Evaluating Ibrutinib in Patients With Heavily Pretreated Hairy Cell Leukemia

Treatment with ibrutinib offered durable disease control in patients with heavily pretreated classic and variant relapsed hairy cell leukemia (HCL) who were not expected to derive benefit from purine analogues, according to a study published in Blood. Lead author Kerry Rogers, MD, of The Ohio State University Comprehensive Cancer Center, said these findings suggest ibrutinib “may provide a less immunosuppressive alternative than frequently used purine nucleoside analogues (PNAs), such as cladribine and fludarabine.”

This open-label phase II study enrolled 37 patients with relapsed classic (n=28) or variant HCL (n=9). Those with classic HCL were required to have previously received treatment with a PNA or been considered medically unfit to receive this therapeutic approach. All previously treated and treatment-naïve patients with variant HCL were included in the study.

Initially, the first 13 patients received daily oral ibrutinib 420 mg. For subsequent patients, this dose was doubled to 840 mg due to a lack of objective responses in the first group. As responses were reported with the 420 mg dose after 32 weeks, the investigators amended the trial protocol to administer the 420 mg dose to newly enrolled patients due to concerns of toxicities at the higher dose. Patients who received the 840 mg dose were able to decrease to the initial 420 mg. Treatment continued until either the occurrence of unacceptable toxicities or disease progression.

The primary endpoint of the study was a 32-week overall response rate (ORR), including both complete response and partial response. Additional secondary endpoints were toxicities and tolerability, progression-free survival (PFS), and overall survival (OS).

Of 36 patients who were tested for BRAF p.V600E, a total of 20 had the mutation. The median duration of disease course in the overall cohort was 9.8 years. Previously, patients had been treated with a median of four therapies, and all had received PNAs. Only two patients with variant HCL had not received treatment.

At the median follow-up period of 3.5 years, 15 patients were still taking ibrutinib, while 22 patients had discontinued treatment because of progressive disease (n=9), adverse events (AEs; n=7), patient or investigator decision (n=4), and death (n=2).

“[Ibrutinib] may provide a less immunosuppressive alternative than frequently used purine nucleoside analogues, such as cladribine and fludarabine.”

—Kerry Rogers, MD

Overall, the 32-week ORR was 24%, which increased to 36% at 48-week follow-up. The best ORR calculated at any time was 54%. While the median PFS was not reached, the estimated 36-month PFS rate was 73%. The median OS was 69 months, while the estimated 36-month OS rate was 85%.

According to a univariate analysis, a per one-year increase in age was inversely associated with response (odds ratio = 0.90), indicating patients of more advanced age may have a lower likelihood of response to ibrutinib.

Common AEs included diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Treatment-related hematologic AEs were anemia (43%), thrombocytopenia (41%), and neutropenia (35%).

Investigators also measured immunoglobulin (Ig) levels for 18 months following treatment with ibrutinib. They observed significant reductions from baseline in serum IgG, with no change in IgA or IgM, but whether these findings have implications for infection risk in patients with HCL remains unclear. The authors added that further research is necessary to understand ibrutinib’s mechanism of action in HCL, which is different from that in CLL.

This study is limited by its recruitment of only relapsed and refractory patients, most of whom did not derive prolonged benefit from purine analogues and were negative for the BRAF p.V600E mutation. These findings may not be applicable to patients with newly diagnosed disease.

The authors report no relevant conflicts of interest.


Rogers KA, Andritsos LA, Wei L, et al. Phase 2 study of ibrutinib in classic and variant hairy cell leukemia [published online ahead of print, 2021 Mar 22]. Blood. doi: 10.1182/blood.2020009688.