Blood Journal
Leading the way in experimental and clinical research in hematology

A two-step approach to myeloablative haploidentical stem cell transplantation: a phase I/II trial performed with optimized T-cell dosing

  1. Dolores Grosso1,*,
  2. Matthew Carabasi1,
  3. Joanne Filicko-O'Hara1,
  4. Margaret Kasner1,
  5. John L. Wagner1,
  6. Beth Colombe2,
  7. Patricia Cornett Farley3,
  8. William O'Hara4,
  9. Phyllis Flomenberg5,
  10. Maria Werner-Wasik6,
  11. Janet Brunner7,
  12. Bijoyesh Mookerjee1,
  13. Terry Hyslop1,
  14. Mark Weiss1, and
  15. Neal Flomenberg1
  1. 1 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States;
  2. 2 Department of Tissue Typing, Thomas Jefferson University Hospital, Philadelphia, PA, United States;
  3. 3 Stem Cell Processing Laboratory, Thomas Jefferson University Hospital, Philadelphia, PA, United States;
  4. 4 Department of Pharmacy, Thomas Jefferson University Hospital, Philadelphia, PA, United States;
  5. 5 Department of Infectious Diseases, Thomas Jefferson University Hospital, Philadelphia, PA, United States;
  6. 6 Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, United States;
  7. 7 Center for International Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, United States
  1. * Corresponding author; email: dolores.grosso{at}jefferson.edu

Abstract

Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe graft-versus-host (GVHD) is usually absent. However, little is known regarding optimal T cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2 step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T cell tolerization. A CD34 selected HSC product (HSCT step 2) was infused after CY. A dose of 2 x108/kg T cells resulted in consistent engraftment, immune reconstitution, and acceptable rates of GVHD. Cumulative incidences of grade III-IV GVHD, non-relapse mortality and relapse-related mortality were 7.4%, 22.2%, and 29.6% respectively. With a follow-up of 28-56 months, 3 year probability of overall survival for the whole cohort is 48% and 75% in patients without disease at HSCT. In the context of CY tolerization, a high, fixed dose of haploidentical T cells was associated with encouraging outcomes especially in good risk patients, and can serve as the basis for further exploration and optimization of this 2 step approach. This study is registered at www.clinicaltrials.gov as NCT00429143.

  • Submitted July 7, 2011.
  • Accepted August 17, 2011.