Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma

V. Subbiah, S. Kuravi, S. Ganguly, D. R. Welch, C. J. Vivian, M. U. Mushtaq, A. Hegde, S. Iyer, A. Behrang, S. M. Ali, R. W. Madison, J. M. Venstrom, R. A. Jensen, J. P. McGuirk, H. M. Amin, R. Balusu

Research output: Contribution to journalArticlepeer-review

Abstract

Background: More than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma. Materials and methods: We studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations. Results: In our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy. Conclusions: This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.

Original languageEnglish (US)
Article number100172
JournalESMO Open
Volume6
Issue number4
DOIs
StatePublished - Aug 2021

Keywords

  • ALK inhibitor
  • NPM1-ALK+ ALCL
  • apoptosis
  • clinical trial
  • complete response
  • precision medicine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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