Interruptions of Ibrutinib Lead to Worse Outcomes in Patients With CLL

Dose modification of ibrutinib does not appear to impact outcomes in patients with chronic lymphocytic leukemia (CLL), but temporary interruption of the treatment has negative impacts on outcomes.

Those are the findings of new research published this month in the journal Cancer Medicine. Ibrutinib has been approved by the FDA for the treatment of previously untreated CLL and relapsed/refractory CLL. However, the drug’s cost and toxicity profile, among other factors, could potentially limit the drug’s success outside of the clinical trial setting, according to corresponding author Sameer A. Parikh, MBBS, of the Mayo Clinic.

For instance, a 2018 study showed more than 4 in 10 patients treated with ibrutinib for CLL eventually discontinued the treatment. While the study raised important questions about ibrutinib adherence, it did not describe the extent to which physicians lowered doses of the drug, nor did it note the clinical impacts of such decisions.

Parikh and colleagues wanted to gain more knowledge about the topic, noting that poor compliance, and improper interruptions or dose decreases could increase the risk of drug resistance or dampen the beneficial effects of the drug.

To study the question, the team crafted a retrospective study using the Mayo Clinic’s CLL database. They examined the reasons for dose reductions and interruptions of ibrutinib, and then correlated those changes with patient outcomes.

Of the 209 patients included in the analysis, 131 had unmutated IGHV, 38 had TP53 disruption, and 47 were previously untreated. Among the group, 87 patients started ibrutinib on a reduced dose (less than 420 mg per day). Of those, 43 reductions were due to physician preference, 33 were due to concomitant medications, and 11 reductions were made for other reasons.

Over the course of 281 patient-years of treatment, 91 patients had a temporary interruption of ibrutinib. Those interruptions were due to non-hematologic toxicity (54%), surgical procedures (29%), hematologic toxicity (10%), and other causes (7%).

After a median follow-up of 24 months, Parikh and colleagues write that temporary interruption of ibrutinib (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS. On the other hand, only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. There was no correlation between initial dose or dose modification and EFS or OS.

Parikh said the findings shouldn’t be interpreted to say that lower doses of ibrutinib are a good idea for most patients. He and colleagues still recommend the 420 mg dose, in part because that’s what’s been approved by the FDA and studied extensively.

“To determine if lower doses might be effective in all patients, properly conducted clinical trials need to be done,” he said. However, he said the data should provide some reassurance to physicians who find it necessary to reduce doses of ibrutinib during the treatment of CLL.

Parikh also pointed to one notable wrinkle in the data suggesting that while interruptions of ibrutinib due to toxicities have negative implications for patient outcomes, interruptions for the purpose of surgery (due to increased bleeding risk) do not.

“This is not surprising given that patients who had toxicity from therapy had more dose reductions and dose interruptions leading to a decrease in efficacy of therapy,” he said.

Reference

Parikh, SA, Achenbach, SJ, Call, TG, et al. The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice. Cancer Med. 2020;00:1-10. doi:10.1002/cam4.2998.