TY - JOUR
T1 - A Phase Ib Trial of AVID200, a TGFβ 1/3 Trap, in Patients with Myelofibrosis
AU - Mascarenhas, John
AU - Migliaccio, Anna Rita
AU - Kosiorek, Heidi
AU - Bhave, Rupali
AU - Palmer, Jeanne
AU - Kuykendall, Andrew
AU - Mesa, Ruben
AU - Rampal, Raajit K.
AU - Gerds, Aaron T.
AU - Yacoub, Abdulraheem
AU - Pettit, Kristen
AU - Talpaz, Moshe
AU - Komrokji, Rami
AU - Kremyanskaya, Marina
AU - Gonzalez, Agapito
AU - Fabris, Frank
AU - Johnson, Kathryn
AU - Dougherty, Mikaela
AU - McGovern, Erin
AU - Ossa, Juan Arango
AU - Domenico, Dylan
AU - Farnoud, Noushin
AU - Weinberg, Rona Singer
AU - Kong, Amy
AU - Najfeld, Vesna
AU - Vannucchi, Alessandro Maria
AU - Arciprete, Francesca
AU - Zingariello, Maria
AU - Falchi, Mario
AU - Salama, Mohamed E.
AU - Mead-Harvey, Carolyn
AU - Dueck, Amylou
AU - Varricchio, Lilian
AU - Hoffman, Ronald
N1 - Publisher Copyright:
© 2023 The Authors; Published by the American Association for Cancer Research.
PY - 2023/9/15
Y1 - 2023/9/15
N2 - Purpose: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organome-galy, 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 hemato-poiesis, 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 throm-bocytopenia 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.
AB - Purpose: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organome-galy, 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 hemato-poiesis, 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 throm-bocytopenia 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.
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U2 - 10.1158/1078-0432.CCR-23-0276
DO - 10.1158/1078-0432.CCR-23-0276
M3 - Article
C2 - 37439808
AN - SCOPUS:85171394138
SN - 1078-0432
VL - 29
SP - 3622
EP - 3632
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -