Review Finds Questions Remaining About Ibrutinib Dose Modification in CLL

A new review evaluating ibrutinib dose modifications in patients with chronic lymphocytic leukemia(CLL) finds there remains a lack of clarity on how such changes affect clinical outcomes.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib was approved back in 2014 as a second-line therapy for CLL, with a standard dose of 420 mg per day. In the years since, however, treatment with ibrutinib has evolved significantly in clinical practice, according to a team of investigators including corresponding author Janice Gabrilove, MD, of the Icahn School of Medicine at Mount Sinai. In real-world use, patients prescribed ibrutinib for CLL include patients younger than those included in the original clinical trials, as well as patients with unfavorable prognostic factors and comorbidities that were used to exclude patients from the original trial.

“The purpose of this review was to examine our current knowledge of dose modifications in ‘real-world practice’ for patients with CLL, and its potential clinical impact, as published in the literature,” write Gabrilove and colleagues. Their results are published in the Journal of Hematology & Oncology.

In their search of medical literature, the authors found a total of 29 studies to review; 14 were clinical trials and the remaining 15 were “real-world practice” studies.

The authors’ analysis showed similar discontinuation rates among the clinical trials and real-world studies (32% and 33.5%, respectively). One difference, however, was the cause of the discontinuations; in the clinical trials the more common reason was CLL progression, while toxicity was more common in real-world settings, they report. In the largest of the “real-world” studies, the most common toxicities were arthralgia, atrial fibrillation, and rash.

Current dosing recommendations suggest a reduction in ibrutinib dosing for patients who also require a moderate or strong CYP3A inhibitor.

The authors note that physicians may see this an opportunity for cost savings, by routinely placing patients with ibrutinib on a lower dose and pairing it with an inexpensive CYP3A inhibitor.

“However, the safety of this approach, the long-term tolerability, and the clinical efficacy of ibrutinib therapy in this context has not been formally evaluated,” they caution. The authors write that a well-designed prospective clinical trial ought to be undertaken before the approach should be considered in clinical practice.

More broadly, Gabrilove and co-authors also report that prolonged reductions or interruptions in ibrutinib dosing appear to worsen outcomes in patients, “though it remains unclear whether it is due to the patient’s inability to receive the standard dose, or whether it results from the dose modification itself.” Those findings are not universal, however. Some studies have suggested dose reductions do not negatively affect treatment efficacy. Such findings are controversial, the authors report, but also serve to highlight the significant questions remaining.

At present, the authors suggest sticking with the best practice of reducing ibrutinib based on concomitant use of CYP3A inhibitors or due to patient liver disease comorbidity.

“Based on this review, these dosing recommendations, as well as clinical judgment, should guide dosing parameters in an effort to optimally balance clinical therapeutic efficacy and safety,” they write.

Reference

Hardy-Abeloos C, Pinotti R, Gabrilove J. Ibrutinib dose modifications in the management of CLL. J Hematol Oncol. [Published online June 5, 2020]. doi:10.1186/s13045-020-00870-w