Oral Medication to Treat Myelofibrosis

Jakafi^® (ruxolitinib)

The FDA approved Jakafi^® (ruxolitinib) in November 2011 to treat patients with myelofibrosis, a bone marrow disease. The oral drug, marketed by Incyte Corp, is a janus kinase inhibitor intended for intermediate or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis.

Patients are advised to take 20 mg of ruxolitinib twice daily if they have a platelet count >200 × 10⁹ per liter. If their platelet count is between 100 × 10⁹ per liter, they should take 15 mg twice daily, while they should take 5 mg twice daily if they have a platelet count between 50 × 10⁹ per liter and <100 × 10⁹ per liter. The drug can be taken with or without food.

In June 2013, the product’s prescribing information was updated to indicate patients should have their blood counts monitored every 2 to 4 weeks until the doses of ruxolitinib are stabilized and then as clinically indicated. If patients have thrombocytopenia while taking ruxolitinib, they should have their dosage modified or interrupted.

Ruxolitinib was approved under the FDA’s priority review program, in which the agency reviews drugs within 6 months if they may offer significant improvements compared with available therapies or if they provide treatment for diseases that do not have any currently FDA-approved drugs. It was also granted orphan drug status because myelofibrosis affects <200,000 people in the United States.

Patients with myelofibrosis typically have an enlarged spleen, anemia, and decreased white blood cells and platelets. They usually survive with the disease for 2 to 11 years. Symptoms related to the disease include fatigue, abdominal discomfort, pain under the ribs, satiety, muscle and bone pain, itching, and night sweats. During the trials that tested ruxolitinib, the most common serious side effects associated with the drug included thrombocytopenia, anemia, fatigue, diarrhea, dyspnea, headache, dizziness, and nausea.

The FDA approved ruxolitinib based on the results of 2 randomized phase 3 trials: COMFORT-I and COMFORT-II (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment). The studies included patients with myelofibrosis who took ruxolitinib and compared them with groups receiving placebo or best available therapy.

This First Report Managed Care Product Spotlight provides a summary of the pivotal trials that evaluated the safety and efficacy of ruxolitinib.

COMFORT-I TRIAL

Below is a summary of a randomized, double-blind, placebo-controlled phase 3 trial that evaluated the efficacy of ruxolitinib compared with placebo in patients with intermediate-2 or high-risk myelofibrosis.

Reference

Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.

Study Objective

The trial was designed to assess the efficacy and safety of ruxolitinib for patients with intermediate-2 or high-risk myelofibrosis.

Method

The authors randomly assigned patients at 89 sites in the United States, Australia, and Canada in a 1:1 ratio to receive oral ruxolitinib or placebo. Patients in the ruxolitinib group received 15 mg tablets twice daily if they had a platelet count of 100 × 10⁹ per liter to 200 × 10⁹ per liter and 20 mg twice daily if they had a platelet count >200 × 10⁹ per liter. If patients experienced toxicity or had a lack of efficacy when taking ruxolitinib, they had their dosage adjusted.

Each night, patients completed the modified Myelofibrosis Symptom Assessment Form, an electronic diary that the authors used to evaluate symptoms such as night sweats, itching, abdominal discomfort, pain under the ribs on the left side, early satiety, muscle or bone pain, and inactivity. Scores ranged from 0 (absent symptoms) to 10 (worst imaginable symptoms).

Data analysis occurred when half of the patients remaining in the study completed the week 36 visit and when all of the patients finished an evaluation at week 24 or discontinued treatment.

Population

From September 2009 through April 2010, the authors enrolled 309 patients: 155 in the ruxolitinib group and 154 in the placebo group. At baseline, there were no significant differences between the groups with the exception of age (66 years for the ruxolitinib group and 70 years in the placebo group; P<.05). Approximately 55% of patients were male, 38.2% had intermediate-risk disease, and 61.2% had high-risk disease. The median spleen volume was >2500 cm³, which the authors noted was >10 times greater than the normal spleen volume.

Inclusion criteria for the study included patients who were ≥18 years of age, had primary myelofibrosis, postpolycythemia vera myelofibrosis, or postessential thrombocythemia myelofibrosis, had a life expectancy of at least 6 months or longer, had an International Prognostic Scoring System score of 2 (intermediate-risk) or ≥3 (high-risk), and an Eastern Cooperative Oncology Group performance status score of 3 or less.

Primary end point

• Proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks

Secondary end points

·      Duration of the reduction in spleen volume

·      Proportion of patients with a reduction in the total symptom score of ≥50% or more from baseline to week 24

·      Change in total symptom score from baseline to week 24

·      Overall survival

Results

The authors concluded that patients taking ruxolitinib had significant clinical benefits compared with those receiving placebo, including a reduction in spleen size, a lessening of debilitating myelofibrosis-related symptoms, and an improvement in overall survival.

After 24 weeks of treatment, 41.9% of patients in the ruxolitinib group had a reduction of ≥35% in spleen volume compared with 0.7% of patients in the placebo group (odds ratio [OR], 134.4; 95% confidence interval [CI], 18.0 to 1004.9; P<.001). In addition, among the patients who had data available at baseline and week 24, the 139 patients receiving ruxolitinib had a mean reduction in spleen volume of 31.6%, while the 106 patients receiving placebo had a mean increase of 8.1%.

There was a durable reduction in spleen volume for most patients, according to the authors. Of the patients with a spleen volume reduction of ≥35%, 67.0% had a reduction in spleen volume that was maintained for at least 48 weeks.

From baseline to week 24, 45.9% of patients in the ruxolitinib group had a ≥50% reduction in the total symptom score compared with 5.3% of patients in the placebo group (OR, 15.3; 95% confidence interval [CI], 18.0 to 1004.9; P<.001). Of the patients who had data available at baseline and week 24, the 129 patients receiving ruxolitinib had a mean reduction improvement in the total symptom score of 46.1%, while the 103 patients receiving placebo had a mean worsening of 41.8% (P<.001).

In addition, 11.0% of patients in the ruxolitinib group and 10.6% of patients in the placebo group discontinued the drug due to adverse events. There were 10 deaths in the ruxolitinib group compared with 14 deaths in the placebo group (hazard ratio [HR], 0.67; 95% CI, 0.30-1.50; P=.33).

The groups had a similar rate of nonhematologic adverse events. The following events occurred more frequently in the ruxolitinib group: ecchymosis, dizziness, and grade 1 or 2 headache. Grade 3 or 4 adverse events occurred more frequently in the placebo group, including abdominal pain, fatigue, and dyspnea. The most frequent hematologic adverse events were thrombocytopenia and anemia.

COMFORT-II TRIAL

Below is a summary of a randomized, phase 3 study that evaluated the efficacy of ruxolitinib compared with best available therapy in patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis.

Reference

Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.

Study Objective

The trial was designed to assess the efficacy and safety of ruxolitinib for patients with primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis.

Method

The authors randomly assigned patients in a 2:1 ratio to receive ruxolitinib or the best available therapy, including available treatments or no therapy. Patients in the ruxolitinib group received 15-mg tablets twice daily if they had a platelet count ≤200 × 10⁹ per liter and 20 mg twice daily if they had a platelet count >200 × 10⁹ per liter. If patients developed neutropenia or thrombocytopenia, they could decrease their dosage. They were also allowed to increase the dosage to 25 mg twice daily to increase the drug’s efficacy. Patients continued on therapy until meeting the criteria for disease progression.

The patients had their spleen volume assessed by magnetic resonance imaging or computed tomography every 12 weeks. They had their spleen and liver volumes assessed by outlining the circumference of the organ and determining the volume using a least-squares analysis. At each visit, they had their spleen length assessed by manual palpation.

Population

From July 1, 2009, through January 22, 2010, the authors enrolled 219 patients: 146 in the ruxolitinib group and 73 in the best available therapy group. At baseline, there were no significant differences between the groups. Median age was approximately 67 years, 40% had intermediate-risk disease, and 60% had high-risk disease. Approximately half the patients had primary myelofibrosis, approximately one third had postpolycythemia vera myelofibrosis, and the remainder had postessential thrombocythemia myelofibrosis.

Inclusion criteria for the study included patients who were ≥18 years of age, had primary myelofibrosis, postpolycythemia vera myelofibrosis, or postessential thrombocythemia myelofibrosis, had a palpable spleen 5 cm or more below the coastal margin, had not received a janus kinase inhibitor, had an International Prognostic Scoring System score of 2 (intermediate-risk) or ≥3 (high-risk), and an Eastern Cooperative Oncology Group performance status score of ≤3.

Primary end point

• Reduction of ≥35% in spleen volume from baseline at week 48

Secondary end points

• Reduction of ≥35% in spleen volume from baseline at week 24
• Length of time that a reduction on spleen volume of at least 35% was maintained
• Time to a reduction in spleen volume of ≥35% from baseline
• Progression-free survival
• Overall survival

Results

The authors concluded that patients receiving ruxolitinib had more durable reductions in splenomegaly and disease-related symptoms and improvements in role functioning and quality of life compared with those receiving best available therapy.

After 48 weeks of treatment, 28% of patients in the ruxolitinib group had at least a 35% reduction in spleen volume compared with no patients in the best available therapy group (P<.001). At week 24, 32% of patients in the ruxolitinib group had at least a 35% reduction in spleen volume compared with no patients in the best available therapy group (P<.001).

In addition, after 48 weeks, patients in the ruxolitinib group had a mean reduction in spleen length of 30.1% compared with a mean increase of 7.3% in the best available therapy group (P<.001). At week 24, patients in the ruxolitinib group had a mean reduction in spleen length of 29.2% compared with a mean increase of 2.7% in the best available therapy group (P<.001).

Further, 8% of patients in the ruxolitinib group and 5% of patients in the best available therapy group discontinued treatment because of adverse events. The most common adverse event was diarrhea, found in 23% of patients. However, grade 3 or 4 diarrhea occurred in only 1% of patients. The most common grade 3 or 4 nonhematologic adverse events were abdominal pain in the ruxolitinib group (occurring in 3% of the patients) and dyspnea and pneumonia in the best available therapy group (each occurring in 4% of the patients). The authors noted that thrombocytopenia and anemia occurred more frequently in patients receiving ruxolitinib, although only 1 person in each group discontinued the study due to thrombocytopenia.

SAFETY NOTES

The product’s Prescribing Information notes that ruxolitinib can cause thrombocytopenia, although the condition can be reversed and managed by reducing the dosage or temporarily stopping treatment. The drug can also cause anemia and neutropenia as well as serious bacterial, mycobacterial, fungal, and viral infections.

Before taking ruxolitinib, patients are advised to alert their healthcare professionals if they have an infection, liver or kidney problems or are on dialysis. They should also tell them if they are pregnant or plan to become pregnant or are breast feeding or plan to breast feed. It is unknown if ruxolitinib will harm unborn babies or passes into breast milk.

Jakafi Facts

•    Jakafi was approved by the FDA on November, 16, 2011, to treat patients with myelofibrosis

•    Jakafi is marketed by Incyte Corp