Mycophenolate Mofetil (MMF) with or without Tracolimus (FK506) as a Second Line Treatment for Steroid-Resistant Acute Graft-Versus-Host Disease. The Experience of Saint Louis Hospital.
Authors: Fisher Gustavo , Rocha Vanderson , dos Santos Moema , Devergie Agnes , Robin Marie , de Latour Regis P. , Ribaud Patricia , Ferry Christele , Gluckman Eliane , Socie Gerard 
Published: October 2019

Abstract
Acute GVHD remains a major problem following allogeneic HSCT. Use of steroids is the first line to treat aGVHD, with an overall improvement of 55%, but durable responses of 35%. Recently, results of a randomized trial testing ATG in patients non-responding to steroids have been disappointing. Drugs such as MMF or FK506 have been used as GVHD prophylaxis, but few data is available as a second line treatment of steroid-resistant aGVHD. We conducted a prospective phase II trial in our unit to test the role of MMF associated or not to FK506 in steroid-resistant aGVHD in 53 patients. Four criteria of steroid-resistant aGVHD were defined: A) no improvement of signs of skin GVHD after 1 week of treatment with prednisolone 2mg/kg; B) signs of skin progression or no response of visceral (gut or liver) GVHD 3 days after treatment; C) visceral signs of progression 2 days after treatment; D) progression to organ stage 4 (Gluksberg classification) 1 day after treatment. Response of signs of aGVHD to MMF (30 mg/kg day) or FK506 (0.05mg/kg/day) was defined as complete remission (CR) (all organs); partial remission (PR) or failure (progression even in one organ). HSCT were performed from 1999 to 2004 for patients with hematological malignancies (73%) or aplastic syndromes (27%). The median age was 29 y (5–58) (34% of children) and the median follow-up time was 24 mo (1–54). The donor was HLA identical in 23 (43%) and unrelated in 30 (57%) (including 18 cases of HLA mismatched). Myeloablative conditioning regimen was used in 77%. As GVHD prophylaxis CsA+MTX was used in 26 patients (68%), CsA alone in 14 (26%) and in 3 patients CsA+ steroids. Bone Marrow cells were used in 62% of the cases, PB in 25% and CB in 13%. Treatment of aGVHD consisted in prednisolone 2mg/kg IV in all patients associated to CsA. Once criteria of resistance were established, CsA was stopped and replaced by MMF and/or FK506. FK was not added if renal insufficiency was observed. Criteria of steroid-resistant aGVHD were A in 7 patients; B in 26; C in 19, and D in 1 patient. Steroid resistant acute GVHD grade I was observed in 9 patients (17%); II in 26 (49%); III in 19 (36%) and IV in 3 (6%). MMF was used in 15 patients (28%) and associated to FK506 in 38 (72%). Median time to start second line treatment was 16 days (7 to 100). Complete response in skin was observed in 74% of the patients, 66% in gut and 75% in liver. However, overall CR was observed in 21 patients (40%), partial response in 5 (9%) and failure in 27 (51%). Median time to obtain CR or PR was 8 days (2–20) after starting second line treatment. Cumulative incidence of CR at one year was 39%. Recipient’s age, CMV serology, source of stem cells, conditioning regimen, HLA incompatibility were not associated with CR; there was not statistical difference of CR if MMF was used alone or associated to FK. For those patients with aGVHD in progression, third line treatment consisted most frequently in the use of high dose steroids or ATG/ALG. Overall survival at 1y was 35±7%; it was 74±10% for patients achieving CR (n=21), 5±4% for non-responders (n=27) and 4 out of 5 patients with PR died. Cause of death was commonly associated to infections. In conclusion, in this phase II trial, use of MMF and/or FK506 is an option to treat steroid resistant GVHD but did not result in 1-y survival rate that would justify to set-up a larger randomized study.