FDA Grants Ruxolitinib Breakthrough Designation for Acute GVHD


The FDA has granted a breakthrough therapy designation to ruxolitinib for the treatment of patients with acute graft-versus-host disease.

Steven Stein, MD

The FDA has granted a breakthrough therapy designation to ruxolitinib (Jakafi) for the treatment of patients with acute graft-versus-host disease (GVHD), according to Incyte, one of the developers of the JAK1/JAK2 inhibitor.

The designation was based on 2 small studies demonstrating high response rates with ruxolitinib in patients with GVHD. Both studies were presented at the 2015 ASH Annual Meeting.

“Receiving breakthrough therapy designation from the FDA recognizes the severe nature of acute GVHD, the clear unmet medical need of these patients, and the potential, based on clinical evidence to-date, for ruxolitinib to address the urgent needs of patients with this life-threatening disease,” Steven Stein, MD, chief medical officer at Incyte, said in a statement. “We are committed to working closely with the FDA in an effort to bring ruxolitinib to patients with GVHD as soon as possible.”

One of the studies the FDA reviewed was a retrospective analysis of 95 patients who developed corticosteroid-refractory (SR) acute (a) or chronic (c) GVHD following allogeneic hematopoietic cell transplantation for a hematologic malignancy. Fifty-four patients had SR-aGVHD (grade III or IV) and 41 patients had SR-cGVHD (moderate or severe).

The patients, who were from 19 stem cell transplant centers in the United States and Europe, all received ruxolitinib as salvage-therapy. The median number of prior GVHD treatments was 3 for both the SR-aGVHD (range, 1-7) and SR-cGVHD (range, 1-10) patient groups. Median follow-up was 26.5 weeks (range, 3-106) and 22.4 weeks (range, 3-135), respectively.

The overall response rate was 81.5% (n = 44) in the SR-aGVHD group and 85.4% (n = 35) in patients with SR-cGVHD. The median time to response was 1.5 weeks (range, 1-11) and 3 weeks (range, 1-25), respectively. Patients with SR-aGVHD had a 6-month overall survival (OS) rate of 79% (95% CI, 67.3-90.7) and the 6-month OS was 97.4% (95% CI, 92.3-100) in the SR-cGVHD arm.

During ruxolitinib therapy, cytopenia occurred in 55.6% (n = 30) of the SR-aGVHD arm and 17.1% (n = 7) of the SR-cGVHD arm. Rates of CMV reactivation were 33.3% (n = 18) and 14.6% (n = 6), respectively.

The second study the FDA considered for the breakthrough designation involved 16 patients with hematologic malignancies who received transplants and developed quiescent (n = 12) or de novo (n = 4) severe (NIH criteria) steroid-dependent cGVHD. The transplants included unrelated donor (n =14), matched sibling (n = 2), blood (n = 15), and marrow (n = 1).

Areas affected by the cGVHD included the skin (n = 16), eyes (n = 12), mouth (n = 10), GI tract (n = 8), lungs (n = 4), liver (n = 3), and musculoskeletal system (n = 3). The cGVHD was steroid dependent, with a 24-month (range, 6-53) median duration of continuous exposure to steroids for cGVHD.

Patients received ruxolitinib at 5 mg twice daily as second- (n = 4), third- (n = 7), fourth- (n = 4), or fifth-line (n = 1) salvage therapy. The ruxolitinib dose was raised to 15 mg/daily for 4 patients and 20 mg/daily for 3 patients due to patient weight, physician preference, flare of cGVHD following initial response related to halting immunosuppression, or temporary perioperative hold of ruxolitinib. Patients had a 6-month (range, 1-14) median duration of ruxolitinib treatment.

Patient responses to ruxolitinib were observed at median of 14 days following the start of treatment. The researchers observed complete resolution of clinical manifestations of cGVHD in patients’ lungs, mouth, skin, liver, musculoskeletal system, and GI tract.

Ten patients were able to discontinue prednisone at a median of 72 days (range, 31-120) after starting ruxolitinib. Two patients reduced prednisone to physiologic doses and the other 4 patients were tapering prednisone at the time of the data analysis.

The FDA’s breakthrough designation is meant to expedite the development of therapies that offer substantial benefits over existing options. Under the program, a rolling submission of data is allowed along with more communication with the FDA.

Ruxolitinib is currently approved by the FDA as a treatment for patients with polycythemia vera who are intolerant of or have an inadequate response to hydroxyurea. The JAK1/JAK2 inhibitor also has an FDA-approved indication for the treatment of patients with intermediate or high-risk myelofibrosis.

Incyte reached an agreement with Lilly in March 2016 giving Incyte exclusive rights to develop and market ruxolitinib for GVHD in the United States. In April 2016, Incyte and Novartis reached an agreement allowing Novartis to develop and commercialize ruxolitinib for GVHD in countries outside of the United States.


  1. Zeiser R, Burchert A, Lengerke C, et al. Treatment of corticosteroid-refractory graft-versus-host disease with ruxolitinib in 95 patients. Presented at: 2016 ASH Annual Meeting; December 5-8, 2015. Orlando, Florida; Abstract 858.
  2. Khoury HJ, Kota V, Arellano M et al. Ruxolitinib as sparing agent for steroid-dependent chronic graft-versus-host disease (cGVHD). Presented at: 2016 ASH Annual Meeting; December 5-8, 2015. Orlando, Florida; Abstract 1938.

Among patients who responded to ruxolitinib, GVHD relapse occurred in 3 (6.8%) patients in the SR-aGVHD group and 2 (5.7%) patients in the SR-cGVHD arm. In the overall population, relapse of the primary malignancy was experienced by 5 (9.3%) and 1 (2.4%) of patients with SR-aGVHD or SR-cGVHD, respectively.

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