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.
Highlights
Myelofibrosis is the most aggressive subtype of the Philadelphia chromosome–negative myeloproliferative neoplasms (MPN), which includes essential thrombocythemia and polycythemia vera
Given the limitations of ruxolitinib, novel therapies are needed for myelofibrosis
AURKA inhibition should be further developed as a therapeutic option in myelofibrosis
Summary
Myelofibrosis is the most aggressive subtype of the Philadelphia chromosome–negative myeloproliferative neoplasms (MPN), which includes essential thrombocythemia and polycythemia vera. The vast majority of cases of the MPNs are caused by driver mutations in JAK2, MPL, or Calreticulin (CALR) that lead to hyperactive JAK/STAT signaling [1]. Ruxolitinib fails to target the malignant clone or appreciably reduce the degree of fibrosis [4, 5]. We investigated alternative therapies that may reduce fibrosis and provide additional therapeutic benefit. A major feature of myelofibrosis is the presence of atypical, clustered megakaryocytes, which fail to express the essential hematopoietic transcription factor GATA1 [6, 7]. A number of studies have led to the hypothesis that these atypical
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