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Nonmyeloablative Allogeneic Stem Cell Transplantation: Early Promise and Limitations

Department of Experimental Transplantation and Immunology, National Cancer Institute, Medicine Branch, Bethesda, Maryland, USA

Correspondence: Michael R. Bishop, M.D., Department of Experimental Transplantation and Immunology, National Cancer Institute, Medicine Branch, Bethesda, Maryland 20892, USA. Telephone: 301-435-2754; Fax: 301-480-4354; e-mail: mbishop{at}mail.nih.gov

Allogeneic stem cell transplantation is used to treat a variety of malignant and nonmalignant hematologic diseases. Conventionally, high-dose chemoradiotherapy-based preparative regimens were considered essential both for tumor eradication and facilitation of donor stem cell engraftment. It is now apparent that an immune-mediated graft-versus-tumor effect has a pivotal role in the curative potential of allogeneic stem cell transplantation. This has prompted the development of less toxic, nonmyeloablative but profoundly immunosuppressive preparative regimens, often fludarabine- or radiation-based. Full donor engraftment can be achieved; however, a significant number of patients achieve a mixed chimeric state. Mixed hematopoietic chimerism provides a platform for the use of adoptive immunotherapy using donor lymphocyte infusions to maximize the immune-mediated antitumor effect, but the optimal usage has yet to be determined. Immediate procedure-related mortality with nonmyeloablative regimens has been low, but graft-versus-host disease remains a major clinical concern and treatment challenge. Major tumor responses have been seen in many hematologic malignancies primarily including patients with highly chemorefractory disease. Follow-up data have been short and additional time is needed to determine the efficacy and toxicities of this immunotherapy. This approach has potential for widespread clinical application including HLA mismatched and matched unrelated donor transplantation, exploration of a graft-versus-solid tumor effect, and correction of phenotypic expression in nonmalignant disorders.

Key Words. Graft-versus-host reaction • Hematopoietic stem cell transplantation • Hematologic neoplasms • Human • Nonmyeloablative • Transplantation conditioning • Transplantation immunology

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