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

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.

Keywords: T-cell acute lymphoblastic leukemias; hematological neoplasm; leukemia.

Figure 1.

(A) Routinely stained bone marrow aspirate specimen obtained at relapse demonstrates marked hypercellularity predominantly comprised of medium-sized blasts. Magnification, 40×. (B–D) Immunohistochemical stain performed with anti-BCL2 antibody (clone SP66, Ventana Roche) on formalin-fixed, paraffin-embedded tissue of bone marrow core biopsy specimen obtained at relapse demonstrates uniformly strong BCL2 expression in leukemic blasts (B); normal bone marrow core biopsy specimen as control (C); bone marrow core biopsy specimen with follicular non-Hodgkin lymphoma demonstrating BCL2 positive lymphoma cells (D). Magnification, 40×.

Figure 2.

Timeline of treatment and peripheral blood leukemic blast percentages. (BM) Bone marrow, (D) day, (FLAG) fludarabine, cytarabine, filgrastim (G-CSF), (PB) peripheral blood.

Figure 3.

Missense mutations in JAK3 identified in our patient. Schematic shows JAK3 protein domain structures. Amino acid numbers are shown below. Missense mutations are denoted by circles with codon changes shown. (FERM) The conserved domain named for its founding members (band 4.2, exrin, radixin, and moesin), (JH1) JAK homology domain 1, the functional kinase domain, (JH2) JAK homology domain 2, also known as the pseudokinase domain, (SH2) Src homology domain 2.