Evaluating complete response/remission rate as a surrogate endpoint in relapsed/refractory chronic lymphocytic leukemia

Achieving complete response/remission (CR) by International Workshop on Chronic Lymphocytic Leukemia 2018 criteria indicates complete remission of leukemia in all disease compartments. We evaluated CR rate as a surrogate endpoint for progression-free survival (PFS) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) using data from randomized controlled trials (RCT). A systematic literature review was conducted to identify RCTs with ≥ 2 treatment arms, parallel group design, and reporting CR rate and PFS in patients with R/R CLL/SLL. Association between treatment effects on CR rate and corresponding PFS changes contrasting treatment and control arms was estimated using a weighted linear model, Daniels and Hughes model, and Riley bivariate random-effects meta-analysis. Association between absolute CR rate and PFS within individual treatment arms was estimated using nonparametric (Cox) and parametric (exponential, Weibull, Gompertz) proportional hazards models. Twenty RCTs were identified including 5765 patients with R/R CLL/SLL investigating various treatments (Bruton tyrosine kinase inhibitors, a B-cell lymphoma 2 inhibitor, phosphatidylinositol 3-kinase inhibitors, chimeric antigen receptor T-cell therapy, anti-CD20 monoclonal antibody, chemotherapy). Across RCTs, higher odds of CR resulted in statistically significant lower hazards of disease progression/death, where each 10 % increase in CR rate was associated with a 26 % (95 % confidence interval, 22 %30 %) reduction in risk of progression/death. Cross-validation analyses demonstrated that treatment effects on CR rate reasonably predicted PFS benefits. Results were broadly consistent across different models. This study supports CR rate as an essential treatment goal and a valid surrogate endpoint in R/R CLL/SLL.