Graft-vs.-malignancy with allogeneic blood stem cell transplantation: a potential primary treatment modality

The high-dose chemotherapy and radiation typically used as the preparative regimen for bone marrow transplantation produces considerable morbidity and mortality. An alternative strategy is to utilize a low-dose, non-myeloablative, preparative regimen designed not to eradicate the malignancy, but to provide sufficient immunosuppression to achieve engraftment of an allogeneic hematopoietic graft and allow subsequent development of a graft-vs.-malignancy effect. We studied this approach in patients who were ineligible for standard myeloablative preparative regimens because of advanced age or comorbidities and demonstrated that purine analog (fludarabine or 2-CDA) containing non-myeloablative chemotherapy allows engraftment of HLA-compatible hematopoietic progenitor cells, and extended remissions were observed in approximately half of chemosensitive patients with recurrent AML or CML. Patients with CLL or lymphoma have been effectively treated using a non-myeloablative regimen of fludarabine/cyclophosphamide of fludarabine, cytarabine, cisplatin. This chemotherapy is known to be non-myeloablative and mixed chimerism was anticipated. All patients with engraftment have responded and 67% have achieved complete remission. Maximal responses are slow to develop and occur gradually over a period of several months to one year. Long-term efficacy must still be determined and controlled trials are necessary comparing this approach with alternative therapies as well as standard transplantation regimens.