Year: 2023
Type: article
Study design: Clinical Trial
Abstract: 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.
Source: Clinical Cancer Research
Authors: John Mascarenhas, Anna Rita Migliaccio, Heidi Kosiorek, Rupali Bhave, Jeanne Palmer, Andrew Kuykendall, Ruben Mesa, Raajit K. Rampal, Aaron T. Gerds, Abdulraheem Yacoub, Kristen Pettit, Moshe Talpaz, Rami Komrokji, Marina Kremyanskaya, Agapito Gonzalez, Frank Fabris, Kathryn Johnson, Mikaela Dougherty, Erin McGovern, Juan Arango Ossa, Dylan Domenico, Noushin Farnoud, Rona Singer Weinberg, Amy Kong, Vesna Najfeld, Alessandro Maria Vannucchi, Francesca Arciprete, Maria Zingariello, Mario Falchi, Mohamed E. Salama, Carolyn Mead-Harvey, Amylou Dueck, Lilian Varricchio, Ronald Hoffman
Institutions: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Altius Institute for Biomedical Sciences, Mayo Clinic in Arizona, Atrium Health Wake Forest Baptist, Wake Forest Baptist Comprehensive Cancer Center, Mayo Clinic Hospital, Moffitt Cancer Center, Memorial Sloan Kettering Cancer Center, Cleveland Clinic, The University of Kansas Cancer Center, University of Kansas Medical Center, University of Michigan, U-M Rogel Cancer Center, The University of Texas at San Antonio Health Science Center, New York Blood Center, Azienda Ospedaliero-Universitaria Careggi, Università Campus Bio-Medico, Istituto Superiore di Sanità, University of Utah
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4384120015