Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients

Abstract

We describe our retrospective clinical experience with ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if <25 kg. We excluded patients who received new immune suppressive agents within 2 weeks before initiation of ruxolitinib from response analysis. Patients were called a treatment failure if ruxolitinib was stopped before completion of 4 weeks of therapy because of adverse effects and not because of progression of acute GVHD. Thirteen patients received ruxolitinib, and 11 patients were assessable for response. One patient achieved a complete response, 4 had a partial response, and 2 had no response at 4 weeks after the first ruxolitinib dose. Four patients were treatment failures. Overall response rate was 45%. Adverse effects (n = 13) included grades 3 to 4 elevated alanine transaminase (n = 7), grades 3 to 4 neutropenia (n = 5), and grade 4 thrombocytopenia (n = 3). Infectious complications in patients included for response analysis (n = 11) were Epstein-Barr viremia (n = 2), adenovirus (n = 2), BK (n = 3), bacterial infections (n = 6), and fungal infections (n = 1). Seven of 13 patients were alive at a median follow-up of 401 days (range, 219 to 969) after HSCT. We observed a high rate of reversible adverse effects in children with steroid-refractory acute GVHD and a fair overall response of ruxolitinib as a salvage therapeutic agent. Further pharmacokinetic studies are needed to determine the best-tolerated dose of ruxolitinib that will achieve efficacy without significant adverse effects.

Ruxolitinib for the Treatment of Patients with Steroid-Refractory GVHD: An Introduction to the REACH Trials

“…One patient with cGVHD died from a GVHD flare following ruxolitinib discontinuation; the remaining patients were successfully treated with a low maintenance dose of ruxolitinib or slow tapering following response to treatment. Similar findings have been reported in adult patients with aGVHD or cGVHD [35,[42][43][44] and pediatric patients with aGVHD [45]. These data suggest that ruxolitinib provides clinical benefit and durable responses in patients with SR GVHD; however, further data from large prospective clinical trials are required.…”

Ruxolitinib salvage therapy is effective for steroid‐refractory graft‐versus‐host disease in children: A single‐center experience

“…Neutrophils provide cellular communication between the ileum and mesenteric lymph nodes in GVHD, and JAK1/JAK2 inhibition by ruxolitinib reduces neutrophil influx, which may be the main reason for the high response rate of intestinal aGVHD patients in our study. 15 Khandelwal et al 8 reported that, in their study of aGVHD, there was a considerably lower response rate than in the adult reports, probably because of a strict four-week responseassessment time point. However, we and others generally scored the patients for their best response at any time after starting treatment with ruxolitinib.…”

“…Murine models and adult clinical trials have demonstrated its significant benefit in the salvage therapy of steroid‐refractory GVHD . Although publications on the efficacy of ruxolitinib in adult patients with GVHD have been increasing, studies on children are relatively few …”

“…[3][4][5] Although publications on the efficacy of ruxolitinib in adult patients with GVHD have been increasing, studies on children are relatively few. [6][7][8] Therefore, this study aimed to evaluate ruxolitinib efficacy in children with steroid-refractory acute GVHD (aGVHD) or chronic GVHD (cGVHD). To our knowledge, this is the largest series to be conducted among children.…”

FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease

“…In vitro, T cells exposed to ruxolitinib had reduced proliferation and cytokine production in response to alloantigen [8], and in vivo treatment with ruxolitinib reduced GVHD severity in treatment-naive and steroid-refractory major histocompatibility complex-mismatched murine models [9]. In published case series and retrospective reviews, complete response (CR) rates of 8%-46% and overall response rates (ORR) of 38%-82% were reported for adult and pediatric patients with aGVHD refractory to steroids alone or in addition to other immunosuppressive drugs [8,[10][11][12][13][14][15]. Herein we provide a summary of the Food and Drug Administration's (FDA's) review of ruxolitinib for treatment of SR-aGVHD based on the first prospective trial, the REACH-1 Study.…”