This clinical investigation will attempt to develop a successful strategy for performing HLA-mismatched donor bone marrow transplants, thereby offering potentially curative transplant options to a large number of patients who lack an HLA-matched donor. Previous experimental and clinical data have shown that bone marrow transplants across MHC barriers are frequently complicated by life-threatening graft-versus-host disease (GVHD) and early transplant related mortality. Aggressive pharmacologic immunosuppression, while providing temporary amelioration of clinical manifestations of GVHD, usually aggravates the associated profound state of immunoincompetence. Although GVHD can be effectively prevented by ex vivo T-cell depletion, risks of engraftment failure and leukemic relapse are increased. Previous murine data have shown striking protection from acute GVHD mortality, and preservation of a graft-versus-leukemia effect with use of high dose, short course interleukin-2 (IL-2) following mismatched donor transplants. Murine and miniature swine data also exist to support the role of mixed T-cell depleted autologous and MHC- mismatched allogenic marrow in the prevention of acute GVHD mortality. Optimal GVHD protection may be obtained, moreover, by the combination of IL-2 and mixed marrow infusion. The proposed GVHD prophylactic strategy involves early, short course IL-2 in conjunction with cyclosporine and for mismatched donor marrow recipients, cyclosporine and corticosteroids. Optimization of this regimen will then allow for future studies involving co-infusion of autologous marrow or specific cellular subsets (such as cells with alpha Beta TCR+CD4-CD8-phenotype) with IL-2 enhanced regulatory activity. In order to define toxicities and maximally tolerated dose of IL-2, the first phase of this trial will involve patients with advanced leukemia and matched or mismatched related donors. The second phase of the trial will evaluate the GVHD protective effect of IL-2 at maximally tolerated dose among a similar group of patients. Serial immune function studies will be performed in order to evaluate the mechanism of action of IL-2. The long term goal of this trial will include maximization of GVHD protection by the addition of IL-2 dependent autologous cellular populations that are believed to be instrumental in inhibition of the graft vs. host reaction.
| Chaires, Jonathan B; Ren, Jinsong; Hamelberg, Donald et al. (2004) Structural selectivity of aromatic diamidines. J Med Chem 47:5729-42 |
| Sykes, M; Preffer, F; McAfee, S et al. (1999) Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. Lancet 353:1755-9 |
