Non-Myeloablative Allogeneic Hematopoietic Transplantation and Induction of Graft-Versus-Malignancy

Abstract

The high dose chemotherapy and radiation typically used as the preparative regimen for bone marrow transplantation produces considerable morbidity and mortality, and limits the use of this modality to a minority of patients who are young and in good general medical condition. Recent experimental and clinical data indicate that, in addition to the cytotoxic effect of the preparative regimen, an immune-mediated effect significantly contributes to the therapeutic benefit of allogeneic stem cell transplantation. This has been well documented in animal models^1,2 and in human clinical transplantation. Higher risk of relapse goes after T-cell-depleted ^3,4 or syngeneic transplant.^5,6 Also there is reduced risk of leukemia relapse in patients with acute and chronic graft-versus-host disease (GVHD).^7,8 Elimination of residual disease, as detected by cytogenetics or polymerase chain reactions techniques in diseases such as chronic myelogenous leukemia (CML) which may take six to twelve months after transplant presumably due to an ongoing graft-versus-leukemia effect.⁹ Withdrawal of immunosuppression given for prevention of GVHD can occasionally lead to restoration of remission in patient relapsing after transplants.¹⁰ However, the most direct evidence of this graft-versus-malignancy (GVM) effect is the observation that infusion of donor lymphocytes can re-induce remission in patients who relapse after allogeneic transplantation.^11,12 This GVM has been shown in myeloid diseases where is has been most effective against CML and to a lesser extent in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). They have also been shown in multiple myeloma^13,14 chronic lymphocytic leukemia (CLL),¹⁵ low grade lymphoma¹⁶ and solid tumors.^17,18