Phase 2 study of ibrutinib in classic and variant hairy cell leukemia

Abstract

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Conflict of interest statement

Conflict-of-interest disclosure: K.A.R. receives research funding from AbbVie, Genentech, and Janssen, and participated in advisory boards for Acerta Pharma, Pharmacyclics, AbbVie, Genentech, Innate Pharma, and AstraZeneca. L.A.A. consults for AstraZeneca. A.S.R. serves on an independent data safety monitoring board for Telios Pharma. M.A. has consulted for AstraZeneca. J.S.B. has received consulting fees from AbbVie, AstraZeneca, and KITE Pharma. A.D. is employed by Gilead. R.J.K. receives research support from agreements between the National Institutes of Health and AstraZeneca, Genentech, Teva, and Novartis and is a coinventor on the National Institutes of Health patent for moxetumomab pasudotox. G.L. receives research funding from Genentech, Stemline, Novartis, and Beckman Coulter. D.J. receives research or testing support from Pharmacyclics, AbbVie, Novartis, MingSight, Acerta Pharma, ArQule, and Sunesis. C.A.S. served on a data safety monitoring board for Pharmacyclics and receives research funding for clinical trials. J.A.J. is employed by and has equity in Bristol Myers Squibb. M.R.G. has severed on a data safety monitoring committee for Acerta Pharma and Axio and has consulted for AstraZeneca and Pharmacyclics. The remaining authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

Response to ibrutinib. Response to ibrutinib is shown at both preplanned response assessments at 32 and 48 weeks. Patients with either a CR or a PR were considered responders. Patients who died before the 32-week response assessment and those who were off-study and therefore not assessed for response are shown. These data are also found in supplemental Table 5. One patient is still receiving treatment but has not reached the 48-week assessment and is included in the 32-week assessment and best response for any cycle totals.

Figure 2.

Patient survival and response. (A) PFS and OS after starting ibrutinib. The median for PFS was not reached, and the median OS was 69.1 months. (B) Swimmers plot with outcomes for each individual patient. Gray shading shows time before the first formal response assessment. Before that, patients were assessable for disease progression and survival but not remission. Patient 1 continued to receive treatment despite PD in the marrow because of the clinical benefit. Patients who discontinued therapy without disease progression discontinued for either AEs or death. Note that there is no patient 24 or patient 38 because those patients were found to be ineligible at screening and they received a study number but did not start study treatment. C, classic; V, variant.

Figure 3.

pERK status during treatment and clinical outcome. (A) pERK expression in HCL cells in the bone marrow are shown for 4 representative patients at screening and week 48 of ibrutinib treatment. pERK expression is shown as red cytoplasmic staining. Leukemia cells were identified by a PAX5 stain with brown nuclear staining when present. The use of both stains identifies pERK expression specifically in the leukemia cells. The presence of cytoplasmic pERK is shown with thick arrows and the absence is shown with thin arrows. Patient 2 has vHCL and had a diffuse infiltrate of leukemic cells at both screening and week 48 of treatment. The leukemia cells were negative for pERK staining at every time point tested. Patients with vHCL have previously been shown to not have pERK, and this may not be a prosurvival signal in these patients, given that vHCL and cHCL have relatively different biology. The remaining 3 patients (3, 8, and 30) all have cHCL and a durable benefit from ibrutinib with a PFS of more than 2 years, and all were continuing to receive ibrutinib at the last follow-up. They all had different changes in pERK status after starting treatment. Patient 3 had pERK in the leukemia cells at screening that was absent by week 48, patient 8 had persistent presence of pERK at all time points tested, and patient 30 had a subset of pERK-positive leukemia cells at screening and at week 48. (B) Swimmer’s plot with pERK status at screening, week 32, and week 48 for all patients for whom samples were available. Both patients with vHCL (patient 2 and patient 4) were pERK negative at every time point tested, which is consistent with what was previously described in patients with vHCL. Many patients with persistence of pERK continued to receive ibrutinib without progression for an extended period. This supports that (contrary to what was shown with vemurafenib) the presence of pERK during ibrutinib treatment may not predict a shorter PFS and argues that the mechanism of effect of ibrutinib may not involve decreasing ERK phosphorylation.