Jakafi (ruxolitinib) - 3 indications

Scroll down for information on each indication:

• the treatment of myelofibrosis; approved November 2011
• the treatment of polycythemia vera; approved December 2014
• the treatment of steroid-refractory acute graft-versus-host disease; approved May 2019; expanded in September of 2021 to include chronic GVHD after failure of one or two lines of systemic therapy in patients >12 years of age.

General Information

Jakafi (ruxolitinib) is a kinase inhibitor.

Jakafi is specifically indicated for the following conditions:

• intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults
• polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea
• steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older
• for treatment of chronic GVHD after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older

Jakafi is supplied as a tablet for oral administration. Scroll down for recommended dosing/administration for each condition.

Mechanism of Action

Jakafi (ruxolitinib) inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. 

Side Effects

Adverse effects associated with the use of Jakafi in myelofibrosis and polycythemia vera may include, but are not limited to, the following:

• thrombocytopenia
• anemia
• bruising
• dizziness
• headache
• diarrhea

Adverse effects associated with the use of Jakafi in acute graft-versus-host disease may include, but are not limited to, the following:

• anemia
• thrombocytopenia
• neutropenia
• infections
• edema

Indication 1 - myelofibrosis

approved November 2011

Dosing/Administration

The recommended starting dose of Jakafi is based on platelet count. A complete blood count (CBC) and platelet count must be performed before initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Doses may be titrated based on safety and efficacy.

Platelet Count                                     Starting Dose

Greater than 200 × 109 /L                    20 mg orally twice daily

100 × 109 /L to 200 × 109 /L                15 mg orally twice daily

50 × 109 /L to less than 100 × 109 /L    5 mg orally twice daily

See drug label for specific dose modifications and dose reductions.

Clinical Trial Results

The FDA approval of Jakafi for myelofibrosis was based on two randomized phase III studies (Studies 1 and 2). In both studies, subjects had palpable splenomegaly at least 5 cm below the costal margin and risk category of intermediate 2 or high risk. The starting dose of Jakafi was based on platelet count. Subjects with a platelet count between 100 and 200 X 10(9)/L were started on Jakafi 15 mg twice daily and subjects with a platelet count greater than 200 X 10(9)/L were started on Jakafi 20 mg twice daily. Doses were then individualized based upon tolerability and efficacy.
Study One
This double-blind, randomized, placebo-controlled study enrolled 309 subjects who were refractory to or were not candidates for available therapy. The subjects received Jakafi or matching placebo. The primary efficacy endpoint was the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at Week 24 as measured by MRI or CT.
Study Two
This open-label, randomized study in enrolled 219 subjects who received Jakafi or best available therapy. The primary efficacy endpoint was the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at Week 48 as measured by MRI or CT.
Results
A significantly larger proportion of subjects in the Jakafi group achieved a 35% or greater reduction in spleen volume from baseline in both studies compared to placebo in Study 1 and best available therapy in Study 2. A similar proportion of subjects in the Jakafi group achieved a 50% or greater reduction in palpable spleen length. In Study 1, 65% of subjects in the Jakafi arm reached the primay endpoint versus 1% in the placebo arm. In Study 2, 41% of subjects in the Jakafi arm reached the primary endpoint versus 0% in the placebo arm.

Indication 2 - polycythemia vera

approved December 2014

Dosing/Administration

The recommended starting dose of Jakafi is 10 mg twice daily. Doses may be titrated based on safety and efficacy. See drug label for specific dose modifications and dose reductions.

Clinical Trial Results

FDA approval was based on the RESPONSE trial, 222 patients with polycythemia vera were randomized to Jakafi or best available therapy, which included hydroxyurea, interferon, observation and other treatments. The primary endpoint was the proportion of subjects achieving a response at Week 32, with response defined as having achieved both hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and spleen volume reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32). At week 32, 24 percent of patients treated with Jakafi achieved a complete hematologic remission (CHR) compared with 9 percent for best available therapy. Additionally, 88.5 percent of patients maintained a CHR at week 48. Hematocrit control without phlebotomy was achieved for 60 percent of patients treated with Jakafi compared with 20 percent receiving best available therapy. Overall, 21 percent of patients who received Jakafi met the primary endpoint criteria compared with 1 percent for best available therapy. 

Indication 3 - steroid-refractory acute graft-versus-host disease and chronic GVHD

approved May 2019

Dosing/Administration

The recommended starting dose of Jakafi is 5 mg given orally twice daily. Consider increasing the dose to 10 mg twice daily after at least 3 days of treatment if the ANC and platelet counts are not decreased by 50% or more relative to the first day of dosing with Jakafi. Tapering of Jakafi may be considered after 6 months of treatment in patients with response who have discontinued therapeutic doses of corticosteroids. Taper Jakafi by one dose level approximately every 8 weeks (10 mg twice daily to 5 mg twice daily to 5 mg once daily). If acute GVHD signs or symptoms recur during or after the taper of Jakafi, consider retreatment.

Clinical Trial Results

The FDA approval of Jakafi for acute graft-versus-host disease was based on REACH1, an open-label, single-arm, multicenter study of Jakafi in combination with corticosteroids in patients with steroid-refractory grade II-IV acute GVHD. Of the 71 patients recruited into REACH1, 49 patients were refractory to steroids alone, 12 patients had received two or more prior anti-GVHD therapies and 10 patients did not otherwise meet the FDA definition of steroid-refractory. Jakafi was administered at 5 mg twice daily, and the dose could be increased to 10 mg twice daily after three days in the absence of toxicity. The efficacy of Jakafi was evaluated based upon Day 28 overall response rate (ORR), defined as a complete response (CR), very good partial response or partial response based on the Center for International Blood and Marrow Transplant Research (CIBMTR) criteria. The Day 28 ORR in the 49 patients refractory to steroids alone was 57 percent with a CR rate of 31 percent.

The FDA approval for steroid-refractory chronic GVHD after allogeneic stem cell transplantation was based on the REACH3 study. The randomized, open-label, multicenter study compared Jakafi to best available therapy (BAT). The primary endpoint of overall response rate (ORR) at Week 24 (i.e., Cycle 7 Day 1) was 49.7% for Jakafi compared to 25.6% for BAT. Furthermore, the ORR through Cycle 7 Day 1 was 70% for Jakafi compared to 57% for BAT.