Non-myeloablative hematopoietic cell transplantation as immunotherapy for hematologic malignancies

Conventional approaches to hematopoietic stem cell transplantation (HSCT) carry risks of morbidity and mortality from regimen-related toxicities, which have restricted the procedure to relatively young patients in good medical condition. This age restriction is unfortunate because the median age of patients with most candidate diseases (e.g., acute and chronic leukemias, myelodysplasia, myeloproliferative diseases, myeloma, and non-Hodgkin lymphoma) for HSCT is greater than 60 years. In non-myeloablative allogeneic HSCT, high-dose cytotoxic therapy as the conceptual basis for treating hematopoietic malignancies has been replaced by graft-versus-tumor effects. The use of potent pre- and postgrafting immunosuppression derived from preclinical studies has allowed omission of myeloablative cytotoxic therapy without compromising hematopoietic donor cell engraftment. This results in a marked reduction in transplant-related toxicities which makes older or medically infirm patients candidates for this treatment option. Initial results in patients with a variety of hematologic malignancies have been encouraging, with documented sustained cytogenetic and molecular remissions in a substantial number of sometimes heavily pretreated and previously refractory patients. While patients with hematologic malignancies will likely require conversion to full donor hematopoiesis for long-term disease control, a state of mixed donor/host hematopoietic chimerism might suffice to 'cure' the disease phenotypes in various non-malignant diseases. Strategies aimed at inducing donor-specific tolerance and optimizing post-transplant immunosuppression may eventually eliminate the need for pre-transplant total body irradiation which is relevant for minimizing late toxicities.