Edouard Forcade

Iptacopan, an oral Factor B inhibitor, is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). In clinical trials it was safe and effective but real‐world data, particularly in patients with associated bone marrow failure, remain limited. A retrospective, multicenter study was conducted in patients with PNH who received iptacopan monotherapy in the UK and France between July 2021 and July 2025. Patient demographics, prior treatment and indication for switch were collected, as were hematological parameters at baseline, 3, 12 and 24 months. Outcomes included breakthrough hemolysis, infections, thrombotic events, treatment discontinuation and death. A total of 151 patients were included with a median treatment duration of 238 days. Iptacopan produced significant increases in mean hemoglobin, from 104 g/L at baseline to 127 g/L at 3 months, with improvements sustained to 24 months. A total of 76% achieved a hemoglobin ≥ 120 g/L by 12 months, compared with 21.9% at baseline, with transfusion independency in 88%. There was no statistical difference in responses between patients with and without history of bone marrow failure. Breakthrough hemolysis occurred in 6.6% of patients, with a mean hemoglobin fall of 24 g/L. Suspected bacterial infections occurred at a rate of 0.18 per patient‐year, but there were no meningococcal or pneumococcal infections. There were no thromboses, and no deaths related to iptacopan. This cohort demonstrates that iptacopan produces sustained improvements in patients with PNH, irrespective of prior complement inhibition or history of bone marrow failure. Longer follow‐up is needed to characterize long‐term efficacy and infection risk.

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 (alloHSCT) is a potentially curative treatment for high-risk acute myeloid leukemia (AML), and outcomes are strongly influenced by disease status at transplantation. In transplants using conventional graft-versus-host disease (GVHD) prophylaxis, outcomes also depend on the number of induction courses required to achieve first complete remission (CR1); however, this has not been evaluated in patients receiving post-transplant cyclophosphamide (PTCy). We retrospectively analyzed 677 adult AML patients transplanted in CR1 between 2012 and 2022 using PTCy-based GVHD prophylaxis. Outcomes were compared between patients achieving CR1 after one induction course ( n = 518) and those requiring two courses ( n = 159). Baseline characteristics, donor type, conditioning intensity, graft source, engraftment, and rates of acute and chronic GVHD were comparable between groups. Patients requiring two inductions had a higher 2-year cumulative incidence of relapse (27% vs. 19.3%; HR 1.75, p = 0.003). However, no significant differences were observed in 2-year overall survival (62.8% vs. 69%), leukemia-free survival (61.1% vs. 65%), GVHD-free/relapse-free survival (46.3% vs. 50.4%), or non-relapse mortality (11.9% vs. 15.7%). In AML patients receiving alloHSCT with PTCy, outcomes were largely similar regardless of whether CR1 was achieved after one or two-induction courses, with relapse incidence being higher in patients requiring 2 inductions.

The RACE study (NCT02009747) compared horse antithymocyte globulin (hATG) plus cyclosporine A (CsA) ± eltrombopag as initial immunosuppressive treatment (IST) for severe aplastic anemia. Here we report the final 2‐year analysis of this prospective randomized phase III study. One hundred ninety‐seven treatment‐naive patients were randomized to standard IST (hATG 40 mg/kg × 4 days and CsA 5 mg/kg/day; arm A; n = 101) or standard IST + eltrombopag at the dose of 150 mg/day (arm B; n = 96) from day +14 until 6 months (or 3 months, in case of complete response). The median follow‐up was 23.2 months. The 2‐year cumulative incidence of complete response was significantly superior in arm B (62.4% vs. 35.3%; p < 0.001). The 2‐year overall survival (OS) was 86% in arm A and 91% in arm B ( p = 0.081), with hazard ratio (HR), adjusted for age and disease severity, of 0.54 ( p = 0.064). The 2‐year disease‐free survival (DFS) was 56% vs. 37% (adjusted HR = 0.49; p < 0.001), while event‐free survival (EFS) was 48% vs. 32% ( p < 0.001), with adjusted HR = 0.54 ( p < 0.001), both significantly superior for arm B. The cumulative incidence of relapse was comparable in the two arms, while evolution to clinical paroxysmal nocturnal hemoglobinuria was 8% in arm A and 1% in arm B ( p = 0.041). The risk of clonal evolution remained negligible, with one patient in arm A and two in arm B developing karyotypic abnormalities. The initial hematological response benefit of eltrombopag added to IST as front‐line treatment of AA is associated with better 2‐year OS, DFS, and EFS without increased risk of secondary myeloid malignancies.

Allogeneic hematopoietic cell transplantation (allo-HCT) can cure acute leukemia, but relapse and non-relapse mortality restrict its success. Existing models focus on single prognostic areas and are not designed to predict leukemia-free survival (LFS), the outcome that best reflects allo-HCT’s curative intent. In this large retrospective cohort of allografted AL patients ( N = 24,317), we combined key pre-transplant patient, disease, and treatment factors into a practical holistic H-score to predict post–allo-HCT LFS. Component weights were derived from Cox-regression hazard ratios in a training cohort ( N = 19,029). The model was validated in a geographically split testing cohort (N = 4760), with outcomes assessed using Kaplan-Meier analysis and multivariate Cox models. In the overall cohort ( N = 24,317), 2-year overall survival and LFS were 64% and 56%, respectively. The H-score stratified patients into four risk groups, with 2-year LFS ranging from 66.2% in the low-risk group to 32.0% in the very high-risk group. The H-score was the strongest independent predictor of LFS ( p < 0.0001), outperforming individual indices and offering more refined risk stratification. The H-score was also an independent predictor of overall survival, relapse, and non-relapse mortality. While individual prediction is limited, the H-score aids patient counseling and provides a useful baseline for comparing new transplant treatments.

The International Prognostic Index (IPI) is an essential prognostic tool for patients with large B-cell lymphoma (LBCL). To compare outcomes after chimeric antigen receptor T-cell (CART) therapy and allogeneic stem cell transplantation (alloSCT) in relation to IPI risk factors, we analyzed 515 LBCL patients receiving CART (n = 303) or alloSCT (n = 212) as ≥third-line treatment, registered with EBMT (2016–2021). Patients treated with CART were older (median 62.4 vs 51.1 years), had higher IPI scores (48.2% vs 20.8% high/high-intermediate risk), and a higher incidence of refractory disease (84.1% vs 34.6%). At 24 months, overall survival (OS) was 49% vs 41%, progression-free survival (PFS) was 37% vs 32%, relapse-incidence (RI) was 56% vs 38%, and non-relapse-mortality (NRM) was 7% vs 30%, respectively. In multivariate analysis, CART therapy showed superior OS primarily due to significantly lower NRM, while RI was higher. The survival benefit of CART was significant in patients with low/low-intermediate IPI (OS HR 0.43, 95% CI 0.31-0.60), but not observed in high-risk patients. Elevated LDH eliminated the PFS advantage of CART over alloSCT. Poor outcomes after CART in patients with high-risk disease support early preparation for alloSCT for eligible patients.

Mantle cell lymphoma (MCL) predominantly affects older adults, and treatment options for relapsed/refractory (R/R) disease remain limited. Brexucabtagene autoleucel (brexu-cel) has demonstrated high efficacy in R/R MCL, but data in older adult populations are scarce. This retrospective, real-world analysis evaluated patients aged ≥70 years with R/R MCL treated with brexu-cel and reported to the EBMT registry between 2020 and 2024. A total of 233 patients from 96 centers across 13 countries were included (median age at infusion, 74.6 years; 44% >75 years). Most had Eastern Cooperative Oncology Group (ECOG) 0 to 1 (89%) and were heavily pretreated; 62% had prior Bruton tyrosine kinase inhibitor exposure. At day +100, the best overall response was complete remission in 78% and partial remission in 13%. At 30 days, the cumulative incidence of any-grade cytokine release syndrome was 80% (grade ≥3, 9%) and immune effector cell–associated neurotoxicity syndrome was 57% (grade ≥3, 22%). At 1 year, overall survival (OS) was 74%; progression-free survival (PFS), 62%; relapse/progression incidence, 25%; and nonrelapse mortality (NRM), 13%. Patients aged >75 years had outcomes comparable with those aged 70 to 75 years. In multivariable analysis, ECOG ≥2 remained the strongest predictor of inferior OS (hazard ratio [HR], 4.50; P< .001) and PFS (HR, 3.10; P< .001), whereas age was not independently associated with outcomes. Brexu-cel is effective in patients aged ≥70 years with R/R MCL, achieving high remission rates and meaningful survival, despite a relatively high incidence of NRM. Functional status, rather than age, should guide eligibility.