Pharmacodynamic approach to assessing leukopenia as a marker of treatment efficacy in CDK4/6 inhibitor therapy in patients with HR+/HER2- metastatic breast cancer: a multicenter real-world study

Relevance. The introduction of CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) into clinical practice has significantly improved the treatment outcomes of patients with metastatic HR+/HER2-breast cancer. However, the lack of reliable predictors of therapy response limits the possibilities of personalization of treatment. Leukopenia, the most common hematological complication of CDK4/6 inhibitor therapy, not only reflects the degree of myelosuppression but also serves as an indirect indicator of the pharmacodynamic effect associated with the suppression of bone marrow cell proliferation through a mechanism similar to the targeted effect on the tumor. Despite individual studies demonstrating a potential link between leukopenia degree and therapy effectiveness, data from actual clinical practice remain contradictory and insufficiently systematized.

Objective. This study retrospectively examined the possible predictors of CDk4/6 inhibitor effectiveness in clinical practice.

Materials and methods. A retrospective, multicenter analysis of data from 170 HR+/HER2-breast cancer patients treated with CDK4/6 inhibitors (palbociclib or ribociclib) in five cancer centers in Siberia and the Far East from 2019 to 2020 was conducted. The patients were stratified into two groups based on the maximum degree of toxicity according to CTCAE v5.0: group 1 (leukopenia G0–1, n=81) and group 2 (leukopenia G≥2, n=89). The primary and secondary endpoints were overall survival (S) and progression-free survival (PFS).

Results. Patients in group 2 (leukopenia G≥2) showed a statistically significant increase in median OS compared with group 1 (leukopenia G0-1): 60.0 months (95 % CI: 32.0–72.0) versus 42.0 months (95 % CI: 30.0–60.0), respectively (risk ratio [HR] 0.64; 95 % CI: 0.42–0.97; p=0.034). In the analysis of progression-free survival (PFS), an improvement trend was observed in group 2 (median 68.0 vs 60.0 months), but it did not reach statistical significance (p >0.05).

Conclusion. In a real-world study, the development of grade 2 and higher leukopenia during CDK4/6 inhibitor therapy was associated with improved OS. These data confirm that the degree of myelosuppression can serve as a valuable and readily available predictive biomarker of treatment effectiveness.

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