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

Authors: Kumar, A.; Vardhana, S.; Moskowitz, A. J.; Porcu, P.; Dogan, A.; Dubovsky, J. A.; Matasar, M. J.; Zhang, Z.; Younes, A.; Horwitz, S. M.
Article Title: 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-alpha and interferon-gamma and favored a Th1 phenotype. Our data suggest that ibrutinib inhibition of ITK has limited clinical activity in T-cell lymphoma.
Keywords: inhibitor; receptor; response criteria; differentiation; expression; disease; itk
Journal Title: Blood Advances
Volume: 2
Issue: 8
ISSN: 2473-9529
Publisher: American Society of Hematology  
Date Published: 2018-04-24
Start Page: 871
End Page: 876
Language: English
ACCESSION: WOS:000430753300006
DOI: 10.1182/bloodadvances.2017011916
PMCID: PMC5915998
PUBMED: 29669753
Notes: Article -- Source: Wos
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MSK Authors
  1. Zhigang Zhang
    237 Zhang
  2. Steven M Horwitz
    343 Horwitz
  3. Alison Moskowitz
    136 Moskowitz
  4. Matthew J Matasar
    116 Matasar
  5. Anita Kumar
    50 Kumar
  6. Anas Younes
    187 Younes
  7. Ahmet Dogan
    162 Dogan