Pharmacological methods to reduce disease recurrence

Abstract

Allogeneic stem cell transplantation is an increasingly important treatment option in patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Although there has been substantial progress in reducing transplantation-related mortality (TRM), little progress has been made in reducing the risk of disease relapse, which continues to represent the major cause of treatment failure in patients allografted for AML and MDS. Experience with myeloablative conditioning regimens has demonstrated that, although intensification of the preparative regimen reduces relapse risk, any survival benefit is blunted by a concomitant increase in TRM. A similar inverse correlation between relapse risk and TRM is observed in patients allografted using a reduced-intensity conditioning regimen. However, the markedly lower toxicity of such regimens has permitted the design of novel conditioning strategies aimed at maximizing antitumor activity without excessive transplant toxicity. Coupled with recent advances in drug delivery and design, this has allowed the development of a spectrum of new conditioning regimens in patients with high-risk AML and MDS. At the same time, the optimization of a graft-versus-leukemia (GVL) effect by minimizing posttransplantation immunosuppression, with or without the infusion of donor lymphocytes, is essential if the risk of disease relapse is to be reduced. Recently, the delivery of adjunctive posttransplantation therapies has emerged as a promising method of augmenting antileukemic activity, either through a direct antitumor activity or consequent upon pharmacological manipulation of the alloreactive response. Taken together these advances present a realistic possibility of delivering improved outcome in patients allografted for high-risk AML or MDS.