Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases.

Abstract

Toxicities of high-dose conditioning regimens have limited the use of conventional unrelated donor hematopoietic cell transplantation (HCT) to younger, medically fit patients. Based on preclinical studies, an HCT approach has been developed for elderly or medically infirm patients with HLA-matched or mismatched unrelated donors. In this study, 52 patients with hematological diseases were included. Most (88%) had preceding unsuccessful conventional HCT or refractory/advanced disease. Patients were treated with fludarabine 30 mg/m(2)/d from days -4 to -2, 2 Gy total body irradiation on day 0, cyclosporine at 6.25 mg/kg twice daily from day -3, and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Durable donor chimerism was attained in 88% of the patients. By day 28, a median of 100% of CD56(+) cells were of donor origin. Granulocyte and T-cell donor chimerism increased to medians of 100% on day 56 and day 180 (range, 55%-100%), respectively. Acute GVHD, grade II, was seen in 42% (CI, 29%-56%); grade III in 8% (CI, 0%-15%); and grade IV in 13% (CI, 4%-23%) of patients; it was fatal in 9%. The 100-day transplantation-related mortality was 11%. Complete remissions, including molecular remissions, were seen in 45% of patients with measurable disease before transplantation. Mortality from disease progression was 27% at one year. With a median follow-up of 19 months, 18 of the 52 patients (35%) were alive and 25% were in remission. HCT from HLA-matched or mismatched unrelated donors can be performed with a reduced intensity conditioning regimen in patients ineligible for conventional HCT.

• Authors: Dietger Niederwieser, Michael Maris, Judith A Shizuru, Effie Petersdorf, Ute Hegenbart, Brenda M Sandmaier, David G Maloney, Barry Storer, Thoralf Lange, Thomas Chauncey, Michael Deininger, Wolfram Pönisch, Claudio Anasetti, Ann Woolfrey, Marie-Terese Little, Karl G Blume, Peter A McSweeney, Rainer F Storb
• Journal: Blood (Blood) Vol. 101 Issue 4 Pg. 1620-9 (Feb 15 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12393457 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Immunosuppressive Agents
• Cyclosporine
• Vidarabine
• Mycophenolic Acid
• fludarabine

Topics

• Adult
• Aged
• Child
• Cyclosporine (administration & dosage)
• Female
• Graft vs Host Disease (epidemiology, mortality)
• Hematologic Diseases (mortality, therapy)
• Hematopoietic Stem Cell Transplantation (mortality)
• Histocompatibility
• Histocompatibility Testing
• Humans
• Immunosuppressive Agents (administration & dosage)
• Male
• Middle Aged
• Mycophenolic Acid (administration & dosage, analogs & derivatives)
• Peripheral Blood Stem Cell Transplantation (mortality)
• Remission Induction
• Survival Rate
• Tissue Donors
• Transplantation Chimera
• Transplantation Conditioning (methods)
• Vidarabine (administration & dosage, analogs & derivatives)
• Whole-Body Irradiation