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Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment

About Ruxolitinib (Also Known as INCB018424)

Ruxolitinib: A potent JAK1 and JAK2 inhibitor1

This information is provided to US healthcare professionals who are considering enrolling a patient in the RESPONSE trial.

The Janus kinase (JAK) pathway has many different molecules that contribute to the signaling process. The balance of the activity among these components is critical to normal myeloid cell growth, cell survival, and differentiation of blood cells as well as the maintenance of a functioning immune system. Dysregulation of JAKs or any other components of the pathway may lead to imbalances in blood cell production or immune function.2,3

The JAK2V617F mutant allele is present in over 95% of cases of polycythemia vera (PV). This mutation results in constitutive activation of the JAK pathway.4 Although JAK2 mutational status is helpful in myeloproliferative neoplasm (MPN) diagnosis, it is not a predictive marker of response to JAK inhibitor treatment.5,6 This may be due in part to other mechanisms of dysregulation of JAK signaling, such as excess cytokines or other receptor or kinase mutations, implicated in MPNs.7-9 Therefore, inhibition of the JAK pathway represents a promising approach in the research into these disorders, regardless of a patient's mutational status.1,7

Ruxolitinib is a potent and selective JAK1 and JAK2 inhibitor that is currently under investigation for the treatment of MPNs. As a dual JAK1 and JAK2 inhibitor, this agent has the potential to modulate 2 important kinases that play a role in MPNs.1 Ruxolitinib is an investigational compound for PV. There is no guarantee that this compound will become commercially available for use in PV patients.

In preclinical studies, ruxolitinib reduced the pro-inflammatory cytokine signaling mediated by JAK1 and JAK2, as well as inhibited hematopoiesis outside the bone marrow mediated by JAK2.1 Both of these pathways have been implicated in MPN progression.7,10 In PV, an early clinical study in patients refractory to or intolerant of hydroxyurea has suggested that ruxolitinib treatment can result in the normalization of hematocrit, white blood cell count, and platelet count while eliminating the need for phlebotomy, as well as reduction in palpated spleen length and improvement in symptomatic burden including pruritus, night sweats, and bone pain.11 Data to date suggest that the clinical effects of ruxolitinib occur independent of JAK2 mutational status.10

Ruxolitinib may cause low blood cell counts (white blood cells, red blood cells, platelets); in most cases, these low blood cell counts can be reversed within a few days by stopping ruxolitinib or reducing the dose.10

Additional clinical investigations are underway in order to further evaluate these potentially disease-modifying clinical outcomes.10


1.Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115:3109-3117.
2.Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol. 2008;19:385-393.
3.Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. Int J Hematol. 2010;91:165-173.
4.Morgan KJ, Gilliland DG. A role for JAK2 mutations in myeloproliferative diseases. Annu Rev Med. 2008;59:213-222.
5.Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807.
6.Thiele J, Kvasnicka HM. The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Curr Hematol Malig Rep. 2009;4:33-40.
7.Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program. 2009:636-642.
8.Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:1140-1151.
9.Kralovics R. Genetic complexity of myeloproliferative neoplasms. Leukemia. 2008;22:1841-1848.
10.Data on file, Incyte Corporation.
11.Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of INCB018424, an oral, selective JAK1/JAK2 inhibitor, in patients with advanced polycythemia vera (PV) and essential thrombocythemia (ET) refractory to hydroxyurea. Presented at: 51st American Society of Hematology (ASH) Annual Meeting and Exposition; December 5-8, 2009; New Orleans, LA.