Ruxolitinib: Novel Drug for Myelofibrosis

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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.


In November 2011, ruxolitinib (Jakafi) was approved for treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.1,2

Approval was based on two phase III trials in patients with intermediate- or high-risk myelofibrosis: a double-blind trial comparing ruxolitinib (n = 155; 15–20 mg orally twice daily based on baseline platelet counts) vs placebo (n = 154) and an open-label trial comparing ruxolitinib (n = 146; same dosage) vs best available therapy (n = 73). Ruxolitinib treatment was continued as long as patients continued to benefit or until unacceptable toxicity was seen. In the two studies, 50% and 53% of patients had primary myelofibrosis, 31% and 31% had post–polycythemia vera myelofibrosis, and 18% and 16% had post–essential thrombocythemia myelofibrosis.

In the first study, 35% or greater reduction in spleen volume at 24 weeks (the primary endpoint) occurred in 42% of ruxolitinib patients vs 1% of placebo patients (P < .0001). In the second study, 35% or greater reduction in spleen volume at 48 weeks (the primary endpoint) occurred in 29% of ruxolitinib patients vs 0% of patients in the best available care group (P < .0001).

A 50% or greater reduction in symptom score at 24 weeks (key secondary endpoint) occurred in 46% of ruxolitinib patients vs 5% of placebo patients (P < .0001) in the first study. In the second study, a 35% or greater reduction in spleen volume at 24 weeks (key secondary endpoint) occurred in 32% vs 0% (P < .0001).

At the time of approval, 75% of the patients in the first study and 67% of those in the second who had a reduction in spleen volume of at least 35% had maintained this reduction.

How It Works

Ruxolitinib inhibits JAK1 and JAK2 kinases, which mediate signaling of cytokines and growth factors important to hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors and activation and localization of STATs to the nucleus, resulting in modulation of gene expression. Myelofibrosis is associated with dysregulation of JAK signaling.

How It Is Given

The starting dose of ruxolitinib is based on platelet count: 20 mg twice daily for counts greater than 200 × 109/L and 15 mg twice daily for counts of 100 to 200 × 109/L. Treatment should be interrupted for counts less than 50 × 109/L and can be restarted at full or reduced doses depending on the magnitude of recovery of platelet count.

Dose adjustments can also be made based on platelet count (see prescribing information). Complete blood counts and platelet counts must be performed prior to starting treatment, every 2 to 4 weeks until dose is stabilized, and as clinically indicated thereafter.

Safety Profile

In the phase III trials, the most common hematologic adverse events (> 20%) in patients receiving ruxolitinib were thrombocytopenia and anemia. The most common nonhematologic adverse events (> 10%) were bruising, dizziness, and headache. Adverse events of grade 3 or greater that occurred more frequently with ruxolitinib vs placebo in the double-blind trial were thrombocytopenia (13% vs 1%) and anemia (45% vs 19%). Similar results were observed in the second study.

Ruxolitinib carries warnings/precautions for thrombocytopenia, anemia, neutropenia, and infections.

Important Long-term Observations

Tefferi and colleagues3,4 have reported on unfavorable long-term outcomes of ruxolitinib treatment in the 51 patients treated at their institution (Mayo Clinic) from among a total of 153 participating in a phase I/II trial in myelofibrosis.5 The 51 Mayo Clinic patients were enrolled from October 2007 through February 2009 and followed through July 2011 at the most recent reporting. Of these patients, 47 (92%) have discontinued treatment. The median time on treatment was 9.2 months. Discontinuation rates at 1, 2, and 3 years were 51%, 72%, and 89%, respectively. Reasons for discontinuation included loss or lack of response/disease progression (~34%), toxicity with/without lack of response/disease progression (~34%), patient/physician choice, often associated with lack of response (~13%), and death during the study (~4%).

Most patients experienced acute relapse of their symptoms and splenomegaly during treatment discontinuation. In 5 patients (11%), hospitalization following emergency department visits was required for acute relapse, rapid and painful enlargement of the spleen, and acute hemodynamic decompensation, which occasionally led to a septic shock-like syndrome.

At the time of reporting, 18 patients (35%) had died and 5 (10%) had leukemic transformations. There was no significant difference in survival rate between the 51 ruxolitinib-treated patients and a cohort of 410 patients with primary myelofibrosis who were treated with standard therapy at the Mayo Clinic in the most recent 10-year period.

Tefferi and colleagues stated: “Our experience calls for full disclosure of the ruxolitinib withdrawal syndrome to patients with [myelofibrosis] before initiating ruxolitinib therapy, and treatment discontinuation must be done under close physician supervision and preferably in a tapering schedule.”4


1. U.S. Food and Drug Administration: Ruxolitinib. Available at Accessed September 28, 2012.

2. JAKAFITM (ruxolitinib) tablets prescribing information. InCyte Corporation, November 2011. Available at Accessed September 28, 2012.

3. Tefferi A, Litzow MR, Pardanani A: Long-term outcome of treatment with ruxolitinib in myelofibrosis. Correspondence. N Engl J Med 365:1455-1457, 2011.

4. Tefferi A, Pardanani A: Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 86:1188-1191, 2011.

5. Verstovsek S, Kantarjian H, Mesa RA, et al: Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 363:1117-1127, 2010.