The Combination of Cyclosporine and Mycophenolate Mofetil Is Less Effective Than Cyclosporine and Methotrexate in the Prevention of Acute Graft-Versus Host Disease after Allogeneic Stem Cell Transplantation from Unrelated Donors
Authors: Yerushalmi Ronit , Shem-Tov Noga , Danylesko Ivetta , Nagler Arnon , Shimoni Avichai 
Published: October 2019

Abstract
Allogeneic Stem cell transplantation (SCT) from unrelated donors is a potential curative approach for a variety of hematological malignancies. Acute graft-versus-host disease (GVHD) is a major treatment-related complication. Several regimens for GVHD prevention have been explored, but no regimen has shown superiority over the others. We performed this retrospective analysis to compare outcomes following two of the most frequently used regimens, the combination of cyclosporine A and a short course of methotrexate (MTX group) and the combination of cyclosporine A and mycophenolate mofetil (cellcept, CC group). The study included 472 patients (pts) given unrelated donor transplant over an 11 year period in a single institution. The median age was 55 years (range, 18-76). The diagnoses included acute leukemia/MDS (66%), lymphoproliferative diseases (including lymphoma and myeloma, 24%), chronic myeloproliferative disorders (including CML, 7%) and non-malignant disorders (3%). The status at SCT was early (28%), intermediate (24%) and advanced (47%) according to CIBMTR criteria. The conditioning regimen was myeloablative (MAC, 19%), reduced-intensity (RIC, 39%) and reduced-toxicity myeloablative (41%). All pts were given ATG during conditioning. 97% of all pts had PBSC as the stem cell source for SCT. 71% had a 10/10 HLA match and 29% had ≤9/10. 13% had a comorbidity index >2. In all, 314 pts were in the MTX group and 158 in the CC group. The CC group included older pts (median age 57 Vs. 52 years, respectively, P=0.002), a lower percentage had MAC (9% Vs. 24%, P=0.005), more pts had lymphoproliferative disease and less acute leukemia (P=0.02). More pts had advanced disease at SCT (63% Vs. 37%, P=0.001) and more had a high comorbidity score (18% Vs. 11%, P=0.05). Engraftment was faster after CC, day 11 vs 14, respectively (P=0.001). Acute GVHD grade II-IV occurred in 47% (95% CI, 40-56) vs 27% (22-33), P=0.001). Acute GVHD grade III-IV occurred in 28% (95% CI, 21-37) vs 12% (9-17), P=0.001). Multivariate analysis (MVA) identified HLA mismatch (HR, 2.5, P=0.001), RIC (HR 0.6, P=0.03) and the use of CC in GVHD prevention (HR 2.3, P=0.001) as risk factors for acute GVHD. Chronic GVHD was 30% (26-34) and was similar after CC and MTX. With a median follow-up of 52 months (range, 5-151) 175 pts are alive, 145 died of treatment related causes (NRM) and 152 of relapse. 5-year NRM was 44% (37-53) and 24% (20-30) after CC and MTX, respectively (P=0.001). The difference was due to excess death due to GVHD with similar non-GVHD related NRM. MVA identified age>55 years (HR 1.5, P=0.04), less than 10/10 matching (HR 2.3, P=0.001), advanced disease (HR 2.0, P=0.001), high comorbidity score (HR 1.8, P=0.02) and the use of CC (HR 1.6, P=0.02) as independent factors predicting NRM. However, the CC and MTX group were not balanced in terms of risk factors, with the CC group including pts with a higher risk for acute GVHD and NRM. To minimize this potential bias we analyzed these outcomes on the basis of the intention to treat. During the years 2008-2009, the leading GVHD prevention regimen for unrelated donor SCT in our institution included CC, 90 of 101 pts transplanted in this period had CC (90%). During the other years CC was used according to the attending physician discretion in 68 of 371 SCT (18%). The group transplanted in 2008-9 was well matched with the other periods in all pt characteristics. Acute GVHD grade II-IV occurred in 50% (41-61) in the years 2008-9 when CC was used predominantly and 30% (25-35) in the other periods (P=0.006). Acute GVHD grade III-IV occurred in 27% (CI, 19-39) vs 15% (11-19), respectively (P=0.008). NRM was 34% (26-44) vs 30%, respectively (p=0.58). GVHD related death was higher in 2008-9 but non-GVHD death was lower, resulting in similar NRM. Relapse mortality was similar after CC and MTX. Among all pts, CC was associated with a lower 5-year overall survival, 28% (21-35) and 41% (35-46), respectively (P=0.005). However, with the time period intention to treat analysis, OS was identical, 36% (P=0.81). In conclusion, cyclosporine and CC is associated with faster engraftment and possibly with less organ toxicity than cyclosporine and MTX. However, it is associated with inferior prevention of acute GVHD, more GVHD related death and possibly with increased NRM. Cyclosporine and MTX should remain the standard GVHD prevention regimen for unrelated donor SCT.
*AN and AS equally contributed.

Disclosures
Nagler: Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.