Practical management of patients with myelofibrosis receiving ruxolitinib

Abstract

Myelofibrosis (MF) is characterized by bone marrow fibrosis, progressive anemia and extramedullary hematopoiesis, primarily manifested as splenomegaly. Patients also experience debilitating constitutional symptoms, including sequelae of splenomegaly, night sweats and fatigue. Ruxolitinib (INC424, INCB18424, Jakafi, Jakavi), a JAK1 and JAK2 inhibitor, was approved in November 2011 by the US FDA for the treatment of intermediate- or high-risk MF, and more recently in Europe and Canada for the treatment of MF-related splenomegaly or symptoms. These approvals were based on data from two randomized Phase III studies: COMFORT-I randomized against placebo, and COMFORT-II randomized against best available therapy. In these studies, ruxolitinib rapidly improved multiple disease manifestations of MF, reducing splenomegaly and improving quality of life of patients and potentially prolonging survival. However, as with other chemotherapies, ruxolitinib therapy is associated with some adverse events, such as anemia and thrombocytopenia. The aims of this article are to provide a brief overview of ruxolitinib therapy, to discuss some common adverse events associated with ruxolitinib therapy and to provide clinical management recommendations to maximize patients’ benefit from ruxolitinib.

Keywords::

• JAK inhibitor
• myelofibrosis
• myeloproliferative neoplasms
• ruxolitinib
• splenomegaly

Financial & competing interests disclosure

C Harrison has received honoraria from Novartis, Sanofi-Aventis, Celgene and Shire; received research funding from Novartis and Shire; acted as a consultant to YM BioSciences, S*BIO, Sanofi-Aventis and Novartis. R Mesa has received research funding from Incyte, NS Pharma, Eli Lilly, Sanofi-Aventis and YM BioSciences. D Ross has received honoraria from Novartis, BMS and Shire; received research funding from Novartis. A Mead has received honoraria from Novartis, Sanofi-Aventis and Shire. C Keohane has received research funding from Novartis. J Gotlib has received honoraria from Incyte and Gilead; received research funding from Incyte, Sanofi-Aventis and Gilead; and acted as a consultant to Incyte and Gilead. S Verstovsek has received honoraria from Novartis; has received research funding from Incyte. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. The authors would like to thank Candice L. Willmon, PhD, and Daniel Hutta, PhD, for medical editorial assistance with this manuscript.

Key issues

• • Myelofibrosis (MF) is a relatively rare condition and with new MF therapies becoming commercially available, it is important to review the clinical challenges of treating MF and to become familiar with how to manage patients receiving JAK inhibitor therapy.

• • Ruxolitinib is a JAK1 and JAK2 inhibitor that rapidly improved multiple disease manifestations of MF, reducing splenomegaly and improving quality of life (QoL) of patients, and potentially prolonging survival.

• • Ruxolitinib was approved based on data from two pivotal randomized Phase III trials: The COMFORT trials compared ruxolitinib with placebo or physician’s choice of best available therapy (BAT).

• • JAK-STAT signaling is critical for normal hematopoiesis, so reversible suppression of myelopoiesis is an expected consequence of inhibiting this pathway.

• • Cytopenia due to ruxolitinib treatment can be managed with dose reduction and/or interruptions.

• • Overall, grade 3/4 AEs and biochemical abnormalities were infrequent, and were rarely reported more often in the ruxolitinib arms of the COMFORT studies than in the control.

• • With diligent monitoring and dose adjustment in response to AEs, the authors expect that successful treatment with ruxolitinib will help many patients to regain QoL, and have prolonged survival.