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 Table of Contents  
Year : 2013  |  Volume : 4  |  Issue : 3  |  Page : 89-95

Development of ruxolitinib as a myelofibrosis therapy

1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX USA
2 King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

Date of Web Publication19-Dec-2013

Correspondence Address:
Srdan Verstovsek
Department of Leukemia, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Suite 428, Houston, TX 77030, USA

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1658-5127.123299

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Myelofibrosis (MF) is a hematologic malignancy characterized by proliferation of an aberrant myeloid-derived stem cell clone, leading to inefficient hematopoiesis and bone marrow fibrosis. Typical clinical manifestations include progressive anemia and splenomegaly, which leads to several debilitating symptoms, including fatigue, night sweats, itching, appetite loss, and bone pain. Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway dysregulation is a common feature of MF. Ruxolitinib, an oral JAK1/JAK2 inhibitor, was recently approved by the US Food and Drug Administration and European Medicines Agency for the treatment of MF patients. In clinical trials, patients treated with ruxolitinib had significant reductions in spleen size and improvements in their constitutional symptoms and quality of life (QoL), with possibly prolonged survival. The most common adverse events were anemia and thrombocytopenia. Here, we review the most recent clinical data on ruxolitinib and discuss its use in MF patients.

Keywords: Anti-JAK2, myelofibrosis, ruxolitinib

How to cite this article:
Verstovsek S, Almomen AK, Newberry KJ, Aleem A. Development of ruxolitinib as a myelofibrosis therapy. J Appl Hematol 2013;4:89-95

How to cite this URL:
Verstovsek S, Almomen AK, Newberry KJ, Aleem A. Development of ruxolitinib as a myelofibrosis therapy. J Appl Hematol [serial online] 2013 [cited 2023 Sep 30];4:89-95. Available from: https://www.jahjournal.org/text.asp?2013/4/3/89/123299

  Introduction Top

Myelofibrosis (MF), the most aggressive of the classic (BCR-ABL1-negative) myeloproliferative neoplasms (MPNs), is characterized by extramedullary hematopoiesis, progressive anemia, bone marrow fibrosis, and osteosclerosis, which are thought to result from proliferation of an aberrant hematopoietic stem cell clone. [1],[2] Symptoms include splenomegaly, hepatomegaly, anemia, and other peripheral blood cytopenias, pruritus, constitutional symptoms, and bone pain, all of which lead to a poor quality of life (QoL) for patients. [3],[4] MF can occur as a primary disease (primary MF) or can develop secondary to polycythemia vera (PV; post-PV MF) or essential thrombocythemia (ET; post-ET MF); regardless, the clinical characteristics and prognosis are similar, with an average survival duration of approximately 5 years.

In 2005, the discovery of the Janus kinase (JAK) gene mutation at residue V617 (JAK2V617F) in patients with MPNs led to the development of the first targeted therapies for MF. [5],[6],[7],[8],[9] Several JAK inhibitors are in clinical development, and ruxolitinib, an oral JAK1/JAK2 inhibitor, was approved by the United States Food and Drug Administration in 2011 and by the European Medicines Agency in 2012 for the treatment of MF patients. Here, we review the recent clinical data on the use of ruxolitinib in MF patients.

  Clinical presentation and pathogenesis of MF Top

MF is a BCR-ABL1-negative MPN characterized by leukoerythroblastosis, dysfunctional bone marrow hematopoiesis, myeloid progenitor cell proliferation, and abnormal cytokine expression. [2],[10],[11] Extramedullary hematopoiesis occurs in the spleen and liver to compensate for reduced bone marrow function, resulting in painful organ enlargement (i.e. hepatomegaly and splenomegaly). Furthermore, dysfunctional hematopoiesis results in progressive anemia, which can lead to transfusion dependence. Patients often experience symptoms that severely impair their QoL, including fatigue, night sweats, itching, low-grade fever, and bone pain. [3],[12] Splenomegaly often leads to abdominal discomfort, appetite loss, and unintentional weight loss and can result in several complications such as portal hypertension. [1] Disease progression can result in bone marrow failure, progression to acute leukemia, or other complications such as infections, thrombosis, or hemorrhage. [13]

Prognosis and Current Treatments

Prognosis for MF patients depends on several Risk factors, including age (>65 years), hemoglobin level (<10 g/dL), leukocyte count (>25 × 10 9 /L), circulating blasts (≥1%), the presence of constitutional symptoms, platelet count (<100 × 10 9 /L), transfusion dependence, and an unfavorable karyotype. [13],[14] The estimated median survival times range from 2 (high-risk patients) to 11 years (low-risk patients) depending on the number of negative prognostic factors present. Because of the wide range in expected survival times, the general consensus is that prognosis assessments should dictate when transplantation should be considered as a therapeutic option. However, in everyday practice, the usual indications to initiate therapy primarily include significant anemia, poor QoL, or symptomatic splenomegaly.

Hydroxyurea has traditionally been the primary choice for cytoreduction and management of splenomegaly. Splenectomy is sometimes used in cases of painful splenomegaly that are refractory to treatment; however, this procedure is associated with significant morbidity and mortality. [15] Peripheral blood cytopenias are treated with androgens, corticosteroids, immunomodulatory agents (e.g. thalidomide or lenalidomide), or erythropoiesis-stimulating agents for patients with serum erythropoietin levels <125 U/L (unit/liter). Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative treatment. [16] However, fewer than 10% of patients are eligible for allo-SCT because of advanced age and comorbidities. Both conventional and reduced-intensity conditioning allo-SCT is associated with high treatment-related mortality rates and relapse (estimated 5-year survival, 30-67%). [17],[18] Ideal candidates for allo-SCT are younger patients (<55 years) with few comorbidities who have high or intermediate-risk disease. [19],[20]

Inhibition of JAK Signaling

Role of JAK signaling in MF

Dysregulated signaling through the JAK-signal transducers and activators of transcription (STAT) pathway appears to be an important feature of MF pathogenesis. Hallmarks of this overactive JAK-STAT signaling include proliferation of hematopoietic progenitor cells with upregulated JAK-STAT signaling and a proinflammatory state. [21] JAKs are intracellular tyrosine kinases that relay extracellular signals from various receptors to stimulate cell growth and proliferation (e.g. erythropoietin and thrombopoietin receptors) and the production of proinflammatory cytokines (e.g. cytokine receptors). [22],[23],[24] Although several mutations affecting the JAK-STAT pathway have been identified in MF patients, the most well-studied is the JAK2V617F mutation, which results in JAK-STAT pathway hyperactivation. [25],[26] Although the JAK2 mutation is found in 50-60% of MF patients, [27] the JAK-STAT pathway has been found to be chronically upregulated in all patients with MF, regardless of the JAK2 mutational status, indicating that multiple mechanisms and/or mutations may contribute to this aberrant signaling. [28],[29]


In 2005, the simultaneous discovery of the JAK2V617F mutation by several groups led to the development of JAK inhibitors for MF treatment. [5],[6],[7],[8],[9] The most well-studied of these, ruxolitinib, was approved by the United States Food and Drug Administration in November 2011 for use in patients with intermediate and high-risk disease and by the European Medicines Agency in August of 2012 for the treatment of disease-related splenomegaly or symptoms in adult MF patients. The clinical efficacy and safety of ruxolitinib were evaluated in a phase I/II dose-finding study [30] and two phase III randomized controlled trials of ruxolitinib. [31],[32] The initial phase I/II dose-finding study enrolled patients with JAK2V617F-positive or JAK2V617F-negative MF. A starting dose of 15 mg twice daily with individualized dose adjustments was found to be the most effective and safest dose. Further, suppression of JAK2 signaling was observed in patients with and without the JAK2V617F mutation; therefore, screening for the presence of the JAK2V617F mutation is not necessary before prescribing ruxolitinib. [33] The Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT)-I trial was a double-blind, placebo-controlled phase III trial that included patients with intermediate-2 or high-risk MF. Patients were randomized into two groups and received either a placebo (n = 154) or ruxolitinib twice daily (n = 155); the latter was given in doses of 15 mg for platelet counts of 100-200 × 10 9 /L and 20 mg for counts >200 × 10 9 . The COMFORT-II open-label randomized phase III trial evaluated ruxolitinib (n = 146) versus the best available therapy (n = 73).

Reduction of splenomegaly

In the phase I/II clinical trial of ruxolitinib, spleen response was defined as a ≥50% reduction in palpable splenomegaly; after 3 months of treatment, patients with enlarged spleens at baseline had a response rate of 44%. In the COMFORT-I and II trials, spleen response was defined as a ≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography (corresponding to a ≥50% reduction in palpable splenomegaly). In COMFORT-I, at 24 weeks, 41.9% of patients receiving ruxolitinib had responses, versus 0.7% of those receiving placebo (P < 0.001). Follow-up data showed that the spleen response was durable; among the 100 patients who remained on therapy after a median follow-up of 102 weeks, the median reduction in spleen volume was 32%, and this remained stable even at week 96. [34] In COMFORT-II, 28% of patients in the ruxolitinib group had a response at week 48, while none of the patients receiving the best available therapy had a ≥35% reduction in spleen volume (P < 0.001) [Figure 1]. In a follow-up analysis after a median of 112 weeks, the probability of maintaining a ≥35% reduction in spleen volume was reported to be 75% (95% confidence interval (CI), 61-84%) at week 48 and 58% (95% CI, 35-76%) at week 84. [35] In both trials, most patients who received ruxolitinib experienced some spleen reduction (150 of 155 in COMFORT-I and 132 of 136 in COMFORT-II), while the majority of those receiving placebo (102 of 153) and most of those receiving the best available therapy (28 of 63 evaluated) had spleen growth. Further responses to treatment and reductions in spleen volume were similar across all subgroups analyzed (e.g. type of MF (primary or post-PV, post-ET), gender, age, international prognostic scoring system (IPSS) Risk category, presence or absence of the JAK2V617F mutation, or baseline spleen size). [33]
Figure 1: Reductions in the spleen volumes of patients enrolled in Controlled Myelofibrosis Study with Oral Janus kinase (JAK) Inhibitor Treatment (COMFORT)-II. Best percentage changes in spleen volume at any time within the first 48 weeks for each patient. From Harrison C et al. N Engl J Med 2012;366:787-798. Reprinted with permission from the Massachusetts Medical Society

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Improvements in the QoL and other symptoms

In the phase I/II trial, improvements in MF-related symptoms, including night sweats, itching, bone/muscle pain, and abdominal pain/discomfort, were measured with the Myelofibrosis Symptom Assessment Form (MFSAF). [36] After 1 month of treatment, the majority of patients who received between 10 and 25 mg of ruxolitinib twice-daily had at least a 50% reduction in the combined symptom score (includes scores for night sweats, itching, abdominal pain/discomfort, and bone/muscle pain), which was sustained for 6 months. [30] In the COMFORT-I trial, which utilized the MFSAF version 2.0, 46% of patients in the ruxolitinib group versus 5% in the placebo group (P < 0.001) had improvements of ≥50% in the total symptom score (TSS; includes scores for night sweats, itching, abdominal discomfort, pain under ribs, early satiety, and bone/muscle pain) at 24 weeks [Figure 2].
Figure 2: Improvements in symptom and quality of life in patients treated with ruxolitinib versus those treated with the best available therapy in the COMFORT-II trial. (a) Mean percent changes in the scores from baseline at week 48 on the European Organization for the Research and Treatment of Cancer (EORTC) QoL Questionnaire-Core 30 (QLQ-C30) global health status/quality of life assessment. (b) Mean percent change from baseline at week 48 for selected symptom scores. Orange bars represent patients treated with ruxolitinib; gray bars represent those treated with the best available therapy. From Harrison C et al. N Engl J Med 2012;366:787-798

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In both the COMFORT-I and COMFORT-II trials, ruxolitinib treatment also improved the QoL, as measured by several QoL scoring systems, such as the European Organization for the Research and Treatment of Cancer (EORTC) QoL Questionnaire-Core 30 (QLQ-C30), Patient-Reported Outcomes Measurement System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC), and Functional Assessment of Cancer Therapy-Lymphoma [Figure 2]. [34],[37]

Survival benefits

Comparative analyses of long-term survival data from the phase I/II trial of ruxolitinib with patients enrolled at two different sites (MD Anderson Cancer Center and the Mayo Clinic) and data from historical controls have been reported. [38],[39],[40] Survival data from 107 patients enrolled at MD Anderson and 310 historical control patients who were matched for their characteristics showed a significant survival advantage for patients who received ruxolitinib (P = 0.005).(39,40) In contrast, data from the 51 patients enrolled at Mayo Clinic-Rochester showed no survival difference when compared to 410 historical unmatched (all comers) control patients. [38] The discontinuation rates were higher in the Mayo Clinic cohort (51% at 1 year and 89% at 3 years) than in the MD Anderson cohort (24% at 1 year and 46% at 3 years), [40] which may have affected the results.

A survival analysis from COMFORT-I conducted at a median follow-up time of 51 weeks showed a significant survival advantage with ruxolitinib versus placebo (hazard ratio (HR) =0.50; 95% CI 0.25-0.98; P = 0.04); there were 13 (8.4%) deaths in the ruxolitinib group versus 24 (15.6%) in the placebo group [Figure 3]a. [32] In a longer-term follow-up analysis (median follow-up time of 102 weeks), patients in the ruxolitinib arm continued to show a survival advantage over those in the placebo arm (HR = 0.58; 95% CI 0.32-0.95; P = 0.028). [34] Another follow-up analysis from COMFORT-I showed that weight gain and improvements in cholesterol above the medians were associated with prolonged survival, relative to weight gain or cholesterol improvements below the median (HR = 0.40; 95% CI 0.18-0.90; P = 0.022 and HR = 0.46, 95% CI 0.21-1.01; P = 0.048, respectively). [41]
Figure 3: Improvements in overall survival in patients treated with ruxolitinib. Kaplan-Meier estimates of overall survival for patients enrolled in the (a) COMFORT-I and (b) COMFORT-II trials. Tick marks indicate censoring times for individual patients. Panel A from Verstovsek S et al. N Engl J Med 2012;366:799-807

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In COMFORT-II, at a median follow-up time of 61 weeks, ruxolitinib did not show a survival advantage over the best available therapy (HR = 1.01; 95% CI 0.32-3.24). [31] However, a long-term follow-up (median, 112 weeks) suggested a survival advantage for patients randomized to ruxolitinib (HR = 0.51; 95% CI 0.26-0.99; P = 0.041) [Figure 3]b. [35]

Despite the fact that both COMFORT-I and COMFORT-II allowed the crossover of patients to the ruxolitinib arm, patients exposed to ruxolitinib from the beginning of the study had lower mortality rates than those initially exposed to placebo or the best available therapy. [42] This is likely due to better control of disease symptoms by ruxolitinib, which reduced the levels of inflammatory cytokines that have been proven to be important for MF disease biology and patient outcomes. [42] These findings suggest that ruxolitinib should not be reserved for only the sickest patients, but should be generally introduced as a therapy for patients with symptomatic disease. [33]

Safety and tolerability

Results from the phase I/II and III trials suggest that ruxolitinib is generally safe and well-tolerated. Data from COMFORT-I and COMFORT-II show that the most common high-grade (≥grade 3) adverse events in ruxolitinib-treated patients were thrombocytopenia and anemia, which mainly occurred in the first 2-3 months of treatment. [31],[32] In COMFORT-I, 45% of patients in the ruxolitinib group experienced grade 3 or 4 anemia versus 19% in the placebo group, while 13% of patients treated with ruxolitinib experienced grade 3 or 4 thrombocytopenia versus 1% in the placebo group. Neutropenia was also observed more frequently in patients treated with ruxolitinib than in those treated with placebo (19 versus 7%). In COMFORT-II, 42% of patients treated with ruxolitinib and 31% of those who received the best available therapy had grade 3 or 4 anemia. These hematologic adverse events, which were expected based on the known mechanism of action of ruxolitinib, were generally managed with dose reductions, dose interruptions, or transfusions (for anemia). With appropriate management, the mean platelet counts stabilized and mean hemoglobin levels returned to near baseline levels.

Reductions in red blood cell counts in patients treated with ruxolitinib are usually transient (lasting only the first 6 months of treatment). After appropriate dose adjustments, hemoglobin levels generally rebound to near baseline levels. [33] Importantly, patients who experience ruxolitinib-associated anemia that requires transfusion therapy experience the same degrees of improvements in spleen size and QoL as those without therapy-induced anemia. [33] The overwhelming improvements in constitutional symptoms and splenomegaly significantly outweigh the Risk of transfusion dependency. [42] A long-term follow-up of patients treated with ruxolitinib in COMFORT-I and COMFORT-II revealed no additional safety concerns or unexpected long-term toxicities. [35],[40] Few patients experienced leukemic transformation, and the incidence was similar in the ruxolitinib and placebo/best available therapy groups.

Management of adverse effects

Many patients with advanced MF also have significant anemia that requires transfusion; [26] at the same time myelosuppression, particularly anemia, is the main adverse effect of ruxolitinib. [32] However, the presence of anemia does not preclude the use of ruxolitinib. An additional agent aimed at improving anemia such as danazol, erythropoietin, or low-dose thalidomide can often be used. [43] The ruxolitinib dose can also be modified; the currently recommended ruxolitinib dose is 15 mg, twice daily (BID) in patients with platelets levels of 100-200 × 10 9 /L. [32] Preliminary results from an ongoing Phase II study of ruxolitinib in patients with mild thrombocytopenia (50-100 × 10 9 /L) show that starting at a dose of 5 mg BID and increasing to 10 mg BID, if the treatment was not overly myelosuppressive, was beneficial. [44] A similar dosing strategy has been reported to be useful in patients with significant anemia. [43] However, it should be noted that long-term dosing at 5 mg BID is generally ineffective [30],[34],[40] and should only be used transiently in cases of significant myelosuppression. The dose should be increased to 10 mg BID (or more) once it is safe to do so. The first 2-3 months of treatment are the most crucial time during which the ruxolitinib dose should be monitored. Dose increases should be made monthly during the first 3 months because dose increases after the initial 3 months have been shown to be less effective. [30] In our experience, nearly all patients can be maintained on an effective and safe dose regimen when these guidelines are followed.

Interruption of ruxolitinib therapy generally leads to the return of all constitutional symptoms within 7-10 days. [32] Spleen regrowth also occurs, but at a slower rate. Therefore, proactive dose adjustments of ruxolitinib in cases of decreased blood counts are preferable to therapy interruptions. The tapering of ruxolitinib or the use of corticosteroids upon discontinuation has been suggested to help patients better tolerate the quick return of symptoms. [26],[45] Withdrawal syndrome was described in five patients from one US academic center; however, these have not been reported in any other study with ruxolitinib, with which thousands of patients have been treated to date. [26],[45]

  Conclusions Top

Before the development of JAK inhibitors, no drug therapy had been shown to consistently improve the symptoms and signs of MF. Ruxolitinib has been shown to significantly reduce the most burdensome symptoms of the disease, including those related to splenomegaly, as well as many of the constitutional symptoms associated with MF, thereby improving QoL and allowing patients to live with fewer and more tolerable adverse effects of the disease. Ruxolitinib is a very good therapeutic choice for patients with symptomatic organomegaly (enlarged spleen and/or liver) or symptomatic disease in general (troublesome constitutional symptoms, weight loss, and poor performance status) and is active in all MF subtypes, including patients without the JAK2V617F mutation. Longer-term follow-up data suggest that ruxolitinib may provide a survival advantage for patients with advanced disease. Finally, ruxolitinib is safe and well-tolerated. Hematologic effects such as anemia and thrombocytopenia can be managed with dose reductions (to avoid therapy interruptions) or transient transfusions (in cases of anemia).

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  [Figure 1], [Figure 2], [Figure 3]


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