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Clarifying the Use of Ruxolitinib in Patients With Myelofibrosis

Clarifying the Use of Ruxolitinib in Patients With Myelofibrosis

Myelofibrosis (MF) is a hematopoietic stem cell malignancy classified as a myeloproliferative neoplasm (MPN). The clinical course of individuals with MF is heterogeneous and characterized by constitutional symptoms, bone marrow myeloproliferation and fibrosis, progressive cytopenias, and symptomatic splenomegaly. Historically, patients with this debilitating disease have had limited treatment options, and disease-modifying agents were not available. Hematopoietic stem cell transplantation is the only potentially curative therapy, but it is only an option for select patients. The discovery of an activating point mutation in the Janus kinase 2 gene (JAK2V617F) in a significant portion of patients with MPNs led to improved understanding of the pathobiology of these disorders and prompted rapid development of JAK inhibitors. Ruxolitinib (Jakafi) is the first-in-class and only JAK inhibitor currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with MF; approval was based on the results of the COMFORT (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment) I and II studies. While not a curative option, ruxolitinib offers great palliative potential and results in significant reduction in splenomegaly and improvement in constitutional symptoms in the majority of treated patients, thus improving their quality of life and performance status. Additionally, ruxolitinib is the only agent that has demonstrated a survival benefit in patients with MF. The optimal use of ruxolitinib for MF patients is challenging and complex. In this article, we provide updated data on ruxolitinib therapy for patients with MF and offer expert opinion on the appropriate use of this agent in the community practice.


The myeloproliferative neoplasms (MPNs) are a heterogeneous group of chronic hematological malignancies that are generally divided into the Philadelphia chromosome–positive (Ph-positive) MPNs, which refers to chronic myelogenous leukemia (CML) and the Philadelphia chromosome–negative (Ph-negative) MPNs. The World Health Organization (WHO) classifies polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) as Ph-negative MPNs.[1] PV and ET are both capable of progressing to a fibrotic stage that clinically resembles PMF, and collectively these three disease entities are termed myelofibrosis (MF).

The clinical course of individuals with MF is characterized by constitutional symptoms (fevers, night sweats, and weight loss), bone marrow myeloproliferation and reticulin/collagen fibrosis, worsening cytopenias, thrombosis, and progressive symptomatic splenomegaly. Extramedullary hematopoiesis (EMH) is likely the result of abnormal trafficking of hematopoietic stem cells (HSC) from the bone marrow to organs such as the spleen, liver, and lung, causing organomegaly and sometimes organ dysfunction.[2,3] Common MF symptoms include bone pain, debilitating fatigue, pruritus, abdominal pain, and bowel disturbances. Dyspnea can be due to anemia, pulmonary emboli, congestive heart failure, and/or the development of pulmonary artery hypertension secondary to EMH. Splenomegaly can result in early satiety that further adds to weight loss, abdominal bloating, and severe left-upper-quadrant abdominal pain from splenic infarcts.

An increased rate of thrombotic complications is associated with MF and can occur in the venous or arterial circulation. Conversely, bleeding episodes can also complicate the clinical course of MF and can be attributed to either thrombocytopenia or qualitative platelet dysfunction. Many patients develop anemia during the course of their disease and require red blood cell transfusion support. Often patients who present the biggest therapeutic challenge are those who develop profound transfusion-dependent thrombocytopenia and who in some cases become refractory to platelet transfusions.


Dynamic International Prognostic Scoring System

Thrombotic complications involving the venous and arterial vasculature; bone marrow failure leading to transfusion dependence, increased bleeding, and infection risk; and transformation to acute leukemia contribute to reduced survival in MF patients.[4] The clinical course of MF patients is variable, and risk stratification systems are used to estimate predicted survival in order to select the most appropriate treatment approach for a given patient. The International Prognostic Scoring System (IPSS) incorporates five prognostic clinical variables derived from multivariate analysis, assigning a point each for age > 65 years, leukocyte count > 25 × 109/L, hemoglobin level < 10 g/dL, peripheral blood blast percentage ≥ 1%, and the presence of constitutional symptoms (see Table 1).[4] Four risk groups can be defined—low-risk (0 points), intermediate-1 (1 point), intermediate-2 (2 points), and high-risk (≥ 3 points)—with independent median survivals of 135, 95, 48, and 27 months, respectively. The IPSS score is calculated at time of diagnosis, and the dynamic IPSS (DIPSS) and DIPSS-plus can be used to calculate an individual MF patient’s risk-group status at any point during his or her clinical course.[5,6] DIPSS-plus also incorporates thrombocytopenia, transfusion-dependent anemia, and cytogenetic abnormalities as adverse prognostic markers in addition to the risk factors used in the IPSS. Karyotypic abnormalities are present in approximately 30% to 50% of MF patients, and unfavorable chromosomal abnormalities (complex abnormalities or sole or dual abnormalities that include +8, −7/7q−, i7/7q−, i(17q), −5/5q, 12p−, inv(3), or 11q23 rearrangements) have been incorporated in the DIPSS-plus as negative prognostic indicators. Patients with MF have a median survival of approximately 5 to 6 years from time of diagnosis, but recently a large retrospective study of MF patients from Europe has indicated an improvement in relative survival that is most significant in women, younger patients, and low/intermediate-1–risk subgroups.[4,7]

Therapeutic approaches that address the myeloproliferation (leukocytosis, thrombocytosis) and organomegaly (splenomegaly and hepatomegaly) associated with MF include chemotherapeutic agents such as hydroxyurea, melphalan, busulfan, and cladribine.[8] Radiotherapy can be employed to address symptomatic splenomegaly refractory to medical management, or in cases of EMH affecting the lung or peritoneum, or impinging on nerves. Anemia is common in MF patients and can be multifactorial in origin (possible causes include iron deficiency, B12 deficiency, folate deficiency, ineffective erythropoiesis, splenic sequestration, and hemolysis) and leads to red blood cell transfusion–dependence in many patients. Multiple approaches to the anemia have been evaluated and include erythropoiesis-stimulating agents (ESAs); immunomodulatory agents such as thalidomide (Thalomid), lenalidomide (Revlimid), and pomalidomide (Pomalyst) alone or in combination with prednisone; danazol (Danocrine); and occasionally corticosteroids alone, which can be effective if the anemia is due to an autoimmune hemolytic process.

Stem cell transplantation (SCT) is the only therapeutic option that offers the potential for cure in patients with MF.[9] Although it is generally agreed that MF patients with intermediate-2/high-risk disease are appropriate for consideration of SCT, advanced patient age, significant comorbid conditions, and lack of optimal donor options exclude the majority of patients. SCT utilizing reduced-intensity conditioning (RIC) broadens the eligibility for this definitive approach to include MF patients who are less fit, who have more competing co-morbidities, and are older.[10] The use of alternative donor sources such as haploidentical and cord blood, the role of autologous SCT, and the benefit of preconditioning with a Janus kinase 2 (JAK2) inhibitor are approaches being evaluated in MF patients in a variety of clinical trials.[11,12]


Increased JAK/STAT Signaling in Myelofibrosis

Janus Kinase 2 and MF

The JAK2 tyrosine kinase is a member of a family of key intracellular signaling proteins associated with cytokine receptors such as erythropoietin (EPO), thrombopoietin (TPO), and granulocyte colony–stimulating factor (G-CSF).[13] Binding of the cytokine to the appropriate receptor results in phosphorylation and activation of the JAK kinase, as well as cytokine receptor phosphorylation, recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins, and the activation of multiple downstream signaling events (see Figure). Phosphorylation of STAT in turn leads to the transcription of genes related to survival and proliferation. In 2005, an activating point mutation in the JAK2 gene was identified by four independent groups, providing the first association between a genetic event and Ph-negative MPN pathogenesis.[14-17] A G-to-T point mutation in exon 14 of JAK2, located on chromosome 9p24, is the most commonly observed mutation in Ph-negative MPNs. Expression of JAK2V617F confers cytokine hypersensitivity and cytokine-independent growth of hematopoietic cells. Approximately 50% of MF patients have this mutation. Additionally, mutations of the thrombopoietin receptor (MPL515L/K) have been identified in approximately 3% to 5% of MF patients and represent an upstream event that also leads to constitutive JAK-STAT pathway activation.[18]

It is now recognized that JAK2V617F is not a disease-initiating genetic event, nor is there clear prognostic significance for this mutation in patients with MF.[19] Although JAK2V617F appears to be associated with a higher hemoglobin level and less need for transfusion in MF patients as well as with older age, thrombocytosis, leukocytosis, and splenomegaly, it has not been reported to uniformly influence risk of thrombosis, leukemic transformation, or survival.[20-23] However, low JAK2V617F allele burden may predict for shorter overall and leukemia-free survival compared with patients who have a high burden or JAK2 wild-type.[24]

In recent years a number of mutated genes have been identified in patients with MF and include TET2, ASXL1, IDH1, IDH2, EZH2, LNK, and CBL.[25] Mutations in these genes can co-exist, are found in low frequency, and affect various aspects of hematopoietic cell function and survival. A complex interaction of acquired genetic and epigenetic lesions likely contributes to the molecular pathogenesis, clinical phenotype, and events leading to leukemic transformation.[26] Ongoing laboratory efforts are focused on elucidating the inciting molecular events at the level of the MF hematopoietic stem cell, and ultimately on the identification of therapeutic targets.

There are currently over a dozen oral JAK inhibitors in clinical development for the treatment of MPN.[27-29] These agents differ primarily in their selectivity for JAK2 inhibition and have all been shown to reduce splenomegaly and improve symptoms to varying degrees. Whether significant reduction in JAK2 allele burden, improvement in cytopenias, and restoration of normal polyclonal hematopoiesis are achieved with these agents has not yet been fully documented. Ultimately, whether one agent is superior to the rest is currently unknown and will require a rigorous evaluation in controlled prospective studies.

Other therapies being evaluated for the treatment of MF include interferon-alpha (IFN-α), histone deacetylase inhibitors (HDACi), heat shock protein 90 (HSP90) inhibitors, monoclonal antibodies to transforming growth factor beta (TGF-beta) and lysyl oxidase–like 2 (LOXL2), inhibitors of mammalian target of rapamycin (mTOR), and small molecule inhibitors of the Hedgehog pathway.[30,31] Given the apparently complex pathobiological underpinnings of MF, combinations of agents targeting multiple dysregulated pathways and epigenetic alterations are being evaluated in clinical trials.[32]


In November 2011, ruxolitinib (Jakafi) was approved by the US Food and Drug Administration (FDA) for the treatment of intermediate- and high-risk MF patients, based on the results of two pivotal phase III trials. Ruxolitinib is the only FDA-approved drug for the treatment of this hematopoietic stem cell malignancy, and it has dramatically changed the treatment landscape.[33] As an oral agent that can be prescribed in the community, ruxolitinib offers many patients who did not have access to clinical trials at tertiary care centers an effective treatment option that addresses splenomegaly and other disease-related symptoms.

Dysregulated JAK-STAT activity is present in MF patients, regardless of JAK2 mutational status.[34] Consequently, JAK1 and JAK2 have become the focus of study for pharmacologic intervention in MF. Ruxolitinib is a first-in-class oral small-molecule inhibitor of JAK1/JAK2. Pharmacodynamic assessments performed during preclinical and phase I studies have demonstrated the molecular-biological effect of JAK 1/2 inhibition as manifested by down-regulation of phosphorylated STAT-3 and pro-inflammatory cytokines from patient blood samples after administration of the drug.[34,35] It is believed that reduction in circulating inflammatory cytokines with ruxolitinib therapy is a consequence of JAK1 signaling inhibition and correlates with improvement in constitutional and MF-related symptoms.

The dose-escalation phase I/II study of ruxolitinib in JAK2V617F-positive and JAK2V617F-negative MF patients established 25 mg twice-daily or 100 mg once-daily as the maximum tolerated dose, based on the dose-limiting toxicity of reversible thrombocytopenia.[35] Ruxolitinib at a dose of 15 mg twice-daily was associated with sustained reductions of splenomegaly and constitutional symptoms, with an associated improvement in exercise tolerance, performance status, and meaningful weight gain in MF patients, irrespective of JAK2 mutational status. Approximately half of treated patients achieved a 50% reduction in splenomegaly for ≥ 12 months, and tumor lysis syndrome was rarely seen. Marked suppression of the heightened expression of pro-inflammatory cytokines (interleukin [IL]-6, IL-1ra, macrophage inflammatory protein [MIP]-1β, tumor necrosis factor [TNF]α, and C-reactive protein [CRP]) was seen with ruxolitinib treatment and correlated with improvement in night sweats, fevers, fatigue, weight loss, and pruritus. After 12 cycles of ruxolitinib therapy, a mean maximal suppression of JAK2V617F allele burden of 13% was observed.

Five of the 47 MF patients (11%) treated at Mayo Clinic Rochester experienced a withdrawal syndrome after rapid discontinuation of ruxolitinib.[36] In some cases this was reportedly associated with hemodynamic compromise and a septic-like state.


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