Validation of Minnesota Acute GVHD Risk Score and Identification of New Factors Associated with Initial Response to Steroids: Not All GVHD Is Created Equal
Authors: MacMillan Margaret L. , Holtan Shernan G. , Rashidi Armin , DeFor Todd E. , Brunstein Claudio G , Wagner John E. , Blazar Bruce R. , Weisdorf Daniel J. 
Published: October 2019

Abstract
Introduction: We recently reported on the Minnesota acute GVHD Risk Score that is based on the number of involved organs and severity of GVHD at onset. Using clinical grouping, descriptive statistics and recursive partitioning, we identified poorly responsive, high-risk (HR) acute GVHD by the number of involved organs and severity of GVHD at onset. Patients with HR GVHD were 3 times less likely to respond to steroid therapy and had >2 fold increased risk of mortality and transplant-related mortality (TRM) than patients in the standard risk (SR) GVHD group. This GVHD Risk Score more accurately predicts response, survival and TRM than other published GVHD risk scores based upon clinical grading criteria (BBMT.2015,21:761).
Methods: To validate this Risk Score, we examined a new cohort (2008-2016) of 355 patients (median age 49 years, range <1-75) at the University of Minnesota diagnosed with acute GVHD and treated with prednisone 60 mg/m2/d for 14 days, followed by an 8-week taper.
Results: All patients had >6 months follow-up after steroid initiation (median 3.2 years). 79 (22%) patients had HR GVHD and 276 (78%) had SR GVHD. Demographics were similar in the two groups (Table). Overall response [complete response (CR)+partial response (PR)] was significantly higher in the 276 SR vs 79 HR GVHD patients at day 14 (71% vs 56%, p<0.01), day 28 (74% vs 59%, p=0.02) and day 56 (68% vs. 49%, p<0.01) after steroid initiation (Figure A). Day 28 CR/PR did not differ by initial GVHD grade being 64%, 77%, 65% and 50% for grade I, II, III and IV (p=0.07). HR GVHD was observed in 31% single UCBT recipients, 19% double UCBT recipients and 22% BMT/PBSCT recipients. Notably, Day 28 responses were significantly higher in UCB recipients than others (Figure B). In multiple regression analysis, the odds of day 28 CR/PR were lower in HR vs SR GVHD patients (OR 0.5, 95% CI 0.3-0.8) and in HLA matched URD donor vs other recipients (OR 0.5, 95% CI,0.3-1.1, p<0.01). OR of response was 2 fold higher in UCB (OR 2.2, 95% CI,1.3-3.7, p=0.01) vs. BM/PBSC recipients. Factors significantly associated with greater 2 year TRM included HR GVHD (HR 1.4, 95% CI,1.0-1.9, p=0.05), age ≥60 years (HR 1.7, 95% CI,1.1-2.8, p=0.02) and high risk HCT-comorbidity index (HCT-CI; HR 1.6, 95% CI,1.1-2.2, p=0.01). Similarly, mortality at 2 years was higher in HR GVHD (HR 1.7, 95% CI,1.2-2.4, p<0.01), high risk HCT-CI (HR 1.8, 95% CI,1.3-2.5, p<0.01), and recipients of URD grafts HR 1.9, 95% CI,1.1-3.1, p=0.01). Mortality was lower in early onset GVHD (HR 0.95, 95% CI,0.92-0.99, p=0.04). Two years after initiation of steroid therapy, 92 patients developed chronic GVHD for a cumulative incidence of 26% (95% CI 21-31%). No differences in the incidence of chronic GVHD were observed in those with SR and HR acute GVHD (28% vs 20%, p=0.54). Risks of chronic GVHD however were significantly lower in UCB recipients (HR 0.6, 95% CI,0.5-0.9, p=0.01) and in early onset GVHD (HR 0.95, 95% CI,0.92-0.98, p<0.01), but were higher in patients with high risk HCT-CI (HR 1.7, 95% CI,1.2-2.3, p<0.01).
Conclusions: This analysis confirms that the Minnesota GVHD Risk Score is a valuable, immediately available bedside tool to define risk in patients with acute GVHD and predicts outcomes better than GVHD clinical grades. These results also demonstrate the importance of age, HCT-CI, graft source, and time to onset of GVHD on outcomes after GVHD therapy. Notably, UCB recipients have better responses to steroid therapy and lower subsequent risk for chronic GVHD than other donor sources. These data suggest that a tailored approach to upfront GVHD therapy based upon the Minnesota acute GVHD Risk Score and other risk factors should be considered in order to improve outcomes in patients with acute GVHD. Further studies are needed to explore why cord blood recipients with acute GVHD respond better than BM/PBSC recipients with a similar severity of GVHD.

Disclosures
MacMillan: Angiocrine: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Equillium: Consultancy. Holtan:Incyte: Consultancy. Brunstein:Gamidacell: Research Funding. Wagner:Magenta Therapeutics: Consultancy, Research Funding; Novartis: Research Funding. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Weisdorf:SL Behring: Consultancy; Equillium: Consultancy; FATE: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy.