@article{b2fcda405b30429290e05d826c76ce79,
title = "Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma",
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.",
keywords = "ALK inhibitor, NPM1-ALK+ ALCL, apoptosis, clinical trial, complete response, precision medicine",
author = "V. Subbiah and S. Kuravi and S. Ganguly and Welch, {D. R.} and Vivian, {C. J.} and Mushtaq, {M. U.} and A. Hegde and S. Iyer and A. Behrang and Ali, {S. M.} and Madison, {R. W.} and Venstrom, {J. M.} and Jensen, {R. A.} and McGuirk, {J. P.} and Amin, {H. M.} and R. Balusu",
note = "Funding Information: This work was supported in part by The Cancer Prevention and Research Institute of Texas [grant number RP1100584]; the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy [grant number 1U01 CA180964]; NCATS [grant number UL1 TR000371] (Center for Clinical and Translational Sciences); and The MD Anderson Cancer Center support grant [grant number P30 CA016672]. VS is supported by NIH/NCI [grant number 1R01CA242845-01A1]. DRW thanks support from the Hall Family Foundation endowed Chair in Molecular Medicine and the National Foundation for Cancer Research. RAJ is a recipient of [grant number P30-CA168524] from NCI. Parts of this work have been funded by grant to HMA [grant number R01 CA151533]. RB acknowledges the Sosland Family Foundation Research Award; Hale Family Foundation Research Award; Frontiers Clinical and Translational Pilot Award UL1 TR000001; and American Cancer Society-Institutional Research Grant [grant number ACS-IRG-16-194-07]. We would like to thank Luke Juckett for the initial analysis of the Foundation Medicine Database. The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Research funding/grant support for clinical trials: FUJIFILM Pharmaceuticals USA, Inc. Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berg Health, Incyte, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda and Roche/Genentech, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center. VS was part of a phase II basket trial sponsored by Novartis. Travel: Novartis, PharmaMar, ASCO, ESMO, Helsinn, Incyte, US-FDA. Consultancy/advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, Medimmune, Novartis. SG reports personal fees from Astellas, Seattle Genetics, Sanofi, Daiichi Sankyo, Kite Pharma, Kadmon, and BMS outside the submitted work. JPM reports advisory board, honoraria, and research funding from AlloVir HCP, Juno Therapeutics, Inc. and Gilead-Kite Pharmaceuticals; advisory board for Magenta Therapeutics; and research funding from Novartis, Fresenius Biotech, Astellas, Bellicum Pharmaceuticals, Gamida Cell, and Pluristem Ltd. outside the submitted work. SMA was a former employee at Foundation Medicine. RWM, JMV are employees of Foundation Medicine. All other authors declare no conflicts of interest. Funding Information: This work was supported in part by The Cancer Prevention and Research Institute of Texas [grant number RP1100584 ]; the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy [grant number 1U01 CA180964 ]; NCATS [grant number UL1 TR000371 ] ( Center for Clinical and Translational Sciences ); and The MD Anderson Cancer Center support grant [grant number P30 CA016672 ]. VS is supported by NIH / NCI [grant number 1R01CA242845-01A1 ]. DRW thanks support from the Hall Family Foundation endowed Chair in Molecular Medicine and the National Foundation for Cancer Research . RAJ is a recipient of [grant number P30-CA168524 ] from NCI . Parts of this work have been funded by grant to HMA [grant number R01 CA151533]. RB acknowledges the Sosland Family Foundation Research Award; Hale Family Foundation Research Award; Frontiers Clinical and Translational Pilot Award UL1 TR000001; and American Cancer Society-Institutional Research Grant [grant number ACS-IRG-16-194-07]. We would like to thank Luke Juckett for the initial analysis of the Foundation Medicine Database. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = aug,
doi = "10.1016/j.esmoop.2021.100172",
language = "English (US)",
volume = "6",
journal = "ESMO Open",
issn = "2059-7029",
publisher = "BMJ Publishing Group",
number = "4",
}