Ibrutinib Common in CLL Patients Excluded from Clinical Trials

Ibrutinib demonstrated superior response rates and survival in certain CLL patients despite exclusion from major clinical trials.

Despite omission from major clinical trials including RESONATE-2, there is substantial use of ibrutinib to treat chronic lymphocytic leukemia (CLL) in patients younger than 65 and in those with del(17p13), according to the results of a retrospective study.

“These findings demonstrate the increasing use of ibrutinib in patients under 65. Efficacy and toxicity data for ibrutinib in younger, treatment-naive patients are lacking but crucial as we discuss various front-line options, including ibrutinib, chemoimmunotherapy combinations, and participation in clinical trials,” wrote Anthony R. Mato, MD, MSCE, of Memorial Sloan Kettering Cancer Center, and colleagues wrote in the American Journal of Hematology.

The RESONATE-2 trial randomly assigned treatment-naive patients with CLL to ibrutinib or chlorambucil. The study showed that ibrutinib had a superior overall response rate, estimated 24-month progression-free survival (PFS), and estimated 24-month overall survival (OS). But, the study excluded patients younger than 65 and/or those with del(17p13).

In this study, Mato and colleagues focused on patients that would have been excluded from RESONATE-2. The retrospective study included 391 patients from community and academic centers. Of the included patients, more than half (57%) would not have qualified for RESONATE-2. Forty-one percent of patients were younger than 65 and 30% had del(17p13).

All patients started at a median dose of 420 mg ibrutinib. Patients older than 65 were more likely to start at a lower dose and to have a dose reduction before achieving a stable ibrutinib dose (P = .01 for both). Of those patients who required a reduced dose, the median age was 76. In addition, those patients who started at a reduced dose had worse PFS.

About one in four patients had to discontinue ibrutinib at a median of 13.8 months follow-up. Toxicity was the most common reason for discontinuation. The most common adverse events were arthralgias, fatigue, rash, bruising, and diarrhea.

“A higher percentage of patients in our analysis discontinued therapy due to toxicity than in the RESONATE-2 study, likely reflecting the increased availability of alternative effective biologic therapies and possibly more comorbidity in this patient population,” the researchers wrote.

Progression or disease transformation accounted for a larger proportion of discontinuations than adverse events among patients who would have been excluded from RESONATE-2.

Overall response rate was 81.8%. Those patients younger than 65 and those with del(17p13) had similar response rates. However, patients with del(17p13) had inferior PFS and OS compared to those without del(17p13).

“A trend toward inferior prognosis, without statistical significance, was observed in patients with complex karyotype and del(17p13) as compared to patients with del(17p13) without a complex karyotype,” the researchers wrote.

“As novel agents are increasingly used to manage CLL, insight into outcomes and toxicities for groups lacking robust clinical trial data will allow for more informed decision making as we optimize our approach to CLL,” they concluded.