supplemental methods, tables and figures

Dans une démarche d’harmonisation des pratiques en allogreffe de cellules souches hématopoïétiques, la SFGM-TC a consacré un atelier à la prise en charge de la myélofibrose. Les discussions ont porté sur la sélection des patients, la gestion du ruxolitinib en péri-greffe, le choix du conditionnement et du donneur. L’atelier souligne l’importance d’une approche individualisée intégrant les scores pronostiques cliniques et moléculaires, l’évaluation du risque lié à la procédure et la réponse au traitement. Plusieurs questions persistent, notamment sur le suivi moléculaire dynamique et les modalités optimales du ruxolitinib autour de la greffe.

Abstract: 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.

As part of its initiative to harmonize practices in allogeneic hematopoietic stem cell transplantation, the SFGM-TC devoted a workshop to the management of myelofibrosis. Discussions focused on patient selection, peri-transplant management of ruxolitinib, and the choice of conditioning regimen and donor. The workshop emphasized the need for an individualized approach integrating clinical and molecular prognostic scores, assessment of transplant-related risk, and treatment response. Several questions remain open, particularly regarding the role of dynamic molecular monitoring and optimal peri-transplant ruxolitinib management.

Fit relapsed/refractory (R/R) acute myeloid leukemia (AML) patients usually undergo intensive chemotherapy (IC)-based salvage to bridge them to allogeneic hematopoietic stem cell transplantation (HSCT), but their prognosis remains poor. Azacitidine and venetoclax (AZA/VEN) are increasingly used as salvage therapy in R/R AML with encouraging results, although data remain limited. In this study, we evaluated the post-HSCT outcomes of 75 R/R AML patients from the VENAURA registry who underwent HSCT after AZA/VEN salvage. After a median follow-up of 16.9 months, the estimated 2-year overall survival (OS) was 61.4% (95% confidence interval [CI]: 49.5-68.1%). The 2-year cumulative incidence of relapse (CIR) was 35.1% (95% CI: 20-50.2%). The estimated 2-year non-relapse mortality (NRM) rate was 10.6% (95% CI: 9.8-23.3%). Cytological response at the end of cycle 1 was independently associated with OS and CIR in multivariate analysis. Comparison with 75 pair-matched patients receiving IC-based salvage prior to HSCT revealed similar OS in both groups. CIR was not significantly higher in AZA/VEN-treated compared to IC-treated patients; however, there was a trend toward a lower 2-year NRM rate in the AZA/VEN group. Our data suggest that AZA/VEN represents a feasible bridge-to-transplant option with a favorable toxicity profile.

CHRONOS is a multicenter, retrospective, cohort study involving acute graft-versus-host disease (aGvHD) adult patients with gastrointestinal (GI) symptoms, steroid- and ruxolitinib refractory, who initiated third-line therapy between 30 May 2019 and 30 September 2024. Primary endpoints were all-organ overall response rate (ORR) and GI-specific ORR (GI-ORR) around 28 days after treatment initiation. Secondary endpoints included duration of response, real-world progression-free survival (rwPFS) of underlying malignancy, and overall survival (OS). Fifty-nine patients from 16 sites in Europe were included. On Day 28, ORR was 36% (95% CI: 24-49%), GI-ORR was 37% (95% CI: 25-51%); 29% (95% CI: 11-49%) of responders lost response within 30 days, and 52% (95% CI: 29-72%) within 90 days. Median rwPFS and median OS were both 86 days (95% CI: 54-128 days). Median OS was higher in responders than in non-responders (186 versus 45 days). Over the 12-month follow-up period, 41 patients died, mainly due to aGvHD progression (n = 25), and infectious complications (n = 9). Within 3 months, Grade ≥ 2 infectious events occurred in 51% of patients; Grade 3-4 thrombocytopenia and neutropenia in 64% and 32%, respectively. These findings demonstrate limited effectiveness of third-line therapy in this cohort of steroid- and ruxolitinib-refractory aGvHD patients with GI symptoms.

Measurable residual disease (MRD) is a key prognostic marker in acute myeloid leukemia (AML) but its significance in patients treated with azacitidine and venetoclax (AZA/VEN) outside clinical trials remains unclear. We retrospectively analyzed 220 newly diagnosed AML patients from the French VENAURA registry who achieved composite complete remission and underwent MRD evaluation by multiparametric flow cytometry (MFC, LAIP/LSC) and/or NPM1 RT-qPCR. Median age was 74 years. Cumulative MRD negativity was achieved in 62–67% of patients depending on the method. Attaining MRD negativity at any time was strongly associated with superior overall survival (OS: 31.3 months vs 15.7 months for LAIP, not reached vs 10.8 months for NPM1; all p<0.001) and lower cumulative incidence of relapse. Dual LAIP/LSC negativity conferred the best outcomes (4-year OS ~57%). Importantly, MRD response mitigated the adverse prognostic impact of ELN 2024 intermediate/poor risk, with MRD-negative patients achieving outcomes comparable to favorable-risk cases. MRD kinetics (early vs late responders) did not affect survival, while G-CSF use improved MRD conversion and OS. In real-world AZA/VEN–treated AML, achieving deep MRD negativity—by MFC or NPM1 RT-qPCR—emerges as the dominant prognostic determinant, overriding baseline risk and supporting its integration into response-adapted strategies.

Introduction While the tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes for Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL), relapse remains a significant challenge. More recently, novel immunotherapies such as blinatumomab and CAR-T cell therapy have emerged as highly effective options. Nevertheless, hematopoietic stem cell transplantation (HCT) remains a vital curative strategy to consolidate remission, particularly for patients who are intolerant to these therapies, or in settings where these novel agents have limited accessibility. For patients lacking a matched sibling donor, both auto-HCT and haplo-HCT are feasible options. However, the optimal transplantation strategy between autologous and haploidentical HCT for this population remains to be explored. Methods We retrospectively analyzed data from the European Society for Blood and Marrow Transplantation (EBMT) registry on adult patients with Ph+ B-ALL in first complete remission (CR1) who underwent their first auto-HCT or haplo-HCT between 2010 and 2022. All recipients had received a TKI for induction and/or consolidation therapy before HCT. To balance the cohorts, a 2:1 pair-matching algorithm was applied. Matching was based on an exact match for minimal residual disease (MRD) status prior to HCT and transplant region (China vs. other), as well as propensity score matching for age at HCT, year of HCT, and the time interval between diagnosis and HCT. Results The study comprised 434 patients: 117 in the auto-HCT group and 317 in the haplo-HCT group. Auto-HCT recipients were older than those undergoing haplo-HCT (median age: 46 vs. 38 years, P < 0.001). Patients in the auto-HCT group underwent transplantation in earlier years (median: 2018 vs. 2020, P < 0.001) and had a longer interval from diagnosis to HCT (median: 6.8 vs. 5.8 months, P < 0.001). Regarding MRD evaluation, a higher proportion of auto-HCT recipients achieved MRD negativity prior to HCT compared to haplo-HCT recipients (81.4% vs. 62.3%, P < 0.001). The auto-HCT group had a lower rate of Cytomegalovirus (CMV) seropositivity (51.2% vs. 67.5%, P = 0.01) and used peripheral blood more frequently as the graft source (95.7% vs. 65.9%, P < 0.001). Myeloablative conditioning (MAC) was used less often in the auto-HCT group compared to the haplo-HCT group (72.8% vs. 87.1%, P < 0.001). Baseline characteristics such as sex and Karnofsky Performance Status (KPS) were similar between the two groups. After matching, 97 auto and 159 haplo recipients were included in the analysis. Main causes of death were relapse (88.2% vs 38.7%) and infection (5.9% vs 38.7%) in the auto-HCT group and the haplo-HCT group, respectively. The cumulative incidence of neutrophil recovery at 30 days was 100% in the auto-HCT group and 97.6% (95% CI, 93%-99.1%) in the haplo-HCT group. Platelet recovery at 60 days was 97.8% (95% CI, 89.3%-99.6%) in the auto-HCT group and 94.1% (95% CI, 88.3%-97.1%) in the haplo-HCT group. Regarding transplant outcomes, no significant difference was observed in 3-year Leukemia-Free Survival (LFS) between the auto-HCT and haplo-HCT groups (69.9% vs. 75%; HR, 0.78; P = 0.3). Similarly, 3-year Overall Survival (OS) was at 80.5% for auto-HCT and 78.6% for haplo-HCT; a formal hazard ratio was not calculated as the proportional hazards assumption was violated. Notably, compared to the auto-HCT group, the haplo-HCT group had a significantly lower 3-year relapse incidence (RI) (10.3% vs. 28%; HR, 0.35; P = 0.001) but a significantly higher 3-year non-relapse mortality (NRM) (14.8% vs. 2.1%; HR, 7.46; P = 0.008). Conclusion For Ph+ B-ALL patients in CR1 with TKI therapy before transplantation, auto-HCT and haplo-HCT provide non different LFS, as the significantly lower relapse rate of haplo-HCT is counterbalanced by its higher NRM.

Aplastic anemia (AA) transformation into myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) is associated with a dismal prognosis. Hematopoietic stem cell transplant offers the sole possibility of cure, but data on long-term survival are scarce. We retrospectively analyzed 270 patients transplanted for MDS, AML, or an isolated cytogenetic abnormality after a diagnosis of AA or paroxysmal nocturnal hemoglobinuria reported to the European Society for Blood and Marrow Transplantation (EBMT). The median age at transplantation was 39 years. The 5-year overall survival rate was 64%, and was unaffected by chromosome 7 abnormalities, age at transplant, sex, interval from clonal evolution to transplant, and intensity of conditioning regimen. The 5-year non-relapse mortality rates were 34% (95% Confidence Interval [CI]: 25-42%) for MDS patients and 19% (95% CI: 7-31%) for AML patients, and were higher following a myeloablative conditioning regimen. The 5-year relapse rate was 12% (95% CI: 6-19%) for MDS and 22% (95% CI: 9-35%) for AML. Our study's survival estimates reflect a younger cohort of patients, considering the bimodal distribution of AA. Conditioning regimen intensity did not affect relapse. For MDS patients, pretreating before transplant did not improve survival nor reduce relapse. Transplantation is feasible and effective in achieving long-term survival for transplant-eligible post-AA myeloid neoplasm patients. MDS patients may benefit from upfront reduced intensity conditioning transplant, limiting toxicity without higher rates of relapse. Post-transplant maintenance therapies to reduce the relapse incidence among AML patients might be warranted.

Cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and sometimes fatal diseases. Patients presenting with advanced-stage CTCL usually exhibit poor long-term survival outcomes. Only very few treatments have improved progression-free survival (PFS) in advanced CTCL, and no treatment has increased overall survival (OS). In 2023, the results of the CUTALLO trial supported the hypothesis that hematopoietic stem-cell transplantation (HSCT) was associated with significantly longer PFS as compared with standard-of-care treatment among advanced-stage patients although HSCT did not significantly affect OS. We provide herein the final OS data pertaining to the same patient population after a longer median follow-up of 38.9 months. Of the 99 patients included in the analysis, 55 (56%) were assigned to the HSCT group, whereas 44 (44%) were allocated to the non-HSCT group. The updated survival analysis reported that 16 of 55 patients (29%) in the HSCT group and 22 of 44 patients (50%) in the non-HSCT group died. The median OS was not reached in the HSCT group and 51.5 months (95% CI, 26.9 to 51.5) in the non-HSCT group (hazard ratio, 0.40 [95% CI, 0.20 to 0.80]). Compared with the standard of care for advanced CTCL, after extended follow-up, allogeneic HSCT was associated with significantly longer OS.

La réaction du greffon contre l’hôte aiguë (GVHDa) est une des causes principales de morbidité et de mortalité chez les patients allogreffés de cellules souches hématopoïétiques. Alors que le traitement consensuel de première ligne reste basé sur la corticothérapie systémique depuis de nombreuses années, le ruxolitinib a récemment eu l’autorisation de mise sur le marché et ce traitement est devenu la deuxième ligne de référence. Néanmoins, l’efficacité du ruxolitinib reste limitée à 40 % des patients cortico-résistants, justifiant la question cruciale du choix d’une troisième ligne. Parmi les modalités thérapeutiques décrites, cet atelier a permis de sélectionner la transplantation du microbiote fécal, l’injection de cellules stromales mésenchymateuses et la photophérèse extracorporelle comme celles qui semblent à ce jour les plus prometteuses ou ayant une balance bénéfice/risque conduisant à privilégier leur prescription. L’atelier a également souligné l’importance des travaux visant à produire des marqueurs ou des calculs de scores orientant vers une approche adaptée au risque, la plus précoce possible. À ce jour, à part la calprotectine, aucun marqueur ou score n’est utilisé en routine, mais tous font l’objet d’intenses recherches. Enfin, les mesures associées au traitement spécifique restent primordiales, et les nouveautés en matière d’apports alimentaires, de prophylaxies infectieuses et de régénération tissulaire sont abordées.

Context : Allogeneic stem cell transplantation (alloHCT) is used in majority of acute myeloid leukemia and myelodysplastic syndromes to obtain complete remission. Graft-versus-Host disease (GVHD) and relapse are is the most important complications after alloHCT. Numerous prognostic scores are used pre-transplant to guide therapeutic strategies, but none has been sufficient to predict graft-versus-host disease/relapse-free survival (GRFS). In this study, we studied clinical, biological and therapeutic factors associated with GRFS and attempted to build a predictive score. Material & Methods : Patients over 18 years of age who received a first hematopoietic stem cell transplant between 01/01/2015 and 31/12/2022 at the University Hospitals of Saint-Etienne, Lyon, Grenoble-Alpes and Clermont-Ferrand for acute myeloid leukemia or myelodysplastic syndrome were included. Data was extracted from the allogeneic EBMT registry and patient medical records. Several parameters about clinical and biological characteristics of patient, disease, conditioning regimen and type of donor were studied. Statistics were performed with Kaplan-Meier method and Cox analysis. Regression models and supervised machine learning models were explored by the Henri Fayol Institute of the Ecole des Mines de Saint-Etienne in order to establish a predictive model. Results : Analysis included851 patients. The cohort consisted of 59% men, with a median age of 58 years. More than 70% of the patients received alloHCT for acute myeloid leukemia. The median follow-up was 938 days, and median overall survival was not reached. Median GRFS was 210 days. At the end of follow-up, GRFS was estimated at 30%. Log-rank tests found 15 significant variables. Concerning pre-transplantation characteristics, Performance Status ≥ 2, neutropenia, lymphopenia, low creatinine level, elevated lactate dehydrogenase or c-reactive protein, and pre-transplant hypoalbuminemia were associated with lower survival. Therapy-related disease or secondary to a predisposing hematologic disorder was also predictive of GRFS, as well as adverse 2022 European LeukemiaNet risk group. Patients with refractory disease or positive residual disease before transplantation had poorer survival. A mismatch unrelated donor or a graft CD3+ cell count greater than 10^7/kg were associated with reduced GRFS. Finally, alloHCT performed more than 12 months after diagnosis was linked to improved GRFS. We used these variables to develop predictive models for GRFS using linear regression and machine learning algorithms (Alternating Decision Trees, Random Forest, Support Vector Machine, Association Rules). The highest predictive performance power was achieved by association rules. Non-redundant rules, with a lift greater than 1, a minimal confidence of 0.8 and a minimal support of 0.011 (9 patients) were kept to predict GRFS at 6 months, 9 months, 1 year, 18 months and 2 years. More than 800,000 rules were generated. Accuracy was respectively 0.95, 0.96, 0.90, 0.80, and 0.73 for each timepoint. An online tool is under development to simplify the calculation of the score and will be presented at the meeting.Conclusion : Our findings are consistent with existing literature on GRFS and overall survival following alloHCT. We identified significant clinical, biological and therapeutic parameters for development of a predictive algorithm for GRFS using association rules algorithm.

Background CD19-directed chimeric antigen receptor (CAR) T-cell therapy has revolutionized the prognosis of relapsed/refractory large B-cell lymphoma (R/R LBCL). Infections are one of the major complications of this therapy. Few real-life studies focus on both short and long-term infections and their risk factors following CAR-T cell infusion, and even fewer were conducted on European cohorts. Methods Using the French DESCAR-T registry (NCT04328298), we analyzed the incidence, types, outcomes and risk factors of severe (grade 3 or higher) infections. We report on 2 187 R/R LBCL patients who received commercial anti-CD19 CAR T-cell (75.3% axicabtagene ciloleucel, 22.7% tisagenlecleucel and 2% lisocabtagene maraleucel) from April 2018 to April 2024 in 32 French centers. Bacterial, viral, fungal and parasitic infections were recorded, along with details of the pathogens involved, up to two years after CAR T-cell infusion. The data was collected at key moments during patient follow-up after infusion (day 10, month 1, 3, 6, 12, 18, 24). The median follow-up period was 13 months (interquartile range 6-24.7 months), 30.7% of the initial population remained at year 2. Results A total of 933 infections occurred during the first two years following infusion, most of which occurred during the first 3 months (76.7%, n=716), with an incidence peak during the first 10 days after infusion. Between days 1 and 10, 350 severe infections were documented in 2 153 patients i.e. 0.163 infections per patient during this period. By comparison, there were 0.125 infections per patient between day 10 and the end of month 1, 0.118 between months 1 and 3, 0.074 between months 3 and 6, 0.082 between months 6 and 12, 0.087 between months 12 and 18 and 0.075 between months 18 and 24. After 2 years, 786 patients had died, and infection was the cause of death in 76 of them (9.6%). Most infections were bacterial (55.9%), with the highest proportion occurring in the first month (64.4%). The majority were due to Enterobacterales, coagulase-negative staphylococci (most frequent between days 1 and 10) and non-fermenting Gram-negative bacilli. The proportion of viral infections was low (4.9%) between day 1 and 10, and gradually increased during the first 6 months (40.5% at month 6), with the majority being respiratory viruses. Fungal infections represented 10% of infections. Parasitic infections were rare (0.2%). Multivariate analysis revealed that patients with an ECOG scale ≥ 2 at infusion, cytokine release syndrome, G-CSF administration, which reflects neutropenia, and gamma globulin administration, which reflects deep hypogammaglobulinemia, were at higher risk for infection. Axicabtagene ciloleucel also appeared to be risk factor for infection though there might be an effect size due to its use as the main treatment in this study, and it was used more widely when the risk of infection was not as well managed. Conclusion This real-life study based on a large French cohort shows that severe infections are a frequent complication of CAR-T cell therapy in R/R LBCL patients, with a significant infection-related mortality. The study provides a detailed overview of the pathogens involved and identifies infection risk factors, which may help physicians to better manage and prevent infections.

Background: Relapsed/refractory primary mediastinal large B-cell lymphoma (R/R PMBL) remains a therapeutic challenge, with limited responses to conventional salvage therapies. CAR-T cell therapy has emerged as a potential second-line (2L) option, but access may be restricted. Anti-PD1 checkpoint inhibitors (CPIs) have shown promising efficacy in clinical trials (KEYNOTE-170, CHECKMATE-436), but they lack European regulatory approval and real-world data in PMBL. We conducted a multicenter retrospective study to evaluate outcomes in R/R PMBL patients treated with CPIs. Methods: This study included R/R PMBL patients treated with CPIs, either alone or combined with other agents, across 20 LYSA-affiliated centers in France from 2014 to 2025. Tumor responses were assessed using PET or CT imaging, according to the 2014 Lugano criteria. The best overall response rate (bORR), defined as the proportion of patients achieving complete (CR) or partial (PR) response, was reported. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier (KM) method. Median follow-up was calculated using the reverse KM approach. Results: A total of 100 patients were included (median age 31 years, range 18–82; 51% female), with 98% presenting with a mediastinal mass, 58% with localized disease (stage I–II), 86% with ECOG PS 0–1, 10% with B symptoms, and 9% with a CNS-IPI score ≥4. Seven patients (7%) had central nervous system (CNS) involvement at inclusion. Most patients (95%) were refractory to their last line, with a median of 2 prior regimens (range 1–5), including R-CHOP14 (34%), R-CHOP21 (15%), DA-EPOCH-R (16%), R-ACVBP (25%), and others (10%) as first line. In 2L, 84% received platinum-based chemotherapy; prior autologous SCT and CAR-T were given in 3 and 7 patients, respectively. CPIs included pembrolizumab (n=66), nivolumab (n=33), and atezolizumab (n=1), administered as monotherapy (n=39), in combination with brentuximab vedotin (Bv; n=52), or with other agents (n=9). The median number of CPI cycles was 6 (IQR 3–15; range 1–52), and of Bv cycles was 4 (IQR 2–8; range 1–36). Consolidation therapy (57%) included radiotherapy (RT, n=20), autologous SCT (n=9), allogeneic SCT (n=3), and anti CD19 CAR-T cells (n=25). Treatment was generally well tolerated: 72% of patients experienced no adverse events, and most toxicities were low-grade, immune-related or infectious, consistent with previous reports. The bORR was 84%, including 48% CR and 36% PR. bORR by treatment subgroup was 89% with CPI monotherapy (CR 47%, PR 42%), 78% with CPI+Bv (CR 56%, PR 22%). The median time to best response was 2.9 months for monotherapy, 2.2 months for CPI+Bv. After a median follow-up of 31.8 months (IQR 11.9–51.8), median PFS and OS were not reached. Estimated 2-year PFS and OS rates were 56.6% [IC95: 46.9-68.2] and 75.5% [IC95: 66.5-85.7], respectively. A total of 27 deaths were reported; main cause of death was lymphoma (92.3%). Among the 48 patients who achieved CR, only 3 relapsed (median time to relapse: 12.3 months). Additionally, 54% of patients initially in PR converted to CR over time. In univariate Cox analysis, poor OS was associated with ECOG ≥2 (HR 3.88 [95% CI 1.53–9.84], advanced stage (HR 2.73 [1.25–5.97], CNS-IPI ≥4 (HR 6.66 [2.26–19.64], B symptoms (HR 4.18 [1.38–12.65] and LDH>ULN (HR 4.08 [1.21–13.76]. Hb ≥10.5 g/dL (HR 0.30 [0.14–0.67], platelet count ≥100 G/L (HR 0.20 [0.08–0.51], and female sex (HR 0.41, [0.18–0.94] were associated with better OS. In multivariate analysis, CNS-IPI was independently associated with shorter OS (HR 4.99 [2–3] and 4.48 [4–5]), while female sex (HR 0.19) and Hb ≥10.5 g/dL (HR 0.17) were linked to longer OS. Predictors of shorter PFS in univariate analysis included ECOG ≥2 (HR 3.98 [1.92–8.25]), advanced stage (HR 2.50 [1.30–4.80]), CNS-IPI ≥4 (HR 5.33 [2.19–12.98]), B symptoms (HR 4.41 [1.90–10.26]), and LDH>ULN (HR 3.11 [1.21–8.03]). Conversely, Hb ≥10.5 g/dL (HR 0.38 [0.20–0.75]) and platelets ≥100 G/L (HR 0.31 [0.13–0.70]) were associated with longer PFS. In multivariate analysis, only CNS-IPI remained independently associated with shorter PFS (HR 4.59 [2.09–10.08] for score 2–3; HR 4.78 [1.34–17.05]) for score ≥4. Conclusion: This large real-world cohort confirms the high efficacy and sustained responses of CPIs in R/R PMBL. These results support broader and earlier integration of CPIs in the treatment strategy for this high-risk population.

Primary mediastinal B-cell lymphoma (PMBCL) is a distinct subtype of large B-cell lymphoma with unique clinical, histopathological, and molecular characteristics. Despite its aggressive nature, PMBCL has a high cure rate when managed appropriately. Advances in the understanding of PMBCL biological characteristics, coupled with improvements in diagnostic tools and therapeutic approaches, have significantly improved patient outcomes in recent years. In this article, we present a set of pragmatic guidelines developed by the Lymphoma Study Association (LYSA) for the management of PMBCL. These guidelines address key aspects of diagnosis, staging, response evaluation, and treatment, integrating the latest evidence from clinical trials, expert consensus, and real-world practice. The aim of the guidelines is to provide clinicians with a clear, practical framework to optimize care for patients with PMBCL, ensuring that the best available evidence is translated into clinical practice.

Azacitidine (AZA) plus venetoclax (VEN) is the standard first-line treatment for patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). While current recommendations favor continuous ≥21-day VEN cycles, real-world adaptations using shorter schedules are common, aiming to reduce hematologic toxicity and improve tolerability. However, evidence comparing a 7-day VEN schedule with “standard” ≥21-day VEN remains limited. Methods:Data were retrospectively collected in the VENAURA registry (n = 775) from 10 different French centers (Saint-Etienne, Clermont-Ferrand, Grenoble, Lyon (Hopital Lyon Sud, Centre Léon Bérard), Nîmes, Villefranche sur Saône, Annecy, Valence, Roanne) in Auvergne Rhône Alpes (AURA) region, between January 2019 and February 2024. Patients were included if they received either 7 days or ≥21 days of VEN during cycle 1 in first-line treatment. Overall response rate was defined as in VIALE-A trial with a composite complete remission (CRc) combining complete remission (CR), complete remission with incomplete hematopoietic lineage recovery (CRi), morphological free leukemia state (MFLS). Results:A total of 254 patients were eligible: 202 (80%) received standard VEN and 52 (20%) received the short-course regimen. Median age was 74 years (range 31–92); patients in the short-course group were significantly older (median 76 vs 73 years, p<0.001), with more patients aged ≥80 (29% vs 11%, p=0.002). ECOG ≥2 was similar (27% vs 37%, p=0.58). AML subtypes (de novo, secondary, myelodyplasia-related, therapy-related), mutation profiles (TP53, NPM1, IDH1/2, FLT3-ITD, NRAS, KRAS) and ELN 2024 risk group distribution were balanced between groups. After the first treatment cycle, CRc was significantly lower in the short-course group compared to the standard group (40% vs 57%, p=0.048). When considering the best CRc achieved at any time during treatment, the short-course group also had significantly lower response rates (48% vs 74%, p<0.001). The median number of cycles was 3 in both groups. Among responders (n=190), 66% (short-course) and 61% (standard) achieved best response during the first cycle (p=0.76). Early mortality at 30 and 60 days was 5% and 8%, respectively, in the standard group, and 21% and 27% in the short-course group. With a median follow-up was 23 months, median OS was significantly shorter in the short-course group: 6 vs 13 months (p=0.0023), with a corresponding 2-year OS of 13% (95% CI 6–29) compared to 33% (27–42). Similarly, 2-year LFS was 11% (5–24) vs 24% (18–33) (p=0.0049) in short compared to standard group. Stratified by ELN 2024, 2-year OS and LFS were significantly better with standard VEN in favorable (OS: 40% vs 18%, p=0.02; LFS: 28% vs 17%, p=0.07) and intermediate risk (OS: 38% vs 17%, p=0.05; LFS: 35% vs 13%, p=0.05). In the adverse-risk group, -OS was 16% versus 25% (p=0.47) and LFS was 8% in both groups (p=0.37), with no statistically significant differences observed. In uni-and multivariate analyses, short-course VEN was independently associated with inferior OS (HR 2.22, 95% CI 1.52–3.24, p<0.001) and LFS (HR 2.02, 1.41–2.91, p<0.001). Other independent predictors of poor survival included therapy-related AML (OS: HR 2.18, p=0.004; LFS: HR 1.94, p=0.009) and complex/monosomal karyotype (OS: HR 2.07, p=0.001; LFS: HR 1.55, p=0.042). Conversely, NPM1 mutation predicted improved LFS (HR 0.47, p=0.003), with a trend toward improved OS (HR 0.61, p=0.057). IDH1/2 mutations were also associated with favorable outcomes in univariable analysis (OS: p=0.013; LFS: HR 0.66, p=0.052). ELN 2024 risk classification was significantly associated with both OS (p<0.001) and LFS (p=0.002) in univariate analysis, but did not retain significance in multivariate models. Conclusion:While 7-day VEN may appear feasible in selected patients, our data show inferior outcomes, particularly in those with favorable or intermediate ELN 2024 risk. These patients may benefit most from prolonged venetoclax exposure. Our study is limited by its retrospective nature and potential unmeasured differences in patient fitness. Although ECOG performance status was similar, patients in the short-course group were older and presented at least 1 exclusion criterion upon entry into a clinical trial, possibly reflecting greater frailty. Our findings do not support a generalized use of 7-day VEN schedules, and caution is warranted pending results from prospective randomized trials.