Efficacy and safety of venetoclax-based regimens in chronic myelomonocytic leukemia: A systematic review and meta-analysis.

Abstract

e18593 Background: Chronic myelomonocytic leukemia (CMML) is a heterogeneous myelodysplastic/myeloproliferative neoplasm with limited disease-modifying options beyond hypomethylating agents (HMAs) and allogeneic stem cell transplantation. Venetoclax (VEN), a selective BCL-2 inhibitor, is increasingly used off-label in CMML; however, CMML-specific efficacy and safety data remain fragmented and heterogeneous. We conducted a systematic review and meta-analysis to define clinical outcomes associated with VEN-based therapy in CMML. Methods: A systematic search of PubMed, Embase, and Cochrane CENTRAL from inception through August 2025 was performed in accordance with PRISMA 2020 guidelines. Adult CMML cohorts (≥5 patients) treated with VEN-based regimens and reporting CMML-specific outcomes were included. Random-effects meta-analyses of proportions were conducted for complete remission (CR), marrow complete remission (mCR), and overall response rate (ORR). Heterogeneity was assessed using the I² statistic. Results: Seventeen publications representing nine unique studies were included, encompassing 145 VEN-treated CMML patients. Most regimens combined VEN with azacitidine, decitabine, or oral decitabine–cedazuridine. Responses typically occurred early (within 1–2 cycles), but durability was limited. Pooled response estimates were: CR 19.1% (95% CI, 9.4–34.9; I²=55%), mCR 36.4% (95% CI, 24.7–50.0; I²=21%), and ORR 71.9% (95% CI, 56.5–83.4; I²=56%). Survival outcomes were modest, with median overall survival generally ranging from 10–16 months across real-world cohorts. VEN-based therapy was associated with substantial myelosuppression, including frequent grade ≥3 neutropenia and thrombocytopenia, with clinically significant infectious complications; early mortality remained low. Patients without RAS-pathway mutations and those treated in the frontline or transplant-directed setting appeared to derive greater benefit. Conclusions: VEN-based regimens demonstrate measurable but limited activity in CMML, characterized by high overall response rates but low complete remission rates and modest durability. These findings support a selective role for VEN as treatment intensification or as a bridge to transplantation rather than routine therapy. Prospective CMML-specific trials are needed to define optimal patient selection and therapeutic positioning.