Real-world data from low and middle-income countries on the management of chronic lymphocytic leukemia (CLL) is needed to understand current clinical practices and unmet needs. Delayed or unequal access to novel agents may negatively impact disease outcomes in (RR) CLL.

To describe clinical outcomes of second-line treatment in patients with CLL included in the Brazilian Registry of CLL (BRCLL).

Observational study of second-line CLL treatments started between 2006 and 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.

Second-line treatments for 444 CLL patients were included. Median age at start of second-line treatment was 66 years (range: 23-93), and 264 were male (59%). Binet staging at CLL was A in 139 patients (36%), B in 139 (36%), and C in 107 (28%). Unmutated IGHV was observed in 61% of patients and FISH was performed in 166 patients (37%), of which 33 patients had del(17p) (20%). The most commonly prescribed regimens 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).

Chemotherapy-based second-line CLL treatments were frequent over the reported period, with inferior outcomes for CHOP/CVP-like treatments and monoclonal antibodies with or without steroids. Considering the approval of Bruton tyrosine kinase and BCL2 inhibitors in recent years, a shift towards targeted agents in RR CLL is anticipated, but cannot be established at this time for the majority of patients in second line reported to the BRCLL.

While the adoption of targeted therapies was associated with longer TTNT and OS, access to these agents is still very limited in our setting.