A prospective randomised trial of cyclosporin and methotrexate versus cyclosporin, methotrexate and prednisolone for prevention of graft‐versus‐host disease after HLA‐identical sibling marrow transplantation for haematological malignancy

Abstract

A prospective randomised trial was performed in patients given HLA-identical sibling bone marrow transplants for haematological malignancy comparing the combination of cyclosporin and methotrexate (CM) (n = 20) with the combination of cyclosporin, methotrexate and prednisolone (CMP) (n = 21) as prophylaxis for graft-versus-host disease (GVHD). There was no significant differences between the two arms for the incidence of acute GVHD grades I-IV, acute GVHD grades II-IV, chronic GVHD, interstitial pneumonitis, relapse, survival and disease-free survival. The actuarial incidence of acute GVHD grades II-IV in the CMP group was 10% and in the CM group 15% (ns). The incidence of leukaemic relapse in good risk patients was 42% in the CMP group and 40% in the CM group (ns), although the majority of these relapses were cytogenetic relapses only in patients with chronic myeloid leukaemia. The incidence of acute GVHD grades II-IV in both arms of the current trial was significantly lower than in our previous trial comparing cyclosporin and methotrexate as single agents. Leukaemic relapse is now the principal cause of treatment failure in this patient population. We conclude that prednisolone should not be included as part of the prophylactic GVHD regime and that further improvement in therapeutic outcome is dependent upon better control of the underlying malignancy.

Cyclosporin, methotrexate and prednisolone for graft-versus-host disease prophylaxis in allogeneic peripheral blood progenitor cell transplants

“…Several previous randomized studies in sibling bone marrow transplants, [6][7][8][9][10] although varying in duration of prednisolone prophylaxis and in some, comparing CSA/ MTX/Pred to CSA/Pred have generally found no reduction in acute GVHD incidence. In the unrelated donor bone marrow transplant setting, grade II-IV GVHD incidence did not significantly differ with the addition of prednisolone to CSA/MTX.…”

“…[2][3][4] Several investigators have reported the effects of combining prednisolone with CSA/ MTX in reducing GVHD after marrow allografts. [5][6][7][8][9][10][11][12][13] The schedule of prophylaxis has varied, with prednisolone commencing at days À7, 0, þ 14 or þ 15 and continuing until day þ 35, þ 110 or to day þ 180. A delay in onset of acute GVHD has been described in several series, 6,8,10 but in only one published report in sibling bone marrow recipients has a significant reduction in the overall incidence of grade II-IV acute GVHD been observed.…”

“…[5][6][7][8][9][10][11][12][13] The schedule of prophylaxis has varied, with prednisolone commencing at days À7, 0, þ 14 or þ 15 and continuing until day þ 35, þ 110 or to day þ 180. A delay in onset of acute GVHD has been described in several series, 6,8,10 but in only one published report in sibling bone marrow recipients has a significant reduction in the overall incidence of grade II-IV acute GVHD been observed. 5 In that randomized study, prednisolone was commenced on day þ 14 at a dose of 0.5 mg/kg per day, increased to 1 mg/ kg per day from day þ 21 to day þ 34 then gradually tapered and ceased by day þ 110.…”

Prophylaxis of graft-versus-host disease with cyclosporine–prednisone is associated with increased risk of chronic graft-versus-host disease

“…Other investigators have studied the effect of the addition of PRED to the combination of CYA and MTX. [14][15][16][17] An increase in the incidence of acute and chronic GVHD was noted in one study, 14 with no difference in survival, and in two other studies, no advantage was noted in either survival or the incidence of GVHD. 15,16 In another study, an increase in the incidence of infection was noted with the addition of PRED, 18 but other studies did not confirm this observation.…”

“…[14][15][16][17] An increase in the incidence of acute and chronic GVHD was noted in one study, 14 with no difference in survival, and in two other studies, no advantage was noted in either survival or the incidence of GVHD. 15,16 In another study, an increase in the incidence of infection was noted with the addition of PRED, 18 but other studies did not confirm this observation. 13,16 In a prospective study that compared CYA and PRED with CYA and MTX, Gondo et al 19 showed a lower incidence of chronic GVHD with the former combination, although other studies have noted a higher incidence of chronic GVHD with the CYA and PRED regimen.…”