Cyclosporine alone vs cyclosporine plus methotrexate for post-transplant immunosuppression after HLA-identical sibling bone marrow transplantation: a randomized prospective study

Abstract

Summary:The role of methotrexate (MTX), given with cyclosporine (CS), after HLA-identical sibling bone marrow transplantation needs to be defined. In all, 80 patients with hematologic malignancies were enrolled in a prospective randomized trial. All were given BuCy conditioning. The 40 patients in the CS arm received CS 3 mg/kg/day intravenously, with subsequent oral dosing. Patients in the CS þ MTX arm received, in addition to CS, MTX intravenously, 15 mg/m 2 on day 1, and 10 mg/m 2 on days 3, 6, and 11. Transplantation-related mortality was low in both groups of patients (13 vs 11% for CS vs CS þ MTX groups, P ¼ 0.94). The CS group had a significantly higher frequency of chronic graft-versus-host disease (56 vs 32%, P ¼ 0.05). After a median follow-up of 22.1 months (5.1-47.8 months), three of 30 vs 10 of 28 patients with acute leukemia/myelodysplastic syndrome (MDS) in CS group vs CS þ MTX group relapsed (P ¼ 0.01) yielding better overall survival for patients with acute leukemia/MDS treated with CS (P ¼ 0.02). After HLAidentical sibling bone marrow transplantation, immunosuppression with CS, with or without MTX, resulted in similarly low transplantation-related mortality. In acute leukemia/MDS, decreased relapse with patient survival prolongation was observed in the CS group. The main method of post-transplant immunosuppression after HLA-identical sibling bone marrow transplantation has been the administration of immunosuppressive agents, including methotrexate (MTX), cyclosporine (CS), and glucocorticosteroids. [1][2][3] Early clinical trials were characterized by high transplantation-related mortality, of up to 42% of patients, especially those given CS or MTX alone. 1,2,4-11 Over half of the cases of transplantationrelated mortality were due to interstitial pneumonitis, with or without documented cytomegalovirus (CMV) disease. Post-transplant immunosuppression utilizing combinations of immunosuppressive agents showed a lower incidence of acute graft-versus-host disease (GVHD) and transplantation-related deaths. 3,6-11 Although combination therapy is widely accepted for post-transplant immunosuppression in various settings of allogeneic hematopoietic cell transplantation, including HLA-identical sibling bone marrow transplantation, 12 the optimum regimen for post-transplant immunosuppression in the latter requires further investigation, primarily because recent improvements in the management of patients with GVHD and resulting infectious complications, such as CMV, have been shown to significantly decrease the incidence of transplantationrelated mortality after allogeneic hematopoietic cell transplantation. 13 In addition, several studies have reported increased relapse rates of underlying leukemia resulting from combined immunosuppression after HLA-identical sibling bone marrow transplantation. 7,14 These findings indicate that, in HLA-identical sibling bone marrow transplantation, where the genetic disparity between the donor and the patient is relatively small, optimum posttransplant immunosuppression s...

Outcome of haematopoietic stem cell transplantation for paediatric acute lymphoblastic leukaemia in third complete remission: a vital role for graft‐versus‐host‐disease/ graft‐versus‐leukaemia effect in survival

“…Effective GVHD prophylaxis with CSA and methotrexate is extremely important in reducing TRM following HSCT and dramatically improved HSCT outcome in older studies (Storb et al, 1986). However, recently (Lee et al, 2004) reported a significantly lower relapse rate in the CSA only group compared to CSA plus MTX group with a similar TRM in both groups, suggesting a beneficial GVL effect with the reduction in GVHD prophylaxis. This reduction in GVHD prophylaxis to enhance GVL effect may be a reasonable strategy for patients transplanted in CR3, particularly when utilizing MRD or fully MUD based on current state of the art molecular HLA typing.…”

Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations

“…15 However, the role of MTX, given with CSA after HLA-identical sibling bone marrow transplantation in pediatric ALL, needs to be defined. In a randomized prospective study of 80 patients with hematological malignancies, Lee et al 16 reported a significantly lower relapse rate in the CSA-only group compared to the CSA plus MTX group, with a similar TRM in both groups, suggesting a beneficial GVL effect with the reduction in GVHD prophylaxis. Several other randomized trials have investigated immunosuppression regimens after HLAidentical sibling bone marrow transplantations.…”

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis

“…6 CsA is rarely used alone, except for patients transplanted from sibling donors. 7 To date, there is no report on the use of CsA without MTX in patients transplanted from unrelated donors.…”