, supporting both approaches as viable alternatives in the absence of an HLA-matched donor.

Allogeneic stem-cell transplantation (allo-SCT) is met with increased toxicity and relapse in elderly patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The nonmyeloablative conditioning (NMAC) regimen combining 2GyTBI, fludarabine, and cyclophosphamide (FluCyTBI) with post-transplant cyclophosphamide (PTCy) has been described as well adapted to AML/MDS patients aged ≥70yo in the haplo-identical setting. PTCy has then been implemented as basis for GVHD prophylaxis in allo-SCT with unrelated donors (UD). We here report our experience with a single FluCyTBI+PTCy platform for both haplo and UD allo-SCT in older AML or high-risk MDS patients. We retrospectively analyzed 203 patients transplanted at our center between 2015 and 2024. Median age at transplant was 69. Donors were haplo, mismatched UD, and matched UD in 64%, 18% and 18% of patients, respectively. Day+100 grade III-IV acute GVHD (aGVHD) and 3-y moderate/severe chronic GVHD (cGVHD) rates were 8% and 18%. Donor age ≥35yo was predictive of increased aGVHD III-IV and female-to-male sex-mismatch was associated with increased moderate/severe cGVHD. 3-y NRM rate was 15%. 3-y OS was 62%, with only monosomal karyotype predicting worse survival. FluCyTBI+PTCy is safe and produces promising outcomes in both haplo and UD settings. Beyond HLA-matching, non-HLA donor-related factors constitute critical determinants of patient outcome.

Iron overload after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with oxidative stress and adverse outcomes. Although deferasirox reduces ferritin, its effect on survival remains incompletely characterized. We conducted a prospective observational study across 7 French centers, enrolling 41 patients with acute myeloid leukemia or myelodysplastic syndromes who initiated deferasirox 6 months after allo-HSCT. Eligibility required complete remission, iron overload (ferritin level >1000 μg/L), and preserved organ function. Outcomes were compared with propensity score–matched controls (1:2) from the SFGM-TC registry. End points were overall survival (OS), progression-free survival (PFS), transplant-related mortality (TRM), relapse, and safety. Analyses employed exact matching, inverse probability of treatment weighting (IPTW), and multivariable Cox models. Ferritin level decreased from 1700 μg/L to <1000 μg/L by 18 months. Across analytic methods, deferasirox was associated with a reduced hazard of progression or death (PFS: hazard ratio [HR], 0.41-0.44) and a reduced hazard of mortality (OS: HR, 0.28-0.43). TRM was significantly reduced in propensity score matching and Cox models (HR, 0.21), whereas the IPTW analysis yielded a comparable point estimate (HR, 0.24) that did not reach the significance threshold (P = .063). The probability of relapse (estimated via cumulative incidence of relapse) did not differ significantly. Adverse events were predominantly renal and manageable. Initiating deferasirox 6 months after allo-HSCT was associated with sustained ferritin reduction, a reduced hazard of progression or death (PFS), lower TRM, and a favorable although nonsignificant hazard of mortality (OS), with acceptable safety. These findings support deferasirox as a feasible posttransplant intervention, warranting confirmation in randomized trials.

The growing burden of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) among aging populations underscores the critical need for tailored treatment strategies for elderly patients. While allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative option for eligible patients, its application in older adults is fraught with significant challenges. This review explores recent advancements in optimizing allo-HSCT for elderly patients with AML and MDS. Key considerations include assessing patient fitness, predicting transplant outcomes, refining conditioning regimens, and designing personalized treatment strategies. Optimizing the comprehensive management of elderly patients across the pre-transplant, transplant, and post-transplant phases is expected to broaden access to allo-HSCT and enhance its curative potential.

Les leucémies aiguës myéloïdes (LAM) avec dysplasie, identifiées par la classification OMS 2008 sous le nom de LAM-MRC (« AML with myelodysplasia-related changes »), sont actuellement définies par la présence de critères cliniques, cytologiques et cytogénétiques. Elles forment un groupe hétérogène tant sur le plan biologique que pronostique. Nous avons fait l'hypothèse que la caractérisation moléculaire des LAM-MRC pourrait permettre d'identifier des marqueurs spécifiques associés à ces pathologies et d'en distinguer différents sous-groupes. Nous avons mis en évidence que les LAM-MRC de risque cytogénétique intermédiaire présentent un profil mutationnel spécifique caractérisé par un taux élevé de mutation d'ASXL1 et une faible proportion de mutations de DNMT3A, NPM1 et FLT3. Les LAM-MRC de risque cytogénétique défavorable, essentiellement complexes et/ou monosomales, sont quant à elle associées aux mutations de TP53. Alors que les critères actuels des LAM-MRC ne permettent pas d'en stratifier le pronostic, nous avons montré que les mutations d'ASXL1 ou de TP53 sont des facteurs pronostics péjoratifs majeurs. Ainsi, une reclassification basée sur la présence de ces altérations moléculaires exclusives entre elles permettrait d'affiner le diagnostic et la stratification pronostique de ces maladies. Enfin, dans une stratégie de médecine personnalisée combinant le séquençage à haut débit à des tests de sensibilité thérapeutique in vitro, l'identification de tels marqueurs moléculaires permettraient de prédire la réponse aux traitements, de guider les choix thérapeutiques et d'orienter le développement de nouvelles drogues.