Ruxolitinib: the First FDA Approved Therapy for the Treatment of Myeloﬁbrosis

Published OnlineFirst April 2, 2012; DOI: 10.1158/1078-0432.CCR-11-3145 Clinical Cancer CCR Drug Updates Research Ruxolitinib: The First FDA Approved Therapy for the Treatment of Myelofibrosis John Mascarenhas and Ronald Hoffman Abstract The BCR-ABL1–negative myeloproliferative neoplasms (e.g., essential thrombocythemia, poly- cythemia vera, and primary myelofibrosis) are a group of heterogeneous hematologic malignancies that involve a clonal proliferation of hematopoietic stem cells. Thrombosis, bleeding, and transformation to acute leukemia reduce the overall survival of patients with myelofibrosis, a disease typified by progressive splenomegaly and disease-related symptoms such as fatigue, pruritus, and bony pains. Hematopoietic stem cell transplant offers the only potential for cure in a minority of eligible patients, leaving a serious unmet need for improved therapies. Recent advances in our understanding of the pathogenetic mechanisms underlying these diseases have led to an explosion of clinical trials evaluating novel therapies. The discovery of an activating mutation in the Janus-activated kinase 2 (JAK2) gene provided a therapeutic target to downregulate this activated signaling pathway, which influences the phenotype of these diseases. Ruxolitinib (Jakafi; Incyte) is a small-molecule inhibitor of JAK1/2 that has proved to be effective at reducing splenomegaly and ameliorating symptoms in myeloproliferative neoplasms. Based on the results of 2 pivotal randomized phase III clinical trials, ruxolitinib has become the first therapeutic to be approved by the U.S. Food and Drug Administration for treatment of patients with myelofibrosis. Ruxolitinib offers a well-tolerated oral therapeutic option for patients with myelofibrosis with symptomatic splenomegaly and debilitating disease-related symptoms, but it does not seem to be effective at eliminating the underlying hematological malignancy. Clin Cancer Res; 18(11); 3008–14. Ó2012 AACR. Introduction to be developed for the treatment of CML, and revolu- The myeloproliferative neoplasms (MPN) are a group tionized the treatment of this MPN. of clonal hematological malignancies that originate at the The BCR-ABL1–negative MPNs are not characterized level of pluripotent hematopoietic stem cells (HSC) and by a uniform recurrent cytogenetic or molecular abnor- include chronic myelogenous leukemia (CML), polycy- mality, and thus it is difficult to identify targets for drug themia vera (PV), essential thrombocythemia (ET), and therapies. More than 12 mutations, as well as multiple primary myelofibrosis (PMF). PV and ET can both prog- epigenetic alterations, have been identified in MPNs. ress to myelofibrosis (termed post-ET/PV MF), which is They occur with varying frequencies, and coexpression clinically indistinguishable from PMF. Collectively, PMF patterns reveal a complicated pathobiology that makes it and post- ET/PV MF are referred to simply as MF. CML is unlikely that an agent targeting a single pathway will distinguished from the other MPNs by the requisite be successful in eliminating the malignant HSCs that are presence of the BCR-ABL1 proto-oncogene, which is responsible for MF. Additional mutations in MF cells believed to be the disease-initiating event. BCR-ABL1 is involving genes that encode a growing list of proteins a tyrosine kinase with constitutive activity that deregu- (e.g., MPL, EZH2, ASXL1, IDH1/2, TET2, CBL, IKZF1, lates cell differentiation, division, and adhesion. Imatinib and p53) with varying frequency have been identified. (Gleevec; Novartis) was the first tyrosine kinase inhibitor The acquisition of some of these mutations may be associated with disease progression and/or transformation to leukemia (1). Of the BCR-ABL1–negative MPNs, MF holds the worst Authors' Affiliation: Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York prognosis and is characterized by a chronic yet progressive course, with a median age at diagnosis of 65 years. The Corresponding Author: John Mascarenhas, Tisch Cancer Institute, Mount Sinai School of Medicine, Box 1079, One Gustave L. Levy Place, malignancy occurs at the level of the HSCs, and the marrow New York, NY 10029. Phone: 212-241-3417; Fax: 212-876-5276; fibrosis is believed to be largely a reactive process resulting E-mail: [email protected] from the effects of a number of cytokines elaborated by the doi: 10.1158/1078-0432.CCR-11-3145 cellular progeny of the malignant clone. The elaboration of Ó2012 American Association for Cancer Research. fibrogenic cytokines such as platelet-derived growth factor 3008 Clin Cancer Res; 18(11) June 1, 2012 Downloaded from clincancerres.aacrjournals.org on October 6, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst April 2, 2012; DOI: 10.1158/1078-0432.CCR-11-3145 Ruxolitinib in Myelofibrosis (PDGF), TGF-b, and basic fibroblast growth factor (bFGF) options include pomalidomide (an IMiD), Janus-activated have been implicated in the pathobiology of marrow fibro- kinase 2 (JAK2) inhibitors, histone deacetylase inhibitors sis in PMF, and may be due in part to pathologic interactions (HDACi), and heat shock protein 90 inhibitors (HSP90i). between neutrophils and megakaryocytes belonging to the Stem cell transplantation remains the only therapeutic malignant clonal (2, 3). Cytogenetic studies of fibroblasts option that offers the potential for cure in MF patients, from patients with PMF support the hypothesis that reactive preferably younger patients with a good performance status fibrosis occurs in response to the underlying malignant and an available 10/10 human leukocyte antigens (HLA)- process (4, 5). Clinical features include the presence of matched sibling donor. constitutional signs, progressive hepatosplenomegaly, In 2005, 4 independent laboratory groups reported the gout, and cachexia, and laboratory findings include anemia, finding of an activating point mutation in the JAK2 gene that thrombocytopenia, leukopenia or leukocytosis, and a can be observed in approximately 96%, 50%, and 50% of hypercellular bone marrow with dysplastic megakaryocytic patients with PV, ET, and PMF, respectively (7–10). JAK2 is a hyperplasia and the eventual accumulation of marrow member of a family of cytoplasmic tyrosine kinases that reticulin/collagen fibrosis. The systemic symptoms include include JAK1, JAK3, and Tyk2, and function to transmit fever, weight loss, pruritus, night sweats, and bone pain intracellular signals from cognate growth factor receptors to compromise the quality of life of patients with MF and have transcription complexes mediating the expression of genes been attributed to the elaboration of a number of cytokines, that are responsible for diverse cellular functions such as chemokines, and proteases. Complications related to differentiation, proliferation, and avoidance of apoptosis thrombosis, bleeding, and transformation to acute leuke- (11). JAK1 is known to mediate the effects of proinflam- mia (10–20% during the first decade from diagnosis) con- matory cytokines such as interleukin 2 (IL-2), IL-6, and tribute to an abbreviated lifespan in patients with MF. MF is TNF-a, thereby allowing a JAK1 inhibitor to reduce the associated with a median overall survival of 69 months, effects of these cytokines in a variety of chronic inflamma- with a broad range depending on the degree of advance- tory states, such as psoriasis, atopic dermatitis, and rheu- ment of the disease (6). The International Prognostic Scor- matoid arthritis. JAK1/2 inhibitors may be considered ing System created by the International Working Group for pleiotropic in some respects. They are capable of reducing Myelofibrosis Research and Treatment was developed to the signaling of pathogenic cytokines such as IL-6 and IL-23, define the prognosis of patients with MF, with the hope and as a result can inhibit the production of an array of of determining which therapeutic options are appropri- additional proinflammatory cytokines, chemokines, and ate for individual patients (6). This prognostic scoring adhesion molecules by other cell types, leading to interrup- system is based on 5 independent clinical factors tion of the so-called cytokine cascade. (age > 60, hemoglobin < 10 g/dL, peripheral blood blast A number of tyrosine kinase inhibitors with varying count 1%, presence of constitutional symptoms, and anti-JAK2 potency and specificity, as well as different leukocyte count 25 Â 109/L), all of which have been toxicity profiles, have been or are currently being evalu- determined to be predictive of a poor prognosis following ated in clinical trials. These include lestaurtinib (Cepha- multivariate analysis. Four distinct risk groups can be iden- lon), AZD1480 (AstraZeneca), BMS911543 (Bristol-Myers tified based on the presence of 0 (low risk), 1 (inter- Squibb), CYT387 (YM Bioscience), and SAR302503 mediate risk-1), 2 (intermediate risk-2), or 3 (high risk) [Sanofi-Aventis (12)]. All of these agents were initially of these variables, with median survivals of 135, 95, 48, evaluated in patients with advanced MF because of the and 27 months, respectively (P < 0.001). Patients with limited survival experienced by such patients, which was low/intermediate-1 risk status are typically followed with believed to justify their entry into clinical trials involving a watch-and-wait approach, whereas patients with inter- experimental therapeutics. Initially called INCB18424, mediate-2/high-risk status are treated with traditional ruxolitinib (Jakafi; Incyte), a

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