Rethinking the feasibility and safety of venetoclax-obinutuzumab in chronic lymphocytic leukemia: non-traditional factors may play a role in clinical practice

Abstract

The concept of fitness for novel agents in chronic lymphocytic leukemia (CLL) remains debated. Comorbidities and treatment-related logistics are increasingly recognized as key factors in treatment feasibility. Venetoclax-obinutuzumab (VO) has demonstrated efficacy in both fit and unfit patients in clinical trials, yet real-world data remain limited.

This retrospective, multicenter study analyzed disease- and patient-related factors affecting VO management and outcomes in 271 patients. Fitness was assessed using comorbidity indices (CLL-CI, CIRS, CCI), ECOG-PS, and caregiver need. Adverse events (AEs) and treatment modifications were evaluated across four treatment phases.

Median age was 66 years (19% ≥75); 83% had comorbidities, 34% required polypharmacy, and 10% needed caregiver support. Overall, 96% completed debulking, 89% the full regimen, while 11% discontinued due to toxicity (Tox-DTD). Grade ≥3 AEs occurred in 55%, tumor lysis syndrome in 6%, severe infusion-related reactions in 5%. Overall, 3.3% died during treatment. Unfit patients did not show a significantly higher risk of treatment modifications due to AEs. Dose adjustments were more frequent during debulking. None of the validated fitness scores predicted treatment feasibility or Tox-DTD.

Global feasibility was impacted by age (p .002), prior malignancies (p .003), prolonged steroid pre-treatment (p <.001), and baseline thrombocytopenia (p .013). Tox-DTD correlated with caregiver need (p .029), endocrine comorbidities (p .025), prior malignancies (p .002), hypogammaglobulinemia (p .003), high lymphocyte count (p .034), and prolonged steroid pre-treatment (p .006). In conclusion, this study confirms VO feasibility in CLL clinical practice, highlighting the role of traditionally overlooked factors that ultimately have an impact.