title: Fludarabine-based conditioning secures engraftment of second hematopoietic stem cell allografts (HSCT) in the treatment of initial graft failure.
abstract: Graft failure is associated with a high mortality rate. To date, regimens invoked for second transplants have resulted in inconsistent engraftment with high transplant-related mortality (TRM). We here report 16 consecutive patients, aged 4-59 years, who received second HSCT (HSCT-2) at a median of 45 days following primary or secondary failure of an initial unmodified (N = 3) or T cell-depleted (TCD) (N = 13) HSCT (HSCT-1). HSCT-1 was administered after myeloablative total body irradiation (TBI)- or alkylator-based conditioning for acute leukemias (N = 7), MDS (N = 6), CML (N = 2), and Fanconi anemia (N = 1). All patients experienced 1 or more infectious complications between HSCT-1 and HSCT-2, and 10 patients had active infections at the time of HSCT-2. Cytoreduction regimens used for HSCT-2 included fludarabine (Flu) in combination with cyclophosphamide (CTX) (N = 9), or thiotepa (Thio) (N = 5). In addition, 1 patient received Flu alone and 1 patient Thio combined with CTX. Antithymocyte globulin (ATG) (N = 11) or Alemtuzumab (N = 3) was added pretransplant to prevent rejection. For HSCT-2, donors included HLA-matched (N = 3) or mismatched (N = 8) related, or matched (N = 2) or mismatched (N = 3) unrelated donors. The primary graft donor was used in 6 of 16 cases. The grafts administered were unmodified peripheral blood stem cell transplantation (PBSCT) (N = 5) or bone marrow transplantation (BMT) (N = 3), TCD PBSCT (N = 8). All patients achieved engraftment at a median of 12 days and evaluable patients achieved complete donor chimerism. Six patients are alive with a median follow-up of 49 months, including 4/9 conditioned with Flu/CTX. In this series, outcome was statistically superior for younger patients (<or=20 years). In summary, second HSCT using the combination of a fludarabine- and ATG-based, nonmyeloablative regimen and higher numbers of CD34+ progenitor cells has been associated with acceptable toxicity and allowed consistent engraftment with hematopoietic reconstitution in patients with previous graft failure.
authors.affiliation: Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Chewning
authors.forename: Hugo
authors.initials: H
authors.lastname: Castro-Malaspina
authors.forename: Ann
authors.initials: A
authors.lastname: Jakubowski
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Kernan
authors.forename: Esperanza B
authors.initials: EB
authors.lastname: Papadopoulos
authors.forename: Trudy N
authors.initials: TN
authors.lastname: Small
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Katharine C
authors.initials: KC
authors.lastname: Hsu
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Perales
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
authors.forename: James W
authors.initials: JW
authors.lastname: Young
authors.forename: Susan E
authors.initials: SE
authors.lastname: Prockop
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Collins
authors.forename: Richard J
authors.initials: RJ
authors.lastname: O'Reilly
authors.forename: Farid
authors.initials: F
authors.lastname: Boulad
mesh_terms: D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D046528:Chimerism; D004359:Drug Therapy, Combination; D005260:Female; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D047589:Leukocyte Reduction Procedures; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016879:Salvage Therapy / Q000379:methods*; D019172:Transplantation Conditioning / Q000379:methods*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D014740:Vidarabine; C024352:fludarabine