Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey

Abstract

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Figure 1. Representative responses in patients with acute GVHD of the liver and intestines

A: One patient with histologically proven intestinal GVHD grade IV was treated with ruxolitinib as described in the Methods. No other immunosuppressive therapy was started at the same time-point. The patient also had corticosteroids (blue area) and cyclosporine A (green area) when ruxolitinib was started. The frequency of diarrhea decreased upon treatment with ruxolitinib and corticosteroids could be tapered. B: One patient with clinically diagnosed liver GVHD grade IV was treated with ruxolitinib as described in the Methods. The bilirubin level decreased following ruxolitinib treatment. No other immunosuppressive therapy was started at the same time-point although corticosteroid treatment (blue area) was continued and reduced by 50% in the observation period. There was no change in treatment with regard to potential liver toxic agents throughout the entire time period displayed.

Figure 2. Skin and intestinal GvHD responds to ruxolitinib

A: A representative patient with cutaneous acute GVHD is shown prior and 1 week after ruxolitinib. B: A representative patient with cutaneous chronic GVHD is shown prior and 3 weeks after ruxolitinib. C: Serial biopsies of the intestinal tract of a patient with GVHD is displayed. Biopsies were taken 1 day prior to start of ruxolitinib and 4 weeks after ruxolitinib had been started.

Figure 3. Inflammation related markers in the blood decrease upon ruxolitinib treatment

A–C: CD3⁺HLA-DR⁺ cells, IL-6 and soluble IL-2R were measured one day prior and 5 to 7 days after the start of ruxolitinib in the peripheral blood. The levels of these 3 parameters declined significantly after ruxolitinib treatment when analysed by the Wilcoxon matched-pairs signed rank test. The number of patients are indicated in each graph.

Figure 4. Acute GVHD-relapse free and overall survival

A: The overall survival of all patients treated with ruxolitinib for acute GVHD is displayed. B: The cumulative incidence of acute GVHD relapse is displayed.

Figure 5. Chronic GVHD-relapse free and overall survival

A: The overall survival of all patients treated with ruxolitinib for chronic GVHD is displayed. B: The cumulative incidence of chronic GVHD relapse is displayed.