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-ALKþ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALKþ 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-ALKþ 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-ALKþ 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-ALKþ ALCL provides a strong rationale for a prospective study of ceritinib in ALKþ T-cell lymphomas and other ALKþ hematologic malignancies.

Revolutionizing cancer drug development: Harnessing the potential of basket trials

“…With regard to ALK, 21 patients with various tumor types and ALK mutations/amplification or rearrangements enrolled and were treated with the ALK inhibitor alectinib. In the patients who had ALK rearrangements, the ORR was 30%; in contrast, there were no responses among the patients who had ALK mutations or amplification, 69 opening up the possibility of ALK as a tissue‐agnostic target 70 …”

“…In the patients who had ALK rearrangements, the ORR was 30%; in contrast, there were no responses among the patients who had ALK mutations or amplification, 69 opening up the possibility of ALK as a tissue-agnostic target. 70 Importantly, the MyPathway trial also examined a high TMB basket for the anti-PD-L1 immunotherapy atezolizumab. Ninety patients with 19 tumor types and TMB ≥10 mutations per megabase (mut/Mb) were evaluable for efficacy.…”

Emerging predictive biomarkers for novel therapeutics in peripheral T-cell and natural killer/T-cell lymphoma

“…In a phase two study involving 12 patients with R/R ALK+ ALCL, crizotinib monotherapy resulted in a remarkable ORR of 83.3%, with 7 patients (58.3%) achieving complete response ( 173 ). Likewise, ceritinib was demonstrated to induce durable complete remission on a singular case report ( 174 ). Fukano et al.…”

ALK+ hyaline vascular Castleman disease: a new kid on the block

“…ALK abnormalities, initially described in anaplastic large cell lymphoma, have since been reported in several epithelial, sarcomatoid and melanocytic neoplasms, as well as cases of aggressive histiocytosis 5 . The presence of ALK fusions in benign proliferations, such as HVCD, is relatively rare, with one case of CD recently referenced in one next‐generation sequence (NGS) profiling study of almost 20 000 patients with haematological diseases 6 . Two cases of HVCD with ALK gene missense mutation were reported in the CD cohort of Li et al 4 …”