Ruxolitinib/Etanercept Combo Resolves Steroid-Refractory Acute GVHD Following Allogeneic SCT

A novel treatment of ruxolitinib (Jakafi) combined with etanercept (Enbrel) led to encouraging response and survival rates in patients who developed grades 3/4 steroid-resistant acute graft-versus-host disease (GVHD) after undergoing allogeneic stem cell transplantation (SCT), according to findings presented at the 2019 European Society for Blood and Marrow Transplantation Annual Meeting.

Following treatment with ruxolitinib plus etanercept, the 1-year overall survival (OS) rate was 76.8%. The 1-year OS rate was higher in patients achieving complete response (CR) by day 30 than patients who did not achieve CR (86.1% vs 48.0%; P = .01). The incidence of relapse was 19.9% and the 1-year non-relapse mortality (NRM) rate was 17.9%.

Few new treatment options for patients with grade 3/4 acute GVHD following allogeneic SCT have been developed, even though the response rates to standard steroid therapy are poor, according to Yanmin Zhao, MD, of the Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China, in a presentation during the meeting.

In the multicenter prospective trial, Zhao et al investigated the safety and efficacy of the combination of ruxolitinib plus etanercept for the treatment of patients with acute GVHD that was unresponsive to steroids.

Forty patients with grades 3/4 steroid-resistant acute GVHD that developed after undergoing allogeneic SCT for malignant hematologic disease were enrolled. The patients were from 3 centers over 18 months beginning in January 2017; the median age of 25 (range, 15-59) years.

All patients received ruxolitinib at 5 to 10 mg daily for 2 months, with the dosage gradually tapered over the next month. Etanercept was administrated at 25 mg bi-weekly for 2 to 8 weeks.

Responses were observed as soon 7 days after treatment initiation and the optimal response was seen at a median 13 days (range, 3-34). At day 7, the overall response rate (ORR) was 72.5%, which comprised 10 CRs (25%) and 19 partial responses (PR; 47.5%). At day 15, the ORR was 82.5% (60% CR; 22.5% PR), with the ORR further increasing to 90% (75% CR; 22.5% PR) by day 30.

Evaluation of response per organ showed CR rates in skin of 95.7%, 80.8% in the liver, and 80% in the gut.

During 2 weeks of ruxolitinib/etanercept treatment, interleukin-6, IFN-γ and TNF-α levels decreased and responding patients showed increased levels of peripheral activated Treg cells and an improved Treg/Th17 ratio.

The relapse rate of acute GVHD was determined in patients achieving CR/PR and surviving beyond 60 days; the relapses rate in these patients was 9.38%, with 3 of the 32 responding patients experiencing a relapse of acute GVHD.

The timing of ruxolitinib administration was shown to be an indicator of CR, with patients receiving treatment within 14 days after the onset of acute GVHD having a significantly higher CR rate of 96.2% compared with 42.9% in patients receiving delayed therapy (P = .001).

The presence of gut infection also affected the response; patients without gut infections achieved a significantly higher CR rate of 92.6% compared with 46.2% CR in patients with gut infections (P = .002).

Univariate analysis established the time from onset of acute GVHD to initiation of treatment (Risk ratio [RR], 4.17; P = .011) and the presence of gut infection (RR, 3.31; P = .031) as independent predictors for incomplete response. No association was found between response and donor type (P = .512), disease status at the time of allogeneic SCT (P = .284), grade of gut or liver infection (P = .455 and P = .142, respectively), or cytomegalovirus (CMV) reactivation (P = .569).

After initiation of the combination treatment, at least one infectious episode occurred in 13 (32.5%) patients; pulmonary infectious disease was reported in 22.5% of patients, grade 3/4 cytopenia in 30%, and CMV-reactivation was reported in 47.5% of patients. The authors also compared these data with a historical cohort of 31 patients treated with basiliximab and etanercept for steroid-resistant acute GVHD at their center. In this comparison, there were no significant differences at baseline between the cohorts regarding age, gender, underlying disease status, conditioning intensity, or GVHD characteristics. The 90% ORR with ruxolitinib was similar to that observed with basiliximab (ORR 90.3%); however, the ruxolitinib group achieved more rapid acute GVHD remissions than the basiliximab cohort in the gut of 11 days versus 17 days (P = .026), and in the liver of 21 days versus 28 days (P = .039). The investigators also found that patients receiving the ruxolitinib combination after acute GVHD onset required significantly shorter hospitalization of a median 18 days compared with the basiliximab cohort of a median 29 days (P = .005).

Combined treatment with ruxolitinib and etanercept resulted in rapid complete response to visceral acute GVHD, and the treatment provides a graft antileukemia effect as the relapse rate of primary disease was relatively lower, the authors concluded, adding that the various infection complications associated with ruxolitinib merit more attention.

Zhao Y, Shi J, Luo Y, et al. Ruxolitinib plus etanercept for patients with steroid-refractory acute graft versus host disease after allogeneic stem cell transplantation. Presented at: 2019 European Society for Blood and Marrow Transplantation Annual Meeting; March 24 to 27, 2019; Frankfurt, Germany. Abstract B079.