JAK1/2 Inhibition As a Salvage Therapy for Steroid Refractory Acute and Chronic Graft Versus Host Disease in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients
Authors: Khandelwal Pooja , Teusink-Cross Ashley , Nelson Adam S. , Dandoy Christopher E. , El-Bietar Javier A. , Marsh Rebecca A , Kumar Ashish R , Grimley Michael S , Jodele Sonata , Davies Stella M , Myers Kasiani C. 
Published: October 2019

Abstract
Introduction: The Jak1/2 inhibitor, ruxolitinib, is effective as a salvage therapy for steroid refractory (SR) graft versus host disease (GVHD) in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients. The effectiveness of ruxolitinib for the salvage of SR-GVHD in pediatric HSCT patients has not been studied.
Objective: To evaluate ruxolitnib as a salvage therapy for SR- acute GVHD (aGVHD) and chronic GVHD (cGVHD) in pediatric HSCT recipients.
Methods: We conducted a retrospective review of pediatric HSCT recipients who received ruxolitinib for treatment of SR-GVHD at our center. SR aGVHD and cGVHD were defined as lack of response to high dose corticosteroids (1-2 mg/kg/day) for 1 and 3 weeks, respectively. Ruxolitnib was administered orally at 5 mg twice daily for patients weighing ≥ 25 kg or 2.5 mg twice daily if < 25 kg. The dose was halved if azoles were concurrently administered, and increased to a maximum of 10mg twice daily if the initial dose was tolerated. A complete response (CR) was defined as resolution of acute and chronic GVHD symptoms. Partial response (PR) in aGVHD was defined as improvement in at least 1 stage in 1 organ without worsening of other organ stages, and in cGVHD by at least 50% reduction of current immune suppressive doses, lasting for 4 weeks. No response (NR) was defined as worsening of GVHD or need for escalation of immune suppression. Responses were assessed from the initiation of ruxolitinib until either escalation of immune suppression or ruxolitinib discontinuation. The best response in the above specified time was assessed. Durable response was defined as CR or PR lasting for 3 weeks or greater.
Results: Fifteen patients of median age 8.5 years (range 1.6-16.5 years) received ruxolitinib for acute (n=13) and chronic (n=2) GVHD. Transplant characteristics are shown in table 1.
aGVHD patients: Grades of aGVHD at time of ruxolitinib administration were grade II (n=2), III (n=9) and IV (n=2). Forty-seven percent (n=6) of patients had acute gastrointestinal (GI) GVHD, 6% (n=1) had acute skin GVHD and the remaining 47% (n=6) had multiple organ involvement. aGVHD was diagnosed at a median of 41 days (20-169 days) and ruxolitinib was started at a median of 147 days (range 55-538 days) after HSCT. Patients received a median of 4 immune suppressive medications (range 1-6) prior to starting ruxolitinib. The median initial dose of ruxolitinib was 5 mg twice daily (range 2.5 mg daily- 5 mg twice daily). Doses were escalated in 11/15 patients, and 9/15 patients reached a maximum dose of 10 mg twice daily. Ruxolitinib was discontinued in 28% (n=3) of patients after 2-9 days and these patients were excluded from response analysis. Patients who received additional immune suppressive agents either 2 weeks prior to starting ruxolitnib (n=2) or after 2 weeks after initiation of ruxolitinib (n=1) were also excluded. Of the 7 evaluable aGVHD patients, 14% (n=1) had CR and 72% (n=5) had PR at a median of 20.5 days from initiation of ruxolitinib. NR was observed in 14 %( n=1) patients. Overall response rate of ruxolitinib was 86%. Durable responses were observed in 43% (n=3) of patients.
cGVHD patients: Two patients with severe cGVHD involving skin, eye and GI (n=1), and skin, joints and liver (n=1) received ruxolitinib at 1486 and 2177 days after HSCT, respectively, at a maximum dose of 10 mg twice daily. One patient had PR in 2.5 weeks and one had NR.
Adverse effects in all 15 patients included elevated liver enzymes (n=5; 30%), neutropenia (n=8; 53%) and thrombocytopenia (n=4; 26%) leading to discontinuation of ruxolitinib in 10/15 patients. Infectious complications in the 9 patients who were evaluated for responses included EBV viremia (n=2; 22%), adenovirus viremia (n=1; 11%), BK viremia (n=3; 33%), bacterial infections (n=5; 55%) and fungal infections (n=1; 11%). At a median follow up of 341 days (range 260-2331 days) after HSCT 55% (n=5) of patients were alive.
Conclusion: Ruxolitinib may have a limited role in the durable salvage of acute and chronic SR-GVHD in pediatric HSCT patients and should be used cautiously in patients with pre-existing liver dysfunction or cytopenia. Future large scale studies may be needed to assess the effectiveness of ruxolitinib in pediatric HSCT patients with SR-GVHD.

Disclosures
Davies: Novartis: Honoraria.