Pharmacologic Strategies

The availability of cyclosporine-based pharmacopro-phylaxis in the early to mid 1980s represented a major advance in the field of clinical HSCT. Prospective randomized trials evaluating the combination of cyclosporine and methotrexate compared with cyclosporine or methotrexate alone for leukemia or severe aplastic anemia were conducted.31,32 Significant reductions in the incidence of acute GVHD were seen in both studies. In the case of transplantation for hematologic malignancy (acute myelogenous leukemia in first complete remission or chronic phase chronic myelogenous leukemia) an overall survival benefit was realized. However, for severe aplastic anemia a survival difference did not reach statistical significance. Pharmacologic GVHD prophylaxis alone has been shown to be considerably less effective in the prevention of GVHD following HLA-mismatched donor HSCT.33,34 For recipients of HLA-2 or -3 antigen mismatched non-T-cell-depleted transplants, acute GVHD incidence exceeds 70-80% and transplant-related mortality is very high.33 Despite these limitations, cyclosporine-based pharmacoprophylactic strategies have had a major impact on the practice of clinical HSCT. The reduction in acute GVHD-related morbidity and mortality has allowed for the transplantation of considerably older patients and of patients without HLA genotypically identical sibling donors.

More recently, there have been several reported phar-macologic advances in the prevention of GVHD (Table 98.2). Triple drug immunoprophylaxis (cyclosporine, methotrexate, and corticosteroids) has been shown to be superior to cyclosporine and corticosteroids alone for the prevention of GVHD following HLA-matched donor HSCT for hematologic malignancies.35 The lack of an overall survival benefit (perhaps due to an impairment of the GVM effect) and an increased infection risk associated with more intensive immunosup-pressive regimens have underscored the limitations of this approach.

The introduction of tacrolimus has represented an advance in the management of GVHD. Two multicenter prospective randomized trials comparing tacrolimus and methotrexate with cyclosporine and methotrexate for GVHD prophylaxis following HSCT for hematologic malignancies have been con-ducted.36,37 In the first trial involving HLA genotypi-cally identical sibling donors, a significant reduction in the incidence of GVHD in the tacrolimus-treated patients was observed.36 The second trial involved patients receiving transplants from HLA-matched unrelated donors. Once again, GVHD incidence was reduced in the tacrolimus-treated group.37 In both trials, however, no significant difference in overall survival between two treatment groups was observed. The toxicity profile of tacrolimus was somewhat different than that of cyclosporine. More neurotoxicity was observed with tacrolimus. However, there was less renal impairment and hypertension in tacrolimus-treated patients.

Newer agents are presently being evaluated for GVHD prophylaxis. Rapamycin, an mTOR inhibitor that has been shown to cause G1 cell cycle arrest, has been evaluated in several GVHD prophylaxis strategies.

Table 98.2 GVHD prophylaxis strategies



Methotrexate Methotrexate + CYA or corticosteroids Methotrexate + tacrolimus Methotrexate + CYA + corticosteroids Tacrolimus + sirolimus +/— methotrexate CYA 1 MMF

Limited GVHD protection

Improved prophylaxis compared with single-agent methotrexate; survival advantage in aplastic anemia

Superior prophylaxis compared with CYA/methotrexate but no survival advantage Superior prophylaxis compared with CYA/methotrexate but no survival advantage

Promising GVHD protection in HLA-matched related and unrelated donor settings

Promising GVHD protection with less morbidity than with methotrexate combinations (mucositis, myelosuppression)

Ex vivo T-cell depletion

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