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 treatment options beyond hypomethylating agents (HMAs) and allogeneic hematopoietic stem cell transplantation. Venetoclax, a selective BCL-2 inhibitor, is increasingly used off-label in CMML, but its CMML-specific efficacy and safety remain incompletely defined.

We conducted a systematic review and meta-analysis in accordance with PRISMA 2020. Eligible studies included adult patients with CMML treated with venetoclax-based regimens and reporting extractable CMML-specific outcomes. PubMed, Embase, Cochrane CENTRAL, conference proceedings, and trial registries were searched through August 2025. Random-effects meta-analyses of proportions were performed for complete remission (CR), marrow complete remission (mCR), and overall response rate (ORR).

Seventeen publications representing nine unique studies were included, comprising 145 venetoclax-treated CMML patients. Most regimens combined venetoclax with azacitidine, decitabine, or oral decitabine-cedazuridine, with heterogeneous dosing schedules and frequent CYP3A-guided dose modifications. Responses typically occurred early, within one to two treatment cycles, but durability was generally modest. The pooled CR rate was 19.1% (95% CI: 9.4-34.9; I2 = 55%), the pooled mCR rate was 36.4% (95% CI: 24.7-50.0; I2 = 21%), and the pooled ORR was 71.9% (95% CI: 56.5-83.4; I2 = 56%). Venetoclax-based therapy was associated with substantial myelosuppression, including frequent grade ≥3 neutropenia and thrombocytopenia, with clinically relevant infectious complications. Early mortality was low in studies reporting short-term outcomes.

Venetoclax-based regimens demonstrate measurable but limited activity in CMML, with high overall response rates but low CR rates and modest durability. Prospective CMML-specific trials are needed to define optimal dosing, clarify comparative effectiveness, and identify patients most likely to benefit.