Treatment of steroid-refractory AGVHD (SR-AGVHD): Results in a single center

Introduction Acute graft-versus-host disease (aGvHD) is a signicant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Which despite first line treatment is well stablished (esteroids), second line is not well defined. Objectives Evaluate the results with different second line treatment used and the risk factors associated with of SR-aGVHD. Methods We review the clinical records of 281 consecutive patients undergoing allogenic HSCT from 2005-2015 in our hospital. 53% presented aGVHD. SR-aGVHD was defined as progression after three days, no clinical change in five days or incomplete response after fourteen days of treatment. Results 34 patients (25%) met criteria for SRaGVHD. There were no significant differences between both groups (SR-aGVHD vs No SR-aGVHD) respect to age (recipient/donor), unrelated donor, prophylaxis of GVHD, CD3 lymphocyte and CD34 cell. The median time between transplantation and aGVHD diagnosis was 25 days (7-123). Patients who did no respond on fifth day of steroid treatment have an 80% rate mortality Vs 33% on No SR-aGVHD group (p= 0.03). SRaGVHD: 34 patients presented SR-aGVHD and this was related to: HLA mismatch (35%SR-aGVHD vs 15%No SR-aGVHD, p= 0.008), Male recipient/female donor (38% SR-aGVHD vs 17% No SR-aGVHD, p= 0.02) and advanced underlying disease (56% SR-aGVHD vs 22% No SR-aGVHD, p=0.001). Second line: Basiliximab (82,4%) extracorporeal photopheresis (EP) (2,9%), Timoglobulin (8,8%) and others therapies (5,9%). 2 patients (6%) obtained complete response (CR) and 10 patientes (29%) partial response (PR). Global response (CR, PR) after second line (mainly basiliximab) showed better overall survival (p=0.009). Third line: Basiliximab (8,3%) EP (41,7%), Mesenchymal cells (MSC) (8,3%), Ruxolitinib (16,7%) and Others (24,9%). Ruxolitinib improve GVHD cutaneous and hepatic but not intestinal. The best results were achieved with EP (2CR, 1PR) and Basiliximab/MSC (1PR respectively). Only patients who achieved CR survived. Fourth line: MSC(50%)/Ruxolitinib(50%) does not improve the prognosis. No serious adverse effects were observed with MSC therapy, Basiliximab and EP. 14% of patients showed CMV reactivation with Basiliximab. 27 patients died (80%), 21 patients with early mortality (<6 months) due to refractory aGVHD (40%) or secondary infections (60%). Overall survival at 6 months and 2 year was 28±8% and 0%, respectively. In multivariate analysis the main factor for TRM was the steroid-refractory vs steroid-sensitive (HR 2,00, CI 95% 0.91-4.39 p=0.083) and was unfavorable the association of hepatic and intestinal aGVHD (HR 2.24 CI 95% 0.90-5.57 p=0.082) No SR-aGVHD: 115 patients. TRM-100 was 18% (n=7), mainly due to infection (71%). TRM-1year was 37% (n=15), mainly by GVHD (40%) and infections (40%). Median follow-up of 26 months, OS-6m and 2year were 84 ±3%/75±4%, respectively. TRM was associated with not obtained CR/PR after second line (p=0.001), no CR after third line (p=0.018) and relapse of GVHD despite achieving CR initially (p= 0.004). Conclusions In our series only the patients that obtained CR/PR after second-line or CR after third-line improved OS. The best results in SR-aGVHD were obtained with Basiliximab and extracorporeal photopheresis. TRM was associated with relapse of GVHD and advanced disease to the transplant. Randomized clinical trials are needed to assess different treatment modalities for SR-aGVHD.