Cancer Treatment Today

GVHD is a common and difficult to treat complication of allogeneic transplantation. Chronic GVHD is a major complication of allogeneic stem cell transplantation involving the skin, musculoskeletal system and liver. Chronic GVHD is mediated primarily by T-cells. However, recently there has been emerging evidence that B-cells are also involved.

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 3 or 4) 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 Jakafi as salvage-therapy. The median number of prior GVHD treatments was three for both the SR-aGVHD (range, one to seven) and SR-cGVHD (range, one to 10) patient groups. Median follow-up was 26.5 weeks (range, three to 106) and 22.4 weeks (range, three to 135), respectively.

The overall response rate was 81.5 percent (44 percent) in the SR-aGVHD group and 85.4 percent (35 patients) in patients with SR-cGVHD. The median time to response was 1.5 weeks (range, one to 11) and three weeks (range, one to 25), respectively. Patients with SR-aGVHD had a six-month overall survival (OS) rate of 79 percent and the six-month OS was 97.4 percent in the SR-cGVHD arm.

Among patients who responded to Jakafi, GVHD relapse occurred in three (6.8 percent) patients in the SR-aGVHD group and two (5.7 percent) patients in the SR-cGVHD arm. In the overall population, relapse of the primary malignancy was experienced by five (9.3 percent) and one (2.4 percent) of patients with SR-aGVHD or SR-cGVHD, respectively.

During Jakafi therapy, cytopenia occurred in 55.6 percent (30 patients) of the SR-aGVHD arm and 17.1 percent (seven patients) of the SR-cGVHD arm. Rates of CMV reactivation were 33.3 percent (18 patients) and 14.6 percent (six patients), respectively.

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

Areas affected by the cGVHD included the skin (16 patients), eyes (12 patients), mouth (10 patients), GI tract (eight patients), lungs (four patients), liver (three patients) and musculoskeletal system (three patients). The cGVHD was steroid dependent, with a 24-month (range, six to 53) median duration of continuous exposure to steroids for cGVHD.

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

Patient responses to Jakafi 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 to 120) after starting Jakafi. Two patients reduced prednisone to physiologic doses and the other four patients were tapering prednisone at the time of the data analysis.

In all patients studied, ruxolitinib decreased levels of IL-6 and soluble IL-2 receptor. Treatment-related adverse effects such as thrombocytopenia and anemia were absent.

Te results are impressive as a proof of principle, the data show that therapy directed at the inflammatory milieu of acute GVHD greatly improves the outcome of this disease. Second, ruxolitinib represents a novel therapeutic approach and proved effective in patients who had failed with a number of other agents. Third, hematologic toxicity was not observed, an important consideration in posttransplant patients. Another recent report in Leukemia concluded: “Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.” Zeiser reported a large case series.

In June 2016, Incyte Corporation announced that the FDA has granted Breakthrough Therapy status to Jakafi (outside the U.S.: Jakavi) for the treatment of patients suffering from acute graft-versus-host disease (GVHD). FDA usually grants Breakthrough Therapy status to expedite the development and review of drugs for the treatment of serious or life-threatening conditions, and to help ensure that people have access to them through FDA approval as soon as possible. In order to obtain this status, preliminary clinical evidence is required demonstrating that the drug may have clinically significant improvement over available therapy. Incyte expects to initiate a pivotal development program on Jakafi for GVHD in the second half of 2016. However, the bottom line at this time is that it remains an investigational drug that requires clinical trials to confirm for GVHD and no guidelines currently recommend it. Zeiser in 2015 concluded: “Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.”

Spoerl S et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014 Jun 12; 123:3832. – See more at: http://www.jwatch.org/na34961/2014/06/24/ruxolitinib-graft-vs-host-disease#sthash.xDB6cra5.dpuf

R. Zeiser etal, Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia (2015) 29, 2062–2068;