Cyclosporine A and Mycophenolate Mofetil Versus Cyclosporine A and Methotrexate for Graft Versus Host Disease Prophylaxis after Stem Cell Transplantation from HLA-Identical Siblings.
Authors: Neumann Frank , Graef Thorsten , Tapprich Christoph , Vaupel Matthias , Steidl Ulrich , Germing Ulrich , Fenk Roland , Haas Rainer , Kobbe Guido 
Published: October 2019

Background: The combination of Cyclosporin A (CSA) and Methotrexate (MTX) is considered to be ‘the standard’ regimen for the prevention of graft versus host disease (GVHD) after stem cell transplantation (SCT) from HLA-identical siblings (HIS). Mycophenolate Mofetil (MMF) is an inhibitor of the Purine nucleotide synthesis and impairs proliferation of activated lymphocytes. MMF has been widely used for GVHD prophylaxis after nonmyeloablative SCT whereas experience following myeloablative therapy is still limited.

Methods: We retrospectively studied 93 patients (median age 35 years, range 17–59 years; male 48, female 45) with acute myeloid leukemia/MDS (n=33/3), acute lymphoblastic leukemia (n=20) or chronic myeloid leukemia (n= 37) who received either CSA/MMF (n=26) or CSA/MTX (n=67) as GVHD prophylaxis following high dose chemotherapy alone (n=31) or in combination with TBI (n=62) and consecutive allogeneic SCT from HIS between 1989 and 2003. At the time of transplant all patients were in complete remission (CR) or chronic phase (CP). Median follow up after transplantation was 17 months (range 2–66) in the CSA/MMF group and 39 months (range 1–175) in the CSA/MTX group.

Results: We found no statistically significant difference in the overall survival of the two treatment groups with 2 year survival rates between 65% (CSA/MTX) and 75% (CSA/MMF), nor did they show significant differences in relapse rate or treatment related mortality using univariate- and multivariate analysis (Fisher’s exact test, logistic regression). Moreover the incidences of acute GVHD and chronic GVHD did not differ significantly during the two regimens (Fisher’s exact test, Cox proportional hazard model). Acute GVHD grade II–IV occurred in 39 of 67 (58%) patients when treated with CSA/MTX and in 10 of 26 (38%) patients during treatment with CSA/MMF. Twenty-five of 52 (45%, CSA/MTX) and 12 of 24 (50%, CSA/MMF) patients at risk developed chronic GVHD, respectively. Interestingly, the time until leukocyte reconstitution differed significantly (p<0,0001; hazard ratio 4.69; Fisher’s exact test, Cox proportional hazard model) even independent of stem cell source or conditioning regimen within the two treatment groups. Patients in the CSA/MMF group recovered a WBC>1000/μl after a median of 12 days (range 4–19 days) in contrast to 18 days (range 12–62 days) in the CSA/MTX group.

Conclusion: In conclusion, the results from our single centre retrospective analysis suggest, that the combination of CSA and MMF is at least equivalent to the standard regimen of CSA and MTX for GVHD prophylaxis following transplantation of allogeneic mobilized peripheral blood stem cells from HLA-identical siblings. The toxicity profile of CSA/MMF is superior as reflected by a significantly shorter time to engraftment. As a consequence we do favour the combination of CSA and MMF for GVHD prophylaxis after transplantation of hematopoietic stem cells from HLA-identical siblings.