Steroid Failure At Day 28 After Acute Graft-Versus-Host Disease Treatment and Long-Term Outcomes Following Allogeneic Transplantation: Adverse Impact On Survival and Non-Relapse Mortality But No Increasing Risk Of Relapse
Authors: Moon Joon Ho , Sohn Sang Kyun , Alam Naheed , Uhm Jieun , Gupta Vikas , Lipton Jeffrey H. , Messner Hans A. , Kuruvilla John , Hwan Kim Dennis Dong 
Published: October 2019

Abstract

Background
Acute graft-versus-host disease (aGVHD) is one of major complications following allogeneic hematopoietic stem cell transplantation (HSCT), among which severe aGVHD affects transplantation outcomes adversely. Standard treatment option is steroids for last 4 decades. However, long-term outcomes after aGVHD according to the response to steroids therapy have not been described fully.

Methods
Retrospective data of 393 consecutive patients who received allogeneic HSCT at the Princess Margaret Hospital from Mar 2001 to Oct 2007 were analyzed for the response to steroid therapy and for long-terms outcomes including overall survival (OS), non-relapse mortality (NRM), incidence of relapse, development of chronic GVHD and GVHD-specific survival (GSS). Response was defined as complete response (CR; complete resolution of aGVHD signs/symptoms in all organs involved), partial response (PR; any improvement in aGVHD), stable disease (SD; no improvement or no progression of aGVHD) or progressive disease (PD; worsening of aGVHD in at least 1 organ). Steroid failure was defined the case of SD/PD at day 28.

Results
Out of 393 patients, 305 patients (77.6%) were diagnosed of aGVHD with grade I (n=42, 10.7%), II (n=152, 38.7%), III (n=93, 23.7%), and IV (n=18, 4.6%). Among them, 278 patients (91.1%; 70.7% out of overall population) were treated with systemic steroids. Response to steroids therapy at day 28 was as follows: CR in 137 (49.3%), PR in 85 (30.6%) and SD/PD in 49 patients (17.6%), respectively. Thus, steroid failure was noted in 49 patients (17.6%) in the present study. The risk factors of steroid failure at day 28 were aGVHD grade III-IV (OR 4.116, p<0.001) and liver stage 2-4 GVHD (OR 2.480, p=0.015). Out of 305 patients who developed aGVHD of any grade, 204 patients (66.9%) eventually developed subsequent chronic GVHD including classical type of cGVHD in 89 patients (29.2%) and overlap syndrome in 115 patients (37.7%). Among 278 patients who received steroid therapy for aGVHD, the response to steroid therapy did not show significant association with the type or severity of chronic GVHD. As expected, better survival was noted in the responder group compared to those with steroid failure at day 28. The 5-year overall survival (OS) rates were significantly better in CR (69.94.3%) or PR groups (49.46.0%) compared to SD/PD group (i.e. those with steroid failure at day 28; 24.26.5%; p<0.001). The 5-year aGVHD-specific survival (aGSS) were also different in favor of CR (83.93.4%) or PR groups (71.95.7%) compared to SD/PD group (34.88.0%; p<0.001). The non-relapse mortality (NRM) were significantly higher in SD/PD group (65.08.0%) than in PR (28.15.7%) or CR groups (16.13.4%; p<0.001), while no differences of relapse risk were observed among the groups. In multivariate analysis, the steroids failure at D+28 was an independent risk factor for OS (HR 1.916, 95% CI=1.110-3.307, p=0.020), aGSS (HR 2.213, 95% CI=1.115-4.395, p=0.023), and NRM (HR 2.462, 95% CI 1.224-4.951, p=0.011). However, steroid failure at D+28 was not a risk factor for relapse in multivariate analysis (p=0.111).

Conclusion
Steroids response at day 28 for aGVHD significantly affects long-term outcomes after transplant without increasing relapse risk. Early achievement of response to steroids therapy within day 28 is associated with better OS, GSS and lower NRM.

Disclosures:
No relevant conflicts of interest to declare.