Ibrutinib Effective in Patients with CLL with High-Risk Genomic Mutations

Certain genomic abnormalities are predictive of poor outcomes in chemoimmunotherapy (CIT) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including del(17p)/TP53 mutation, del(11q), and unmutated IGHV. BIRC3, NOTCH1, SF3B1, and XPO1 mutations have also been associated with inferior CIT outcomes in patients with CLL. Ibrutinib, a once-daily Bruton’s tyrosine kinase inhibitor, has been associated with improved progression-free survival (PFS) and overall survival in patients with previously untreated or relapsed/refractory CLL/SLL. Patients with high-risk genomic abnormalities treated with ibrutinib have also demonstrated superior outcomes compared with those treated with competitors. Researchers analyzed two phase III studies of ibrutinib-based therapy in the first-line setting for CLL/SLL. The results of the analysis were presented at the 62nd ASH Annual Meeting & Exposition.

The RESONATE-2 trial randomized patients aged ≥65 years without del(17p) to receive either ibrutinib or chlorambucil. The iLLUMINATE trial randomized patients aged ≥65 years, or <65 years with coexisting conditions or del(17p)/TP53 mutation, to receive either ibrutinib plus obinutuzumab or chlorambucil plus obinutuzumab. Fluorescence in situ hybridization (FISH) or targeted next-generation sequencing was conducted to evaluate for del(17p) and del(11q), or mutations in IGHV, TP53, BIRC3, SF3B1, NOTCH1, or XPO1. PFS and overall response rate (ORR) were examined by subsets per FISH cytogenetics or single gene mutations alone or in combination. Comparisons were made between patients treated with ibrutinib versus chlorambucil therapies, and patients treated with ibrutinib with versus without high-risk genomic CLL features.

Collectively, there were 249 patients treated with first-line ibrutinib-based therapy and 249 patients treated with first-line chlorambucil-based therapy. Median follow-up was 49.1 months.

Ibrutinib-based therapy, compared with chlorambucil-based therapy, was associated with significant improvements in ORR and PFS. When analyzing different high-risk genomic subgroups, PFS rates were significantly higher across the board in patients who received ibrutinib-based therapy compared with chlorambucil-based therapy (63% to 82% vs. 6% to 34%).

Further analyses compared ibrutinib-treated patients with versus without specified high-risk genomic features and found that PFS and ORR did not largely differ among the subgroups. Patients with del(17p)/TP53 mutation/BIRC3 mutation also had improved outcomes (hazard ratio, 1.05; 95% confidence interval, 0.54–2.04).

When analyzing the rates of treatment-emergent adverse events (AEs) across high-risk subgroups after a median of 35.7 to 43.8 months of ibrutinib treatment, there were no significant differences in rates of any-grade or grade ≥3 AEs versus the overall population.