Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

Abstract

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced-intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA-identical sibling donor; 174 patients received cyclosporine (CSA) 1 MMF and 67 received CSA1MTX. Patients receiving MMF 1 CSA had rapid neutrophil (median 11 vs. 19 days with MTX1CSA), and platelet recovery (median 19 vs. 25 days), lower incidence of severe mucositis by OMAS (19% vs. 53%), and shorter length of hospital stay (median 25 vs. 36 days) (P < 0.001 for all comparisons). There were no significant differences in incidence of grade 2-4 (MMF1CSA 37% vs. MTX1CSA 39%) or 3-4 acute GVHD (17% vs. 12%), chronic GVHD (46% vs. 56%), relapse (28% vs. 27%), non-relapse mortality (20% vs. 27%), or overall survival (47% vs. 44%) (P 5 NS for all). However, in multivariable analysis, the use of MMF1CSA was associated with an increased risk of severe grade 3-4 acute GVHD (HR 2.92, 95% CI 1.2-7.15, P 5 0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF1CSA compared to MTX1CSA. Further studies evaluating optimal dosing strategies are needed.

Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: A retrospective (development) and a prospective (validation) study

“…The use of ATG could impair the early development of donor‐derived T cells due to the persistence of these antibodies in the patient for several weeks after administration especially if given too close to graft infusion 11. Similarly, use of MTX is also associated with delayed engraftment and increased risk of graft failure 14, 15. Reducing the intensity of the GVHD prophylaxis regimen by avoiding the use of ATG and MTX will relatively “protect” the naïve T cells from the toxicity of these two drugs and achieved a higher rate of engraftment 29.…”

“…Several studies have compared the outcomes between CBT with or without ATG, and the use of ATG was associated with lower OS and higher NRM, regardless of the lower incidence of GVHD 12, 13. Similarly, use of MTX‐containing regimen for GVHD prophylaxis has been associated with delayed engraftment and increased risk of graft failure in patients with hemoglobinopathies and malignant diseases transplanted with an HLA‐identical sibling CB unit 14, 15…”

“…12,13 Similarly, use of MTXcontaining regimen for GVHD prophylaxis has been associated with delayed engraftment and increased risk of graft failure in patients with hemoglobinopathies and malignant diseases transplanted with an HLA-identical sibling CB unit. 14,15 Thus, we conducted a retrospective study to compare the outcomes of MMAC (Flu/Bu/Cy and CA/TBI/Cy) with MAC (Bu/Cy and TBI/Cy). The GVHD prophylaxis of MMAC included cyclosporine (CSA) and mycophenolate mofetil (MMF) while the GVHD prophylaxis of MAC also included ATG or MTX.…”

Acute Graft Versus Host Disease: A Comprehensive Review

“…A cochrane database systemic review in 2014 showed that a combination of MMF/calcineurine inhibitor compared to MTX/ci showed a more favorable toxicity profile (66). Multiple studies in 2015 showed that a higher dose of Mycophenolate Mofetil reduced aGVHD in Ric double umbilical cord blood transplants.…”

Maximizing the Benefits of Mycophenolate Mofetil as Graft-versus-Host Disease Prophylaxis

“…In contrast, we previously presented, in abstract form, our retrospective experience with MMF in myeloablative sibling donor transplantations (n ¼ 114), with an incidence of grade II to IV acute GVHD of 34% and severe grades III and IV GVHD of 12%, and 3-year nonrelapse mortality of 25%. Only 15% and 21% of deaths were attributed to acute and chronic GVHD, respectively [3], compared with the 49% of deaths related to GVHD reported in Al-Kadhimi's study [1].…”