TY - JOUR
T1 - Hematopoietic cell transplantation in older patients with hematologic malignancies
T2 - Replacing high-dose cytotoxic therapy with graft-versus-tumor effects
AU - McSweeney, Peter A.
AU - Niederwieser, Dietger
AU - Shizuru, Judith A.
AU - Sandmaier, Brenda M.
AU - Molina, Arthur J.
AU - Maloney, David G.
AU - Chauncey, Thomas R.
AU - Gooley, Theodore A.
AU - Hegenbart, Ute
AU - Nash, Richard A.
AU - Radich, Jerald
AU - Wagner, John L.
AU - Minor, Steven
AU - Appelbaum, Frederick R.
AU - Bensinger, William I.
AU - Bryant, Eileen
AU - Flowers, Mary E.D.
AU - Georges, George E.
AU - Carl Grumet, F.
AU - Kiem, Hans Peter
AU - Torok-Storb, Beverly
AU - Yu, Cong
AU - Blume, Karl G.
AU - Storb, Rainer F.
PY - 2001/6/1
Y1 - 2001/6/1
N2 - Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination 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, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications 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 myelosuppression were mild, allowing 53% of eligible patients to have entirely 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 in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of post-grafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies.
AB - Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination 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, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications 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 myelosuppression were mild, allowing 53% of eligible patients to have entirely 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 in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of post-grafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies.
UR - http://www.scopus.com/inward/record.url?scp=0035383762&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035383762&partnerID=8YFLogxK
U2 - 10.1182/blood.V97.11.3390
DO - 10.1182/blood.V97.11.3390
M3 - Article
C2 - 11369628
AN - SCOPUS:0035383762
SN - 0006-4971
VL - 97
SP - 3390
EP - 3400
JO - Blood
JF - Blood
IS - 11
ER -