FDA Extends Review Period for Ruxolitinib in Chronic GVHD

The FDA has extended the review period for the supplemental new drug application for ruxolitinib as a therapeutic option for adult and pediatric patients aged 12 years and older with steroid-refractory chronic graft-versus-host disease.

The FDA has extended the review period for the supplemental new drug application (sNDA) for ruxolitinib (Jakafi) as a therapeutic option for adult and pediatric patients aged 12 years and older with steroid-refractory chronic graft-versus-host disease (GVHD).1

The sNDA was supported by data from the phase 3 REACH3 trial (NCT033112603), where the JAK inhibitor was found to induce a significantly higher overall response rate (ORR) than what had been seen with best available therapy (BAT) in patients with steroid-refractory chronic GVHD; these rates were 49.7% and 25.6%, respectively (odds ratio [OR], 2.99; 95% CI, 0.86-4.80; P <.0001).2

Additionally, the agent improved median failure-free survival (FFS) at week 24 compared with BAT. In the investigative arm, the FFS had not yet been reached vs 5.7 months in the control arm (HR, 0.370; 95% CI, 0.268-0.510; P <.0001). Ruxolitinib also improved symptom burden, defined by the modified Lee Symptom Scale (mLSS), vs BAT, with 24.4% experiencing a clinically meaningful reduction in symptoms vs 11%, respectively (OR, 2.62; 95% CI, 1.42-4.82; P = .0011).

The decision to extend the action date for the application is to allow for more time to review additional data submitted by Inctye, the drug developer, in response to the agency’s information request. The submission has been determined by the FDA to represent a Major Amendment to the sNDA, resulting in a 3-month extension.

The new Prescription Drug User Fee Act target action date is September 22, 2021.

“We remain confident in the data from the REACH3 trial supporting our sNDA submission for ruxolitinib and look forward to continued dialogue with the FDA throughout the remainder of the review process,” Steven Stein, MD, chief medical officer of Incyte, stated in a press release. “We will work closely with the agency and are dedicated to bringing this innovative treatment to patients with steroid-refractory chronic GVHD who urgently need new treatment options.”

A total of 329 patients with chronic GVHD were randomized 1:1 to receive either the JAK inhibitor at a twice-daily dose of 10 mg (n = 165) or investigator-selected BAT (n = 164). Patients continued to receive their regimen of corticosteroids with or without calcineurin inhibitors. BAT was determined prior to randomization and investigators selected from a list of 10 options, which included extracorporeal photopheresis, ibrutinib (Imbruvica), methotrexate, and others.

Notably, crossover from the control arm to the investigative arm was permitted on, or after, day 1 of cycle 7 in patients who did not experience or maintain a complete response (CR)/partial response (PR), developed an adverse effect to BAT, or experienced a chronic GVHD flare.

The primary end point of the trial was ORR, which was defined as the proportion of participants who achieved a CR or PR per National Institute of Health consensus criteria. Important secondary end points comprised FFS and improvement in symptoms based on change in the mLSS at day 1 of cycle 7.

The baseline characteristics were well balanced between the treatment arms. The median age of participants was 49 years (range, 12-76) and the majority were male (61%). Twelve patients were younger than 12 years of age. Moreover, 48% of patients had moderate chronic GVHD, while 52% had severe disease.

At a data cutoff of May 8, 2020, 50% (n = 82) of patients on the investigative arm discontinued treatment vs 74% (n = 122) of those on the control arm. Thirty-seven percent of patients (n = 61) crossed over to the ruxolitinib arm. Patients in the investigative and control arms, respectively, discontinued treatment due to lack of efficacy (15% vs 43%), toxicities (17% vs 5%), and relapse (5% vs 4%).

Of the patients who responded to the JAK inhibitor, 43% experienced a PR and 6.7% had a CR. Of the BAT responders, 22.6% achieved a PR, while 3% had a CR. The best overall response was higher in the investigative arm than in the control arm, at 76.4% vs 60.4%, respectively (OR, 2.17; 95% CI, 1.34-3.52). The median duration of best overall response had not yet been reached with ruxolitinib vs 6.24 months with BAT.

Participants who were administered the JAK inhibitor had a slightly higher rate of all-grade toxicities than those who were given BAT, at 97.6% vs 91.8%, respectively. However, the rates of grade 3 or higher adverse effects (AEs) in the investigative and control arms were 57.0% and 57.6%, respectively.

Moreover, 36.7% and 33.3% of those on the ruxolitinib and BAT arms, respectively, experienced serious AEs. Death rates were comparable between the arms. The risk of death in the ruxolitinib arm was 18.8%, while it was 16.5% in the BAT arm.

Notably, cytopenias were the most common AE experienced with ruxolitinib. Approximately 29% of patients in the ruxolitinib arm reported any-grade anemia and 12.7% had anemia that was grade 3 or higher in severity; in the BAT arm, these rates were 12.7% and 7.6%, respectively. Any-grade thrombocytopenia was reported in 21.2% and 14.6%, respectively, of those in the investigative and control arms; this effect was grade 3 or higher in 15.2% and 10.1% of patients, respectively.

Previously, in May 2019, the FDA approved ruxolitinib for use in adult and pediatric patients aged 12 years and older who had steroid-refractory acute GVHD based on data from the phase 2 REACH1 trial (NCT02953678), which had shown that ruxolitinib plus corticosteroids resulted in an ORR of 57% at day 28 in this patient population, with a CR rate of 31%.3

Moreover, 6-month follow-up data from the phase 3 REACH2 study (NCT02913261) showed that the JAK inhibitor had sustained efficacy with a lower probability of progression or additional systemic therapies in patients with steroid-refractory acute GVHD.4

Ruxolitinib resulted in a longer median duration of response vs BAT, at 163 days vs 101 days, respectively, with a lower probability of loss of response at 6 months (8.73% vs 37.34%) and 12 months (10.16% vs 37.34%). The median FFS was 4.86 months with ruxolitinib vs 1.02 months with BAT (HR, 0.49; 95% CI, 0.37-0.63).


  1. Incyte announces US FDA has extended the sNDA review period for ruxolitinib (Jakafi) in chronic graft-versus-host disease (GVHD). News release. Incyte. June 8, 2021. Accessed June 9, 2021. https://bit.ly/3pC0NZj
  2. Zelser R, Polverelli N, Ram R, et al. Ruxolitinib (RUX) vs best available therapy (BAT) in patients with steroid-refractory/steroid-dependent chronic graft-vs-host-disease (cGVHD): primary findings from the phase 3, randomized REACH3 study. Blood. 2020;136(suppl 1):22-24. doi:10.1182/blood-2020-137694
  3. FDA approves Jakafi (ruxolitinib) for the treatment of patients with acute graft-versus-host disease. News release. Incyte Corporation. May 24, 2019. Accessed June 9, 2021. https://bwnews.pr/3v1NQcw
  4. Mohty M. Ruxolitinib vs best available therapy in patients with steroid-refractory acute graft-vs-host-disease: 6-month follow-up from the randomized, phase 3 REACH2 study. Presented at: Virtual 47th Annual Meeting of the EBMT; March 14-17, 2021; Virtual. Abstract OS8-4. http://bit.ly/3cExjUv.