Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects

Toxicities have limited the use of allogeneic hematopoietic cell transplant ation (HCT) to younger, medically fit patients. in a canine HCT model, a co mbination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP ) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, toget her with the known antitumor effects of donor leukocyte infusions(DLIs), le d to the design of this trial, Forty-five patients (median age 56 years) wi th hematologic malignancies, HLA-identical sibling donors, and relative con traindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and my elosuppression were mild, allowing 53% of eligible patients to have entirel y outpatient transplantations, Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were inc omplete remission, including 8 with molecular remissions. This novel allogr afting approach, based on the use of postgrafting immunosuppression to cont rol graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting, HCT with the induction of potent graft-versus-tumor effec ts can be performed in previously ineligible patients, largely in an outpat ient setting. Future protocol modifications should reduce rejection and GVH D, thereby facilitating studies of allogeneic immunotherapy for a variety o f malignancies. (Blood. 2001;97:3390-3400) (C) 2001 by The American Society of Hematology.