Venetoclax-Based Regimens in Chronic Myelomonocytic Leukemia: A Systematic Review and Meta-Analysis

Chronic myelomonocytic leukemia (CMML) is a biologically heterogeneous myelodysplastic/myeloproliferative neoplasm with limited disease-modifying options beyond hypomethylating agents (HMAs) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Venetoclax (VEN), a selective BCL-2 inhibitor, is increasingly used off-label in CMML, yet CMML-specific efficacy and safety remain incompletely defined. We conducted a systematic review and meta-analysis in accordance with PRISMA 2020, including adult CMML cohorts receiving VEN-based therapy with extractable CMML-specific outcomes. Seventeen publications representing nine unique studies were included, comprising 145 VEN-treated CMML patients. Most regimens combined VEN with azacitidine, decitabine, or oral decitabine-cedazuridine, using heterogeneous dosing schedules with CYP3A-guided dose modifications. Responses occurred early, typically within one to two treatment cycles, but durability was modest. Random-effects meta-analysis yielded pooled complete remission (CR) rates of 19.1% (95% CI, 9.4-34.9; I²=55%), marrow CR (mCR) rates of 36.4% (95% CI, 24.7-50.0; I²=21%), and an overall response rate (ORR) of 71.9% (95% CI, 56.5-83.4; I²=56%). VEN-based therapy was associated with substantial myelosuppression, including frequent grade ≥3 neutropenia and thrombocytopenia, with clinically relevant infectious complications; early mortality was low. In summary, VEN-based regimens demonstrate measurable but limited activity in CMML, with high ORR, but low CR rates. Prospective CMML-specific trials are needed to define optimal use and patient selection.