A Phase Ib Trial of AVID200, a TGFβ 1/3 Trap, in Patients with Myelofibrosis.

Autor:	Mascarenhas J; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Migliaccio AR; Altius Institute for Biomedical Sciences, Seattle, Washington., Kosiorek H; Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, Arizona., Bhave R; Comprehensive Cancer Center of Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina., Palmer J; Mayo Clinic Scottsdale, Arizona., Kuykendall A; Department of Hematologic Malignancy, Moffitt Cancer Center, Tampa, Florida., Mesa R; Comprehensive Cancer Center of Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina., Rampal RK; Leukemia Service, Department of Medicine, Center for Hematologic Malignancies, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York., Gerds AT; Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio., Yacoub A; The University of Kansas Cancer Center, Westwood, Kansas., Pettit K; University of Michigan, Comprehensive Cancer Center, Ann Arbor, Michigan., Talpaz M; University of Michigan, Comprehensive Cancer Center, Ann Arbor, Michigan., Komrokji R; Department of Hematologic Malignancy, Moffitt Cancer Center, Tampa, Florida., Kremyanskaya M; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Gonzalez A; The University of Texas Health Science Center at San Antonio, San Antonio, Texas., Fabris F; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Johnson K; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Dougherty M; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., McGovern E; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Arango Ossa J; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Domenico D; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Farnoud N; Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York., Weinberg RS; New York Blood Center, New York, New York., Kong A; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Najfeld V; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Vannucchi AM; University of Florence, Azienda Ospedaliero Universitaria Careggi, Florence, Italy., Arciprete F; Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy., Zingariello M; Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy., Falchi M; National HIV/AIDS Research Center, Istituto Superiore di Sanità, Viale Regina Elena Rome Italy., Salama ME; Sonic Healthcare, Austin, Texas., Mead-Harvey C; Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, Arizona., Dueck A; Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, Arizona., Varricchio L; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Hoffman R; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Sep 15; Vol. 29 (18), pp. 3622-3632.
DOI:	10.1158/1078-0432.CCR-23-0276
Abstrakt:	Purpose: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFβ, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGFβ 1/3 trap, reduced TGFβ1-induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PC) with wild-type JAK2 rather than JAK2V617F. Patients and Methods: We conducted an investigator-initiated, multicenter, phase Ib trial of AVID200 monotherapy in 21 patients with advanced MF. Results: No dose-limiting toxicity was identified at the three dose levels tested, and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF-directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGFβ1 levels and pSMAD2 in MF cells. Conclusions: AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of patients with MF and should be evaluated further in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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