Failure of tofacitinib to achieve an objective response in a DDX3X-MLLT10 T-lymphoblastic leukemia with activating JAK3 mutations

Jonathan Wong, Meaghan Wall, Gregory Philip Corboy, Nadine Taubenheim, Gareth Peter Gregory, Stephen Opat, Jake Shortt

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4 Citations (Scopus)

Abstract

T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic profiling has shown frequent aberrations in the JAK-STAT pathway, including recurrent mutations in JAK3 (15%-20% of T-ALL cases), suggesting that JAK kinase inhibition may be a promising therapeutic approach. Activating JAK3 mutations are capable of transforming cytokine-dependent progenitor cells in vitro and causing T-ALL-like disease when expressed in hematopoietic progenitors in vivo. We describe a case of relapsed T-ALL in an adult patient, with two JAK3 activating mutations identified by whole-exome sequencing (WES), leading to hypothesis-based treatment with the JAK1 and JAK3 inhibitor, tofacitinib, following failure of salvage chemotherapy reinduction. Despite the molecularly targeted rationale, tofacitinib did not induce an objective clinical response. Our report suggests that the presence of activating JAK3 mutations does not necessarily confer sensitivity to pharmacological JAK3 inhibition.

Original languageEnglish
Article numbera004994
Number of pages13
JournalCold Spring Harbor Molecular Case Studies
Volume6
Issue number4
DOIs
Publication statusPublished - 1 Aug 2020

Keywords

  • hematological neoplasm
  • leukemia
  • T-cell acute lymphoblastic leukemias

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