Several years ago, clinicians began investigating a new tyrosine kinase inhibitor called ibrutinib for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). Early clinical trials indicated that the drug outpaced the prior standard and it was hailed as a revolutionary new treatment. Yet concerns about cardiovascular toxicities somewhat dimmed the celebrations. With the final clinical trial results of ibrutinib for CLL/SLL now published, and years of data accumulated on side effects, researchers are confident that the benefits remain, and the threat of heart toxicity should not stand in the way.

CLL/SLL had been difficult to treat. Certain genetic mutations — 17p deletion, TP53 deletion or mutation, 11q deletion and unmutated immunoglobulin heavy chain variable region gene (IGHV) — put patients at high risk of early death from the cancer. Relapsed disease following initial treatment was also tied with a poor prognosis. Chemoimmunotherapy improved progression-free survival (PFS) and overall survival (OS), but patients who progressed following treatment had few, if any, options.

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Ibrutinib changed this situation for the better. The RESONATE trial, an open-label, phase 3 study comparing this experimental drug to ofatumumab-based chemoimmunotherapy, resulted in superior outcomes for previously treated patients, leading to FDA approval in this setting.1 But adverse events raised concern, in particular arrhythmias and hypertension with prolonged use of ibrutinib. While researchers and patients awaited long-term data from the trial, they also worried about whether cardiac toxicity would halt the revolution in the care of CLL/SLL that ibrutinib seemed to offer.

A study in the American Journal of Hematology presented the final analysis of the RESONATE study.2 In the initial trial, patients with relapsed/refractory CLL or SLL following one or more prior lines of therapy were randomized to receive either ibrutinib (195 patients) or ofatumumab (196 patients). As part of the extended investigation, patients in the control arm were allowed to cross over to ibrutinib based on how they responded to their initial study treatment. 

The first report of RESONATE showed improved efficacy among patients randomized to ibrutinib compared with those treated with ofatumumab. The paper seemed to confirm the initial findings. After 74 months of follow-up, the PFS among patients enrolled in the ibrutinib arm was notably longer — 44.1 months compared with 8.1 months for the ofatumumab arm. (The PFS for ibrutinib was slightly shorter than the 51 months noted in an earlier report from the study.)3 That difference included the 82% of patients with genetically high-risk disease. Five years into the study, the disease in the 40% of patients in the ibrutinib cohort had not progressed, compared with the disease in 3% of patients in the ofatumumab cohort.