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 TALL 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 TALL like disease when expressed in hematopoietic progenitors in vivo. We describe a case of relapsed TALL 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.

Genetic characteristics and treatment outcome in infants with KMT2A germline B‐cell precursor acute lymphoblastic leukemia: Results of MLL‐Baby protocol

“…This transcript has never been previously described in ALL, and the only published case was found in an adult with chronic myelomonocytic leukemia 38 . In another patient with translocation t(X;10)(p11;p12), transcriptome analysis revealed DDX3X::MLLT10 FGt, which was previously described in T‐cell ALL only 39–42 . Another group of interest included two patients with potentially targetable tyrosine kinase fusions.…”

“…38 In another patient with translocation t(X;10)(p11;p12), transcriptome analysis revealed DDX3X::MLLT10 FGt, which was previously described in T-cell ALL only. [39][40][41][42] Another group of interest included two patients with potentially targetable tyrosine kinase fusions. Among them, there were PAX5::JAK2 and SSBP2::FLT3; the latter fusion has never been reported before.…”

Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers

“…As JAK3-activating mutation was frequent in NKTCL pathogenesis, the pan-JAK inhibitor Tofacitinib efficiently reduced phosphorylated STAT5 and cell viability in JAK3-mutant and wild-type NKTCL cell lines and mouse xenografts [19,24]. However, in one case of relapsed T-ALL with two JAK3 activating mutations, Tofacitinib failed to induce a positive clinical response following failure of salvage chemotherapy, indicating that the presence of activating JAK3 mutations did not necessarily guarantee sensitivity to Tofacitinib treatment [110].…”

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

“…Combination of the BCL2 inhibitor Venetoclax with Tofacitinib induced therapeutic responses in some hematological patients with relapsed/refractory T-ALL with surface IL-7R expression or IL-7R-pathway mutations and BCL2 expression [ 248 ]. In contrast, Tofacitinib was not effective in a patient with DDX3X-MLLT10 T-ALL carrying an activating JAK3 mutation [ 249 ]. Therefore, the individual genetic make-up of a hematological malignancy might determine its responsiveness to Tofacitinib treatment.…”