Nonmyeloablative hematopoietic cell transplantation: Replacing high-dose cytotoxic therapy by the graft-versus-tumor effect

Lyle Feinstein*, Brenda Sandmaier, David Maloney, Peter A. McSweeney, Michael Maris, Christopher Flowers, Jerry Radich, Marie Térèse Little, Richard A. Nash, Thomas Chauncey, A. N.N. Woolfrey, George Georges, Hans Peter Kiem, Jan M. Zaucha, Karl G. Blume, Judith Shizuru, Dietger Niederwieser, Rainer Storb

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Conventional allografting produces considerable regimen-related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell-mediated graft-versus-tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre-transplant total-body irradiation (200 cGy) followed by post-transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)-matched sibling donor hematopoietic cell engraftment in 82% of patients (n = 55) without prior high-dose therapy. The addition of fludarabine (90 mg/m2) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non-relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2-4 acute graft-versus-host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI With a median follow-up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long-term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.

Original languageEnglish (US)
Pages (from-to)328-339
Number of pages12
JournalAnnals of the New York Academy of Sciences
Volume938
DOIs
StatePublished - 2001

Keywords

  • Graft-versus-tumor effect
  • Hematopoietic stem cells
  • Nonmyeloablative transplant

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Neuroscience
  • History and Philosophy of Science

Fingerprint

Dive into the research topics of 'Nonmyeloablative hematopoietic cell transplantation: Replacing high-dose cytotoxic therapy by the graft-versus-tumor effect'. Together they form a unique fingerprint.

Cite this