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Supplementary Data from Aurora Kinase A Inhibition Provides Clinical Benefit, Normalizes Megakaryocytes, and Reduces Bone Marrow Fibrosis in Patients with Myelofibrosis: A Phase I Trial

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posted on 2023-03-31, 21:42 authored by Naseema Gangat, Christian Marinaccio, Ronan Swords, Justin M. Watts, Sandeep Gurbuxani, Alfred Rademaker, Angela J. Fought, Olga Frankfurt, Jessica K. Altman, Qiang Jeremy Wen, Noushin Farnoud, Christopher A. Famulare, Akshar Patel, Roberto Tapia, Rangit R. Vallapureddy, Stephanie Barath, Amy Graf, Amy Handlogten, Darci Zblewski, Mrinal M. Patnaik, Aref Al-kali, Yvonne Trang Dinh, Kristen Englund Prahl, Shradha Patel, Juan Carlos Nobrega, Dalissa Tejera, Amber Thomassen, Juehua Gao, Peng Ji, Raajit K. Rampal, Francis J. Giles, Ayalew Tefferi, Brady Stein, John D. Crispino

Figure S1: Alisertib treatment did not result in a consistent cytokine response. Figure S2: Alisertib did not have a consistent effect on TGF-b levels. Figure S3: Alisertib induced GATA1 expression in the SET2 megakaryocytic cell line. Figure S4: AURKA inhibition induces megakaryocytic gene expression. Figure S5: Alisertib increases GATA1 expression in the bone marrow of patients on therapy. Table S1: Correlation of Genotype and prior JAK inhibitor therapy with response and adverse events Table S2: Summary of Treatment Related Adverse Events Table S3: Association between GATA1 staining, degree of fibrosis and clinical response

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Leukemia & Lymphoma Society

Samuel Waxman Cancer Research Foundation

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ARTICLE ABSTRACT

Myelofibrosis is characterized by bone marrow fibrosis, atypical megakaryocytes, splenomegaly, constitutional symptoms, thrombotic and hemorrhagic complications, and a risk of evolution to acute leukemia. The JAK kinase inhibitor ruxolitinib provides therapeutic benefit, but the effects are limited. The purpose of this study was to determine whether targeting AURKA, which has been shown to increase maturation of atypical megakaryocytes, has potential benefit for patients with myelofibrosis. Twenty-four patients with myelofibrosis were enrolled in a phase I study at three centers. The objective of the study was to evaluate the safety and preliminary efficacy of alisertib. Correlative studies involved assessment of the effect of alisertib on the megakaryocyte lineage, allele burden, and fibrosis. In addition to being well tolerated, alisertib reduced splenomegaly and symptom burden in 29% and 32% of patients, respectively, despite not consistently reducing the degree of inflammatory cytokines. Moreover, alisertib normalized megakaryocytes and reduced fibrosis in 5 of 7 patients for whom sequential marrows were available. Alisertib also decreased the mutant allele burden in a subset of patients. Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis. In this study, alisertib provided clinical benefit and exhibited the expected on-target effect on the megakaryocyte lineage, resulting in normalization of these cells and reduced fibrosis in the majority of patients for which sequential marrows were available. Thus, AURKA inhibition should be further developed as a therapeutic option in myelofibrosis.See related commentary by Piszczatowski and Steidl, p. 4868

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    Clinical Cancer Research

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    Clinical Trial ResultsHematological Cancers

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