Effective Treatment with the Selective Cytokine Inhibitor BNZ-1 Reveals the Cytokine Dependency of T-LGL Leukemia.

T-cell large granular lymphocytic leukemia (T-LGLL) is a clonal proliferation of cytotoxic T-lymphocytes that can result in severe neutropenia, anemia, and bone marrow failure. Strong evidence from patients and mouse models demonstrate the critical role of interleukin-15 in T-LGLL pathogenesis. BNZ-1 is a pegylated peptide that selectively inhibits the binding of IL-15 and other gc cytokines to their cellular receptor complex, that has demonstrated efficacy in ex vivo T-LGLL cells and transgenic mice in pre-clinical studies. We conducted a phase I/II trial of BNZ-1 in patients with T-LGLL who had hematocytopenias (anemia or neutropenia) that required therapy. Clinical responses were assessed using hematologic parameters (improvement in hematocytopenias) based off response criteria from the ECOG 5998 T-LGLL trial. BNZ-1 demonstrated clinical partial responses in 20% of patients with T-LGLL with minimal toxicity and the maximum tolerated dose (MTD) was not reached. Further, T-LGLL leukemic cells showed significantly increased apoptosis in response to BNZ-1 treatment as early as day two, including in clinically non-responding patients, with changes that remained statistically different from baseline throughout treatment (p<0.005). We report first-in-human proof that T-LGLL leukemic cells are dependent on IL-15 and that intervention with IL-15 inhibition with BNZ-1 in T-LGLL patients shows therapeutic effects, which carries important implications for the understanding of the pathogenesis of this disease. Clinical Trial # NCT03239392.