Ruxolitinib for steroid‐refractory acute graft‐versus‐host disease

Abstract

Dear EditorsCorticosteroids are still the standard initial therapy for acute graft-versus-host-disease (aGVHD), but are effective in only approximately half of cases [1]. Many treatment options have been tested and used as second line, but none have been established yet as the standard of care.Our institution has been using ruxolitinib for steroidrefractory aGVHD (SR-aGVHD), as well as chronic GVHD, for the past several years. We conducted a retrospective review (approved by IRB) of patients who were treated with ruxolitinib for SR-aGVHD over a 2-year period (2015-2016). SR-aGVHD was defined as no response in any stage of GVHD in any organ after 5 days of steroids initiation or worsening GVHD stage in any organ after 3 days of steroids. Primary aGVHD and aGVHD/chronic GVHD (cGVHD) overlap were both included. We defined high-risk acute GVHD by using acute GVHD risk score refined by Minnesota group [2]. Only patients who received> 14 days of ruxolitinib were considered evaluable for response assessment.Thirty-six patients were included in the analysis described in Table 1. Methylprednisolone 2 mg/kg/day was used as initial steroid in most patients; however, different doses were used at the physician discretion. Twenty-four patients (67%) received at least 14 days of treatment and were evaluable for response; the overall response rate (ORR) was 58% (95% CI 38%-78%) with 25% obtaining a complete (CR). Of those who were evaluable for response, the median overall survival (OS) was 7.4 months (95% CI UTQ-15.9) for responders compared with 0.9 months (95% CI 0.7-1.1) for nonresponders (P < 0.001). The relapse rate of primary disease was 8%; one patient relapsed while on ruxolitinib and two within 6 months following discontinuation. Ruxolitinib was well tolerated; hematologic toxicity was generally mild, and there were no cases of treatment-related mortality reported.The data presented herein are similar to what was recently reported from the REACH1 trial [3]. However, in our study, SR-aGVHD was defined as worsening disease after 3 days of steroids or no improvement in 5 days versus 3 days or 7 days, respectively, in REACH1. In addition, we included patients who received numerous prior treatments for SR-aGVHD, while REACH1 only allowed patients to receive calcineurin inhibitors. Thus, our patients were more heavily treated which may account for differences in response rates; in our study, the ORR was 58% with 25% CR compared to 73% with 56% CR in REACH1. Our study did not have explicit eligibility criterion and may reflect more real-world use of ruxolitinib for SR-aGVHD. Several patients were given very short durations of ruxolitinib < 14 days before transitioning to comfort care or expiring, and these patients were excluded as response was difficult to assess and likely does not reflect the efficacy of ruxolitinib.Additionally, in a moderate/severe cGVHD, ruxolitinib induces high response rates, and reduction to physiologic doses/discontinuation of prednisone was possible in 90% of patients at a median of 106 days (range...

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.…”

When is the best time and grade to start ruxolitinib in corticosteroid‐refractory acute graft‐versus‐host‐disease: A multi‐center research

“…Other systematic reviews of ruxolitinib in corticosteroid-resistant acute GvHD are published which also do not address this question. [3][4][5][6][7][8][9][10][11][12] We wondered how starting ruxolitinib when acute GvHD was grade I rather than grades II-IV or starting ruxolitinib in ≤ 7 days after declaring someone corticosteroid resistant versus > 7 days affected outcomes. We found starting ruxolitinib in ≤ 7 days of declaring corticosteroid failure regardless of GvHD grade improves complete response rate but not OR rates.…”

“…2 nd , the interval from declaring a subject corticosteroid refractory to starting ruxolitinib in the RCT was not specified leaving open the question of the best time to start ruxolitinib. Other systematic reviews of ruxolitinib in corticosteroid‐resistant acute GvHD are published which also do not address this question 3–12 …”

The Heterogenous Effect of COVID-19 on Liver Transplantation Activity and Waitlist Mortality in the United States

“…In an attempt to preserve resources for a surge of COVID-19 patients requiring intensive care unit (ICU) care and ventilator support, elective surgical cases were ordered to be stopped by state and local governments. The handling of life-saving urgent surgeries varied depending on the nature of the case and resource availability ( 1 , 2 ).…”

“…Accordingly, 86% of LT centers in Europe reported testing all donors for COVID-19 and 91% of centers did not transplant organs from COVID-positive donors. In the occurrence of a COVID-positive LT candidate, 55% of centers in Europe canceled the transplant and 34% of centers reallocated the donor organ to another recipient ( 1 ).…”