Reinventing bone marrow transplantation: reducing toxicity using nonmyeloablative, preparative regimens and induction of graft-versus-malignancy

Bone marrow transplantation was initially developed as a means to deliver supralethal doses of chemotherapy and radiation for treatment of malignancies. Myelosuppression is the dose-limiting toxicity for many chemotherapy drugs and whole-body radiation. Many malignancies exhibit a steep dose-response relationship to chemotherapy or radiotherapy. Bone marrow transplantation allows escalation of doses beyond those levels which produce severe bone marrow toxicity. Doses of many agents, particularly alkylating agents and whole body radiation, can be increased three- to fivefold above their conventional maximally tolerated dose. Marrow transplantation was considered a supportive care modality to restore hematopoiesis. It has become clear, however, that the high dose therapy does not eradicate the malignancy in many patients, and that the therapeutic benefit of allogeneic marrow transplantation is largely related to an associated immune-mediated graft-versus-malignancy effect.