Outcomes and Predictors of Response in Steroid-Refractory Acute Graft-versus-Host Disease

Abstract

The prognosis of steroid-refractory acute graft-versus-host disease (aGVHD) is poor, and predictors of response and survival are unclear. In an exploratory analysis of 203 steroid-refractory aGVHD patients with prospectively collected GVHD data who received antithymocyte globulin, etanercept, or mycophenolate mofetil (MMF) as second-line treatment, we determined the predictors of day 28 response, 2-year overall survival, and 2-year nonrelapse mortality (NRM). To minimize the risk of finding false-positive results, we used least absolute shrinkage and selection operator regression, aggressively eliminating variables that are unlikely to be associated with outcome. Day 28 response to second-line therapy was 38% (complete response, 23%), with a 2-year overall survival of 25% and a 2-year NRM of 62%. Factors associated with response were GVHD prophylaxis, organ involvement, and initial aGVHD to steroid-refractory aGVHD interval. Specifically, compared with cyclosporine/MMF as GVHD prophylaxis, the odds ratio (OR) for calcineurin inhibitor/methotrexate was .8 and for cyclosporine/prednisone .6. The OR for aGVHD to steroid-refractory aGVHD interval 14 versus <14 days was 1.3. The ORs for skin only involvement and gut or liver only involvement when compared with multiorgan involvement were 1.4 and 1.2, respectively. The only variable associated with worse survival was age, with a hazard ratio (HR) per decade of 1.04 for overall mortality. Similarly, age was the only variable associated with NRM (HR per decade, 1.02). When compared with complete response, no response at day 28 increased the risk of death (HR, 2.4; 95% confidence interval, 1.5 to 3.7). In conclusion, by means of an underused statistical technique in the field of transplantation, we identified predictors of response and survival in steroid-refractory aGVHD. Our results highlight the importance of developing novel treatment strategies because current treatments yield poor outcomes.

A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease

“…Superior survival with remestemcel-L treatment was sustained through day 180 in patients with a day 28 OR, with 78.9% compared with 43.8% for responders and nonresponders, respectively (P = .001 log rank). Overall survival through day 100 (74.1%) and day 180 (68.5%) with remestemcel-L treatment is a meaningful increment compared with overall 2-year overall survival of 34% with standard of care in aGVHD patients younger than 18 years as reported by Rashidi et al [7]. A trend for greater response was observed in aGVHD grades C and D than in grade B patients-in other words, in patients with more severe disease and higher mortality risk.…”

“…aGVHD is a major cause of morbidity and mortality in adults and children undergoing HSCT [2,4,7,8]. There is a large unmet need for effective treatment.…”

“…Despite overall improvement in transplantation outcomes [6], the cohort of patients who develop aGVHD and subsequently fail to respond to initial steroid therapy continue to have high morbidity and mortality in large part because there are no effective treatment options for these patients. Two recent reports highlight the poor prognosis and consequent therapeutic gap in the management of pediatric aGVHD, particularly among children who fail to respond to initial steroid therapy and have more severe disease based on organ involvement [7,8]. An exploratory analysis of outcomes in 203 patients with steroid-refractory aGVHD, including 61 children up to 18 years of age, reported a 34% day 28 overall response rate (95% confidence interval, 23% to 48%); overall 2-year survival in this cohort was 32% [7].…”

“…Two recent reports highlight the poor prognosis and consequent therapeutic gap in the management of pediatric aGVHD, particularly among children who fail to respond to initial steroid therapy and have more severe disease based on organ involvement [7,8]. An exploratory analysis of outcomes in 203 patients with steroid-refractory aGVHD, including 61 children up to 18 years of age, reported a 34% day 28 overall response rate (95% confidence interval, 23% to 48%); overall 2-year survival in this cohort was 32% [7]. In a cohort of 370 pediatric patients with aGVHD, a high-risk subgroup of 42 patients based on Minnesota risk score who failed to respond to steroid therapy the overall response rate (OR) at day 28 was 48% in the high-risk group (based on Minnesota risk score) who failed to respond to steroid therapy and 2-year survival in these subjects was 35% [8].…”

Extracorporeal Photopheresis (ECP) and the Potential of Novel Biomarkers in Optimizing Management of Acute and Chronic Graft vs. Host Disease (GvHD)

“…There is no standard second line treatment for patients who are either refractory to first line steroids or have steroid dependent aGvHD (63). There is an unmet need for a modality of treatment which offers immunomodulation rather than immune suppression as a way of reducing the effect of GvHD.…”