Since ruxolitinib suppresses the JAK1/2 dependent cytokine response, we hypothesized that ruxolitinib might attenuate the cytokine mediated inflammatory tissue damage in GvHD and thus might favorably affect the severity and course of GvHD after allo-HCT. In vitro, in an allogeneic system (major mismatch mixed-lymphocyte reactions) we demonstrated that co-incubation with ruxolitinib strongly suppressed both the proliferation of allogeneic T cells and the production of inflammatory cytokines [
17]. Using a very aggressive major mismatch mouse model of aGvHD (C57BL/6 on BALBc) ruxolitinib treatment significantly prolonged survival of animals [
17]. In addition, in these animals a reduced weight loss was shown, significantly reduced histopathological GvHD severity, suppression of inflammatory cytokines in the serum and a reduction of donor T cells in GvHD target organs such as the intestines. Moreover, we observed that ruxolitinib led to increased frequencies of FoxP3+ regulatory T cells. This cell type was previously shown to lead to long-lasting tolerance [
18] as compared to the short-term immunosuppression achieved by conventional medication for GvHD.
Because of this strong evidence of activity of ruxolitinib in animal models, we treated six patients with acute and chronic GvHD with ruxolitinib in a pilot trial [
17]. All patients responded with respect to clinical GvHD symptoms and serum levels of pro-inflammatory cytokines. To extend these preliminary findings, we have collected data from a total of 19 stem cell transplant centers in Europe and United States. In this analysis we reported outcome data from 95 patients who received ruxolitinib for corticosteroid-refractory GvHD (skin, mucosa, intestine, liver, lung, musculoskeletal) between 01/2012 and 04/2015 [
19]. Patients were classified as having acute (
n = 54) or chronic (
n = 41) GvHD. The median number of previous GvHD-therapies was 3 for aGvHD (range: 1–7) and 3 for chronic GvHD (range: 1–10). The overall response rate was 81.4% (44/54) in aGvHD comprising 25 CRs (46%). In cGvHD the overall response rate was 85% (35/41). Clinical improvement was at a median time to response of 1.5 (1–10) weeks and 3 (1–25) weeks after initiation of ruxolitinib treatment in acute and chronic GvHD, respectively. GvHD relapsed in 6.8% (3/44) and 5.7% (2/35) of the ruxolitinib-responsive patients with acute or chronic GvHD. In this analysis, the median follow-up was 22 (3–98) and 25 (2–112) weeks for acute or chronic GvHD patients, respectively. Cytopenias (anemia, leukopenia or thrombocytopenia) and Cytomegalovirus (CMV) reactivation were the most frequently observed adverse events during the time of ruxolitinib treatment occurring in both acute (30/54, 55.5% and 18/54, 33.3%) or chronic (7/41, 17% and 6/41, 14.6%) GvHD patients [
19]. Cytopenias had preceded ruxolitinib treatment in 51.8% (28/54) and 14.6% (6/41) of the patients with acute or chronic GvHD. Relapse of the underlying malignancy occurred in 9.2% (5/54) and 2.4% (1/41) of the patients with acute or chronic GvHD, respectively. With a median follow up of 19 months (aGvHD) and 24 months (cGvHD), the 1-year overall survival (OS) was 62.4% for SR-aGvHD (CI: 49.4–75.4%) and 92.7% SR-cGvHD (CI: 84.7–100%) [
20]. The estimated median OS was 18 months for aGvHD and not reached for cGvHD patients. The median duration of ruxolitinib treatment was 5 and 10 months for patients with SR-aGvHD and SR-cGvHD, reflecting the different biology of the diseases. 22/54 (41%) SR-aGvHD patients and 10/41 (24%) SR-cGvHD patients had an ongoing response, were free of any immunosuppression and free of ruxolitinib. In responders, GvHD-relapse or GvHD-progression was observed in 14/45 (31%) and 13/36 (36%) patients with SR-aGvHD and SR-cGvHD. Responses to re-treatment with ruxolitinib or any immunosupressive therapy was seen in 11/14 (78%) and 11/13 (86%) patients with SR-aGvHD and SR-cGvHD, respectively. These findings indicated that patients with SR-aGvHD and SR-cGvHD may benefit long-term from ruxolitinib treatment with an OS that is relatively high for steroid-refractory GvHD.
In addition to these data, a prospective clinical trial testing the effects of the JAK1 specific inhibitor itacitinib (INCB039110) in patients with steroid refractory aGvHD indicated an acceptable safety profile [
21]. This trial tested the effect of 2 different doses (200 mg and 300 mg PO daily). The reported preliminary ORRs were 83% for first-line therapy patients and 64% for steroid refractory patients.