The impact of fitness and dose intensity on clinical outcomes with venetoclax-obinutuzumab in CLL

Venetoclax-obinutuzumab (Ven-Obi) is a standard first-line therapy for chronic lymphocytic leukemia (CLL). The impact of age, fitness, and dose reductions remains unclear. We analyzed patients treated with Ven-Obi in the CLL13 and CLL14 trials, excluding patients with TP53 aberrations. Fitness was assessed using the cumulative illness rating scale (CIRS, >6) and creatinine clearance (≤70 ml/min). Among 410 patients (median age 67), 55.7% were unfit (median age 72) and 44.3% fit (58). Overall response rate (ORR) was 89.5% in unfit and 96.1% in fit patients. Undetectable minimal residual disease (uMRD) <10-4 rates were 80.3% in unfit and 85.1% in fit patients. Progression-free survival (PFS) at 3 years was 86.4% vs 87.5% (HR 1.12, 95%-CI 0.70-1.81, p=0.63). Overall survival at 3 years was 91.8% vs 96.9% (HR 2.02, 95%-CI 0.90-4.55, p=0.088). Adverse events included neutropenia (62.7% unfit, 56.9% fit), infusion-related-reactions (44.3% unfit, 56.9% fit), fatigue (15.8% unfit, 35.9% fit) and infections (57.5% unfit, 69.6% fit). Venetoclax dose reductions <80% occurred in 39.6% of unfit and 17.6% of fit patients, with lower ORR (83.3% vs 98.2%) and uMRD rates (74.2% vs 87.9%) in those with reduced dose intensities, but similar PFS. Dose reductions <70% were associated with shorter PFS. Overall, this study shows comparable efficacy and toxicity of Ven-Obi in fit and unfit patients with CLL.