Hematology

Long-term beti-cel data show durable transfusion independence and iron rebalancing in TDT

Among 63 transfusion-dependent β-thalassemia patients (median age 17), betibeglogene autotemcel achieved durable transfusion independence in most recipients over 5.9 years’ median follow-up. Phase 3 manufacturing changes increased vector copy number and HbAT87Q, raising transfusion-independence rates to 90.2% with hemoglobin around 11 g/dL during independence. Efficacy was similar across ages and genotypes, and most transfusion-independent patients discontinued iron chelation without liver iron accumulation. Markers of ineffective erythropoiesis and iron dysregulation improved, with durable quality-of-life gains and no observed insertional oncogenesis or vector-related malignancies. 1

Venetoclax combinations likely improve survival in older AML ineligible for intensive therapy

This systematic review and meta-analysis of 47 studies evaluated low-intensity regimens in adults ≥55 years with AML unfit for conventional induction. Azacitidine or low-dose cytarabine combined with venetoclax probably reduces mortality and improves remission compared with single-agent HMA or LDAC. These regimens likely improve quality of life, although functional status and detailed QoL reporting were limited. Azacitidine plus IDH1 inhibitors may reduce one-year mortality and improve survival in IDH1-mutated AML, but evidence certainty is lower. 2

Fifteen-day venetoclax–azacitidine induces high responses in untreated higher-risk MDS

This prospective multicenter trial enrolled 28 treatment-naïve higher-risk MDS patients treated with azacitidine plus venetoclax for 15 days per 28-day cycle. Objective response rate was 85.7% by 2006 IWG criteria, including 35.7% complete remission and frequent marrow complete remissions. Responses occurred across molecular and IPSS-R subgroups, and median overall survival was not reached at 8.5 months’ follow-up. Grade 3-4 neutropenia, anemia, and thrombocytopenia were nearly universal, with serious infections in about one-third of patients. 3

Clonal hematopoiesis is frequent in CLL and differentially shaped by therapy

In 620 CLL patients from two randomized trials, clonal hematopoiesis was present in 58.2%, commonly involving DNMT3A, TET2, TP53, and ASXL1. Longitudinal analysis showed most clones persisted, while many patients acquired additional CH mutations during follow-up. BAX- and U2AF1-mutated CH emerged under venetoclax-obinutuzumab, whereas PPM1D-mutated CH arose with chlorambucil-obinutuzumab, indicating therapy-specific selection. Large CH clone size (>10% VAF) independently predicted shorter overall or progression-free survival with placebo or chlorambucil-obinutuzumab but not with targeted therapies. 4