High Response Rates to Ibrutinib Retreatment After Relapsing with First-Line Fixed Duration Ibrutinib + Venetoclax in CLL/SLL

CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of first-line ibrutinib + venetoclax treatment for 2 patient cohorts with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL): minimal residual disease (MRD)–guided randomized-discontinuation (MRD cohort) and Fixed Duration (FD cohort); ibrutinib-based retreatment was permitted per protocol following progression on FD treatment. At the 2023 American Society of Hematology annual meeting, retreatment outcomes in patients from the FD cohort or the MRD cohort placebo arm, as well as updated 5-year follow-up results of the FD cohort, were presented and summarized here.

The study enrolled patients aged ≤70 years with previously untreated CLL/SLL. Eligible patients received 3 cycles of ibrutinib lead-in, followed by 12 cycles of combined ibrutinib + venetoclax (ibrutinib 420 mg/day orally; venetoclax, standard 5-week ramp up to 400 mg/day orally). In the MRD-guided cohort, patients with confirmed uMRD were randomized 1:1 to placebo or ibrutinib, patients who do not have confirmed uMRD were randomized to ibrutinib or ibrutinib + venetoclax. Patients with progressive disease after completion of the FD cohort or MRD cohort placebo arm could reinitiate treatment with single agent ibrutinib.

A total of 202 patients were treated with FD ibrutinib + venetoclax in the FD cohort (n=159) or the MRD cohort placebo arm (n=43); of these, 53 have had PD, with PD occurring >2 years after treatment completion in 65% (n=32/49) of patients.

Of the 53 patients with PD, a total of 22 patients received single-agent ibrutinib. With a median time on retreatment of 17 months, overall response rate (ORR) was 86% including 1 complete response (CR). A total of 6 patients received retreatment with ibrutinib + venetoclax with an ORR of 83%, including 33% achieving a complete response (CR). The most common adverse events (AEs; occurring ≥10%) during single-agent ibrutinib retreatment were COVID-19 (n=6), diarrhea (n=5), hypertension (n=4), and pyrexia (n=3). In the retreated cohort, there were no reports of dose reductions or discontinuations due to AEs.

In the FD cohort (median time on study of 56 months), the 54-month PFS rate was 70% and OS rate was 97%. There was no change from the 4-year follow-up analysis in best response rates, with ORR of 96% achieved including CR/CR with incomplete bone marrow recovery (CRi) rate of 58%. The 54-month progression-free survival (PFS) rate was promising in patients with high-risk features; however, it was lower in the del(17p)/mutated TP53 cohort (45%). There were no new related serious AEs reported since the previous analysis. Second malignancies were reported in 8% of patients.

These results of the CAPTIVATE study show promising efficacy with ibrutinib-based retreatment in patients progressing on first-line FD regimen; at 5 years of follow-up, FD ibrutinib + venetoclax continues to provide deep remissions and PFS benefit, including in patients with high-risk genomic features.


Ghia P, Wierda W, Barr P, et al. Relapse after first-line fixed duration ibrutinib + venetoclax: high response rates to ibrutinib retreatment and absence of BTK mutations in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with up to 5 years of follow-up in the phase 2 CAPTIVATE Study. Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Abstract 633.

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