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

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V. Subbiah¹  S. Kuravi²  S. Ganguly²  D.R. Welch³  C.J. Vivian³  M.U. Mushtaq²  A. Hegde⁵  S. Iyer⁶  A. Behrang⁷  S.M. Ali⁸  R.W. Madison⁸  J.M. Venstrom⁸  R.A. Jensen³  J.P. McGuirk²  H.M. Amin^1,10  R. Balusu² 

[1] Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center;Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center;The University of Kansas Cancer Center;Department of Cancer Biology, University of Kansas Medical Center;Department of Hematology/Oncology, University of Alabama;Department of Myeloma and Lymphoma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center;Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center;Foundation Medicine;Department of Pathology and Laboratory Medicine, University of Kansas Medical Center;Department of Hematopathology, The University of Texas MD Anderson Cancer Center

关键词: precision medicine;    NPM1-ALK+ ALCL;    ALK inhibitor;    apoptosis;    clinical trial;    complete response;   

DOI  :  10.1016/j.esmoop.2021.100172

学科分类：社会科学、人文和艺术（综合）

来源: BMJ Publishing Group

【 摘 要 】

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.

【 授权许可】

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