Incidence and clinical impact of absolute lymphocyte count-only progression in chronic lymphocytic leukemia

An increase in the absolute lymphocyte count (ALC) is a component of progressive disease (PD) in chronic lymphocytic leukemia (CLL) and contributes to progression free survival (PFS) in phase 3 trials. Prior studies with chemoimmunotherapy demonstrated that PD by ALC alone (ALC PD) conferred better outcomes than other modalities of PD (other PD). To evaluate the incidence and impact of ALC PD with modern treatments, we retrospectively examined 339 consecutive CLL/SLL patients treated between 2016 - 2025 at the University of Washington/Fred Hutchinson Cancer Center. Patients received frontline therapy with continuous Bruton tyrosine kinase inhibitors (BTKi, n=179), bendamustine-rituximab (BR, n=66), and time-limited BCL2 inhibitors (BCL2i, n=94). The cumulative incidence of ALC PD was higher with BR than BTKi and BCL2i (p=0.021). Across treatment groups, overall survival (OS) from progression was longer for ALC PD than other PD (median 116 vs 71 months, p=0.0012, HR 3.15, 95% CI 1.52-6.53) with 5-year OS rates of 83% and 56%. Time to next treatment or death (TTNT-D) was longer for ALC PD (median 14 vs 2.2 months, p<0.0001, HR 3.36, 95% CI 2.27-4.95). OS from treatment initiation was longest for non-progressors, intermediate for ALC PD (HR 3.62, 95% CI 1.48-8.85, p=0.005), and worst for other PD (HR 11.7, 95% CI 5.99-22.9, p<0.001). These findings suggest that ALC PD may vary based on treatment modality and is associated with longer survival and TTNT-D. If confirmed in larger phase 3 datasets, future response criteria may consider reporting ALC PD separately from other PD.