Rethinking the feasibility and safety of venetoclaxobinutuzumab in chronic lymphocytic leukemia: nontraditional factors may play a role in clinical practice

The concept of fitness to receive treatment with 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), Eastern Cooperative Oncology Group performance status, and caregiver need. Adverse events (AE) and treatment modifications were evaluated across four treatment phases. The median age of the patients was 66 years (19% ≥75 years old); 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 AE occurred in 55%, tumor lysis syndrome in 6%, severe infusion-related reactions in 5%. Overall, 3.3% of the patients died during treatment. Unfit patients did not show a significantly higher risk of treatment modifications due to AE. 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=0.002), prior malignancies (P=0.003), prolonged steroid pre-treatment (P<0.001), and baseline thrombocytopenia (P=0.013). Tox-DTD correlated with caregiver need (P=0.029), endocrine comorbidities (P=0.025), prior malignancies (P=0.002), hypogammaglobulinemia (P=0.003), high lymphocyte count (P=0.034), and prolonged steroid pre-treatment (P=0.006). In conclusion, this study confirms the feasibility of VO treatment in CLL clinical practice, highlighting the role of traditionally overlooked factors that ultimately do have an impact.