| Autor: |
Brammer JE; Division of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH., Ballen K; Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA., Sokol L; Department of Malignant Hematology, Moffitt Cancer Center, Tampa Bay, FL., Querfeld C; City of Hope Comprehensive Cancer Center, Duarte, CA., Nakamura R; City of Hope Comprehensive Cancer Center, Duarte, CA., Mishra A; Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology and Department of Cancer Biology, Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA., McLaughlin EM; Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH., Feith D; Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA., Azimi N; Equillium Pharmaceuticals, La Jolla, CA., Waldmann TA; Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD., Tagaya Y; Institute for Human Virology, University of Maryland, Baltimore, MD., Loughran T; Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA. |
| Abstrakt: |
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 (IL-15) in T-LGLL pathogenesis. BNZ-1 is a pegylated peptide that selectively inhibits the binding of IL-15 and other γc cytokines to their cellular receptor complex, which has demonstrated efficacy in ex vivo T-LGLL cells and transgenic mice in preclinical studies. We conducted a phase 1/2 trial of BNZ-1 in patients with T-LGLL who had hematocytopenias (anemia or neutropenia) and required therapy. Clinical responses were assessed using hematologic parameters (improvement in hematocytopenias) based on response criteria from the Eastern Cooperative Oncology Group 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 was not reached. Furthermore, T-LGL leukemic cells showed significantly increased apoptosis in response to BNZ-1 treatment as early as day 2, including in clinical nonresponders, with changes that remained statistically different from baseline throughout treatment (P < .005). We report first-in-human proof that T-LGL leukemic cells are dependent on IL-15 and that intervention with IL-15 inhibition with BNZ-1 in patients with T-LGLL shows therapeutic effects, which carries important implications for the understanding of the pathogenesis of this disease. This trial was registered at www.clinicaltrials.gov as #NCT03239392. |
