Aurora kinase A inhibition provides clinical benefit, normalizes megakaryocytes, and reduces bone marrow fibrosis in patients with myelofibrosis: A phase I trial

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. PatnaikAref 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*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4898-4906
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number16
DOIs
StatePublished - Aug 15 2019

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Aurora Kinase A
Primary Myelofibrosis
Megakaryocytes
Fibrosis
Splenomegaly
Bone Marrow
Alleles
Janus Kinases
Therapeutic Uses
MLN 8237
Leukemia
Cytokines
Safety

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Gangat, Naseema ; Marinaccio, Christian ; Swords, Ronan ; Watts, Justin M. ; Gurbuxani, Sandeep ; Rademaker, Alfred ; Fought, Angela J. ; Frankfurt, Olga ; Altman, Jessica K. ; Wen, Qiang Jeremy ; Farnoud, Noushin ; Famulare, Christopher A. ; Patel, Akshar ; Tapia, Roberto ; Vallapureddy, Rangit R. ; Barath, Stephanie ; Graf, Amy ; Handlogten, Amy ; Zblewski, Darci ; Patnaik, Mrinal M. ; Al-Kali, Aref ; Dinh, Yvonne Trang ; Prahl, Kristen Englund ; Patel, Shradha ; Nobrega, Juan Carlos ; Tejera, Dalissa ; Thomassen, Amber ; Gao, Juehua ; Ji, Peng ; Rampal, Raajit K. ; Giles, Francis J. ; Tefferi, Ayalew ; Stein, Brady ; Crispino, John D. / Aurora kinase A inhibition provides clinical benefit, normalizes megakaryocytes, and reduces bone marrow fibrosis in patients with myelofibrosis : A phase I trial. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 16. pp. 4898-4906.
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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.",
author = "Naseema Gangat and Christian Marinaccio and Ronan Swords and Watts, {Justin M.} and Sandeep Gurbuxani and Alfred Rademaker and Fought, {Angela J.} and Olga Frankfurt and Altman, {Jessica K.} and Wen, {Qiang Jeremy} and Noushin Farnoud and Famulare, {Christopher A.} and Akshar Patel and Roberto Tapia and Vallapureddy, {Rangit R.} and Stephanie Barath and Amy Graf and Amy Handlogten and Darci Zblewski and Patnaik, {Mrinal M.} and Aref Al-Kali and Dinh, {Yvonne Trang} and Prahl, {Kristen Englund} and Shradha Patel and Nobrega, {Juan Carlos} and Dalissa Tejera and Amber Thomassen and Juehua Gao and Peng Ji and Rampal, {Raajit K.} and Giles, {Francis J.} and Ayalew Tefferi and Brady Stein and Crispino, {John D.}",
year = "2019",
month = "8",
day = "15",
doi = "10.1158/1078-0432.CCR-19-1005",
language = "English (US)",
volume = "25",
pages = "4898--4906",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

Gangat, N, Marinaccio, C, Swords, R, Watts, JM, Gurbuxani, S, Rademaker, A, Fought, AJ, Frankfurt, O, Altman, JK, Wen, QJ, Farnoud, N, Famulare, CA, Patel, A, Tapia, R, Vallapureddy, RR, Barath, S, Graf, A, Handlogten, A, Zblewski, D, Patnaik, MM, Al-Kali, A, Dinh, YT, Prahl, KE, Patel, S, Nobrega, JC, Tejera, D, Thomassen, A, Gao, J, Ji, P, Rampal, RK, Giles, FJ, Tefferi, A, Stein, B & Crispino, JD 2019, 'Aurora kinase A inhibition provides clinical benefit, normalizes megakaryocytes, and reduces bone marrow fibrosis in patients with myelofibrosis: A phase I trial', Clinical Cancer Research, vol. 25, no. 16, pp. 4898-4906. https://doi.org/10.1158/1078-0432.CCR-19-1005

Aurora kinase A inhibition provides clinical benefit, normalizes megakaryocytes, and reduces bone marrow fibrosis in patients with myelofibrosis : A phase I trial. / Gangat, Naseema; Marinaccio, Christian; Swords, Ronan; Watts, Justin M.; Gurbuxani, Sandeep; Rademaker, Alfred; Fought, Angela J.; Frankfurt, Olga; Altman, Jessica K.; Wen, Qiang Jeremy; Farnoud, Noushin; Famulare, Christopher A.; Patel, Akshar; Tapia, Roberto; Vallapureddy, Rangit R.; Barath, Stephanie; Graf, Amy; Handlogten, Amy; Zblewski, Darci; Patnaik, Mrinal M.; Al-Kali, Aref; Dinh, Yvonne Trang; Prahl, Kristen Englund; Patel, Shradha; Nobrega, Juan Carlos; Tejera, Dalissa; Thomassen, Amber; Gao, Juehua; Ji, Peng; Rampal, Raajit K.; Giles, Francis J.; Tefferi, Ayalew; Stein, Brady; Crispino, John D.

In: Clinical Cancer Research, Vol. 25, No. 16, 15.08.2019, p. 4898-4906.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aurora kinase A inhibition provides clinical benefit, normalizes megakaryocytes, and reduces bone marrow fibrosis in patients with myelofibrosis

T2 - A phase I trial

AU - Gangat, Naseema

AU - Marinaccio, Christian

AU - Swords, Ronan

AU - Watts, Justin M.

AU - Gurbuxani, Sandeep

AU - Rademaker, Alfred

AU - Fought, Angela J.

AU - Frankfurt, Olga

AU - Altman, Jessica K.

AU - Wen, Qiang Jeremy

AU - Farnoud, Noushin

AU - Famulare, Christopher A.

AU - Patel, Akshar

AU - Tapia, Roberto

AU - Vallapureddy, Rangit R.

AU - Barath, Stephanie

AU - Graf, Amy

AU - Handlogten, Amy

AU - Zblewski, Darci

AU - Patnaik, Mrinal M.

AU - Al-Kali, Aref

AU - Dinh, Yvonne Trang

AU - Prahl, Kristen Englund

AU - Patel, Shradha

AU - Nobrega, Juan Carlos

AU - Tejera, Dalissa

AU - Thomassen, Amber

AU - Gao, Juehua

AU - Ji, Peng

AU - Rampal, Raajit K.

AU - Giles, Francis J.

AU - Tefferi, Ayalew

AU - Stein, Brady

AU - Crispino, John D.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - 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.

AB - 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.

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