Aurora kinase A inhibition provides clinical benefit, normalizes megakaryocytes, and reduces bone marrow fibrosis in patients with myelofibrosis: A phase I trial Journal Article
| Authors: | Gangat, N.; Marinaccio, C.; Swords, R.; Watts, J. M.; Gurbuxani, S.; Rademaker, A.; Fought, A. J.; Frankfurt, O.; Altman, J. K.; Wen, Q. J.; Farnoud, N.; Famulare, C. A.; Patel, A.; Tapia, R.; Vallapureddy, R. R.; Barath, S.; Graf, A.; Handlogten, A.; Zblewski, D.; Patnaik, M. M.; Al-Kali, A.; Dinh, Y. T.; Prahl, K. E.; Patel, S.; Nobrega, J. C.; Tejera, D.; Thomassen, A.; Gao, J.; Ji, P.; Rampal, R. K.; Giles, F. J.; Tefferi, A.; Stein, B.; Crispino, J. D. |
| Article Title: | Aurora kinase A inhibition provides clinical benefit, normalizes megakaryocytes, and reduces bone marrow fibrosis in patients with myelofibrosis: A phase I trial |
| Abstract: | Purpose: 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. Patients and Methods: 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. Results: 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. Conclusions: 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. © 2019 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 25 |
| Issue: | 16 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-08-15 |
| Start Page: | 4898 |
| End Page: | 4906 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-19-1005 |
| PUBMED: | 31061068 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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