Pilot trial of ibrutinib in patients with relapsed or refractory T-cell lymphoma

Abstract

Ibrutinib has previously been shown to inhibit Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK), which mediate B-cell and T-cell receptor signaling, respectively. BTK inhibition with ibrutinib has demonstrated impressive clinical responses in a variety of B-cell malignancies. Whether ibrutinib inhibition of ITK can lead to clinical response in T-cell malignancies is unknown. We hypothesized that ibrutinib-mediated ITK inhibition in T-cell lymphoma would result in decreased signaling through the T-cell receptor pathway and promote antitumor immune response by driving selective cytotoxic Th1 CD4 effector T-cell differentiation. This pilot clinical trial evaluated 2 dose levels of ibrutinib: 560 and 840 mg orally daily. Fourteen patients with relapsed, refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma were enrolled. Both dose levels were safe and well tolerated, and no dose-limiting toxicities were observed. One patient achieved a partial response (overall response rate, 8% [1/13]). ITK occupancy studies demonstrated a mean occupancy of 50% (range, 15%-80%). Higher ITK occupancy of more than 50% correlated with higher serum levels of tumor necrosis factor-α and interferon-γ and favored a Th1 phenotype. Our data suggest that ibrutinib inhibition of ITK has limited clinical activity in T-cell lymphoma. This study is registered at www.clinicaltrials.gov as #NCT02309580.

Conflict of interest statement

Conflict-of-interest disclosure: A.K. and S.M.H. have received research funding from Pharmacyclics. A.Y. has received honorarium and research funding from Janssen. J.A.D. is employed at Pharmacyclics. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Response in 1 patient who achieved a partial response to ibrutinib therapy with SS/MF and CLL. (A) Ibrutinib therapy resulted in significant decrease in both abnormal (Abn) B-cell (CLL) and Abn T-cell (Sezary) populations. (B) The patient’s Sezary population at baseline was 2370 cells/mm3; after ibrutinib therapy, his Sezary population has ranged from 803 to 2000 cells/mm3, most recently being 1325 cells/mm3. He had a marked rise in white blood cell count in the setting of acute appendicitis in December 2015. Ibrutinib was held for 84 days during appendicitis treatment (antibiotics and surgery) and recovery. Ibrutinib was restarted March 2016, and the patient has continued on therapy to date.

Figure 2.

Correlative analyses of patients with T-cell lymphoma treated with ibrutinib. (A) Ibrutinib therapy achieved 50% ITK occupancy within 4 hours, which was stable over time. (B) Ibrutinib did not increase the percentage of Th1 cells (CD4+/CXCR3+/CCR6−) in the peripheral blood. (C) Ibrutinib did not increase the percentage of cells producing interferon-γ (IFN-γ) in response to restimulation. (D-F) Ibrutinib did not significantly alter serum levels of interferon-γ (Th1), tumor necrosis factor-α (TNF-α; Th1), or interleukin-10 (IL-10; Th2). (G) Patients in whom ibrutinib therapy resulted in higher ITK occupancy (50% or higher, as measured on C2D1) were more likely to increase Th1 skewing in the peripheral blood in response to ibrutinib monotherapy as compared with patients in whom ibrutinib achieved lower ITK occupancy. P value by unpaired Student t test.