Ibrutinib, a Bruton’s tyrosine kinase inhibitor (TKI), in combination with the B-cell lymphoma 2 (BCL2) protein inhibitor venetoclax is highly effective as first-line treatment for patients with high risk chronic lymphocytic leukemia (CLL), according to results published in the New England Journal of Medicine.

A total of 80 patients at high risk for CLL were enrolled. Researchers investigated a regimen of 420 mg ibrutinib administered daily for 3 cycles followed by the addition of 500 mg venetoclax administered daily using weekly dose escalation for a total of 24 cycles of combined therapy.

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There was a rapid conversion to complete response at the start of combination therapy. At 12 cycles, 88% (29 of 33) of patients had complete remission (CR) or CR with incomplete count recovery, and 61% of patients had remission with undetectable minimal residual disease (MRD), as measured by flow cytometry. In patients aged 65 years and older at 12 cycles, rate of CR or CR with incomplete count recovery was 94%, and rate of remission with undetectable MRD was 61%.

Results were consistent across all patient subgroups, including those with high-risk genetics (17p deletion, 11q deletion, trisomy 12), and independent of IGHV mutation, TP53 mutation, and NOTCH1 mutation.

Grade 3 or higher adverse events occurred in 60% of patients, with neutropenia being the most frequent side effect: 48% of patients experienced grade 3 or 4 neutropenia. The rate of neutropenia and neutropenic fever (5%) was similar to the observed rate in previous venetoclax monotherapy trials. Atrial fibrillation developed in 15% of patients. Side effects had the same frequency among young and elderly patients.

These results are “substantially better than what has been reported with ibrutinib or venetoclax monotherapy for patients with CLL,” the authors noted. Additionally, this combination therapy appears to be superior to chemoimmunotherapy, which has resulted in rates of 40% and 74% for CR and remission with undetectable MRD, respectively, in previous trials.

Of note, elderly patients, who tend to have lower rates of CR and higher susceptibility to toxicities, experienced a significant improvement with the same rate of side effects as young patients. Future studies with longer follow-up are needed to determine appropriate therapy duration and establish the safety and side effect profiles of this combination therapy.

Reference

1.     Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first line treatment of CLL [published online May 30, 2019]. N Engl J Med. doi:10.056/NEJMoa1900574