Real-World Outcomes of Second-Line Chronic Lymphocytic Leukemia Treatments: Retrospective Analysis of the Brazilian Registry of CLL

Abstract

Introduction: Major advances in the treatment of relapsed-refractory (RR) chronic lymphocytic leukemia (CLL) patients were observed in the last decade with the adoption of targeted agents. While a shift away from chemotherapy is expected, the impact of delayed or unequal access to targeted agents in low- and middle-income countries needs to be uncovered through real-world data. Objective: To assess the clinical outcomes of second-line treatment in RR CLL patients included in the Brazilian Registry of CLL (BRCLL). Patients and Methods: This is an observational study of second-line CLL treatments started between January 2006 and December 2021. BRCLL is a prospective non-interventional data collection tool. All participant centers registered their CLL patients online, after study approval at each center's ethical review board. Diagnosis and staging of included CLL patients were performed in accordance with recommendations from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL). Results: Four hundred and forty-four CLL patients in second-line were included. Median age at start of second-line treatment was 66 years (range: 23-93), and 264 were male (59%). At CLL diagnosis, Binet staging was A in 139 patients (36%), B in 139 (36%), and C in 107 (28%). High beta-2-microglobulin levels at diagnosis were found in 58%, and unmutated IGHV was observed in 61% of patients. At diagnosis, FISH was performed in 166 patients (37%), of which 33 patients had del(17p) (20%). The most commonly prescribed second-line treatments were: FC (+/- R) in 160 patients (36%); chlorambucil (+/- R) in 109 (25%); ibrutinib in 63 (14%); CHOP/CVP (+/- R) in 62 (14%); monoclonal antibodies (+/- steroids) in 33 (7%); allogeneic stem cell transplantation in 9 (2%) and venetoclax in 8 (2%). Forty patients (9%) were treated in clinical trials. Median follow-up after second-line treatment was 34 months (range: 3-176). Median time-to-next treatment (TTNT) was 28 months. TTNT was statistically longer in patients who received second-line with ibrutinib or venetoclax in comparison with FC or chlorambucil +/- anti-CD20 (not reached versus 29 months, p<0.0001) or those who received other regimens (CHOP or CVP +/- anti-CD20, monoclonal antibodies +/- steroids - 12 months, p<0.0001). Higher 3-year treatment-free survival (TFS) was also observed with ibrutinib or venetoclax (69% versus 41% and 23%, respectively, p<0.0001). Among patients included in clinical trials, 3-year TFS was also higher (70% versus 38%, p<0.0001). TFS for patients receiving allogeneic stem cell transplantation was 86% at 3 years. Overall survival (OS) probability at 3 years was 71%. OS was significantly shorter in those who received other regimens (CHOP/CVP-like or monoclonal antibodies +/- steroids - 53%), in comparison with those who received ibrutinib or venetoclax (80%, p<0.0001), or FC/chlorambucil-based chemotherapy (69%, p=0.01). Conclusion: Over the reported period, second-line CLL treatments in Brazil were mostly chemotherapy- or chemoimmunotherapy-based, with unfavorable outcomes associated with CHOP/CVP-like regimens or monoclonal antibodies +/- steroids. While the adoption of targeted therapies was associated with longer TTNT and OS, access to these agents is still very limited in the public setting.