A Promising Combination: Venetoclax and Azacitidine in High-Risk MDS

Venetoclax plus azacitidine produced high objective response rates in treatment‑naive higher‑risk myelodysplastic syndrome (HR‑MDS), offering a practical strategy to deepen remissions and expand transplant candidacy in a population with historically poor outcomes.

A prospective multicenter trial reported an overall response rate (ORR) of 85.7% and a complete remission (CR) rate of 35.7%—an immediate clinical signal that may change frontline bridging strategies for eligible HR‑MDS patients.

This open‑label, prospective multicenter study enrolled 28 treatment‑naive HR‑MDS patients and used a 15‑day venetoclax exposure with standard azacitidine dosing on a 28‑day cycle. Patients received venetoclax plus azacitidine, with venetoclax escalated from 100 to 400 mg on days 1–15 and azacitidine 75 mg/m2 on days 1–7. The study's small sample size (n=28) limits the precision of the reported ORR and CR estimates; confidence intervals were not reported in the source and these estimates should be considered preliminary.

The primary endpoint, overall response rate by IWG criteria, was 85.7% (CR 35.7%; mCR 50.0%) with a median time to CR of 2.3 months. Median overall survival was not reached at a median follow‑up of 8.5 months. Follow‑up was short, which limits conclusions about durability and long‑term survival; confirmation of a durable benefit will require longer follow‑up and randomized data.

TP53 abnormalities emerged as a key genomic determinant. Patients with TP53 mutation or deletion maintained high initial response rates but experienced markedly shorter overall survival and lower CR rates (CR ≈14.3% in TP53‑abnormal cases). Other recurrent mutations (IDH1/2, ASXL1, DNMT3A and spliceosome‑related genes) showed variable CR rates—NPM1 and IDH1/2 tended toward higher CR proportions, while ASXL1 and DNMT3A had intermediate results—though small numbers limit formal subgroup inference. Molecular profiling therefore identified heterogeneity in remission depth and should inform individualized selection and monitoring strategies.

Hematologic toxicity was pronounced: grade 3–4 neutropenia occurred in 96.4% of patients, grade 3–4 anemia in 71.4%, and grade 3–4 thrombocytopenia in 64.3%, with serious infections in 35.7% of patients. Toxicities were managed with mandated antibacterial prophylaxis during early cycles, G‑CSF for febrile neutropenia, venetoclax dose adjustments when co‑administered with azole antifungals, and transfusion support as needed. Eleven of 28 patients (39.3%) proceeded to allogeneic hematopoietic stem cell transplant—often after two induction cycles—and most transplanted patients survived through the limited follow‑up, suggesting preliminary bridging potential. These observations require confirmation in larger cohorts with longer follow‑up; the safety profile argues for proactive cytopenia management and coordinated transplant planning when using this regimen.

Three clinical implications follow: patients with preserved baseline neutrophil reserve and those being evaluated for HSCT may derive the greatest immediate benefit; baseline genomic profiling (including TP53 and IDH1/2) can inform pretreatment planning and monitoring expectations; and operational attention to infection prophylaxis, cytopenia surveillance, and early transplant referral is important to safe delivery.

Looking forward, the efficacy and bridging signals reported here warrant validation in larger randomized cohorts with longer follow‑up to define durable survival benefit and refine molecularly guided use.

Key Takeaways:

• 15‑day venetoclax plus azacitidine produced an ORR of 85.7% and CR 35.7% in treatment‑naive HR‑MDS—signaling deeper remissions than HMA alone.
• TP53 abnormalities predict shorter survival despite preserved initial responses; baseline NGS should guide selection and monitoring.
• Profound cytopenias are frequent but manageable with prophylaxis, G‑CSF, dose adjustments, and transfusions; nearly 40% of patients were bridged to HSCT.