title: Partially mismatched pediatric transplants with allogeneic CD34(+) blood cells from a related donor.
abstract: This was a phase I, multi-center study of 13 pediatric patients (median age, 11 years) to evaluate toxicity, hematopoietic recovery, and graft-versus-host disease (GVHD) after allogeneic transplantation of enriched blood CD34(+) cells obtained from genotypically haploidentical but partially HLA-mismatched related donors (8 parents and 5 siblings). With regard to rejection, donor HLA disparity was 1 (5), 2 (6), or 3 loci (2). With regard to GVHD, recipient HLA disparity was 0 (1), 1 (3), 2 (8), or 3 (1). The patients suffered from acute myelogenous leukemia (6), chronic myelogenous leukemia (4), acute lymphoblastic leukemia (2), or hemolytic anemia plus immunodeficiency disorder (1). To reduce the risk of graft failure through the infusion of a large amount of stem cells, peripheral blood cells (PBC) were mobilized by recombinant granulocyte colony-stimulating factor (G-CSF; lenograstim, 10 microgram/kg/d for 5 days) and collected by 2 to 5 aphereses. To both enhance engraftment and reduce GVHD, CD34(+) cells were enriched using immunomagnetic procedures with the Baxter ISOLEX 300 system (Baxter Healthcare Corp, Irvine, CA) and cryopreserved. After variable cytoreductive regimens, a median of 7.7 (range, 2.2 to 14) x 10(6)/kg of CD34(+) cells and 1.03 (0.05 to 2.09) x 10(5)/kg CD3(+) cells were infused. Using Center-specific posttransplant supportive care and immunosuppressive GVHD prophylaxis, two patients experienced early death; one from veno-occlusive disease at day 17 and one from sepsis at day 18. Nine of 11 patients showed signs of engraftment; however, subsequent rejection was seen in 4 patients, 2 of whom had autologous recovery. Eight patients were evaluated in the early phase of marrow recovery. The median number of days to achieve an absolute granulocyte count of 0.5 x 10(9)/L was 14 (range, 9 to 20) and that to achieve a platelet count of 20 x 10(9)/L was 17.5 (range, 12 to 23). Donor chimerism persisted in five patients until death or current survival. All of the surviving patients with functioning-donor-type hematopoiesis were given total body irradiation. De novo acute GVHD (grades II and IV) was observed in two of the eight evaluated patients. Scheduled donor lymphocyte infusion (DLI), using the CD34(-) fraction, was administered to four patients, free of de novo acute GVHD, beginning between 28 to 43 days after transplant. Three of these patients developed acute GVHD (grades I, II, and IV). Cytomegalovirus infection was a major infectious complication but was successfully managed with gamma-globulin and gancyclovir treatment with or without additional DLI. Five patients are currently surviving, free of disease, with a follow-up ranging from 476 to 937 days. Each survivor has functioning hematopoiesis, three of donor origin and two of autologous origin. In conclusion, our results show that enriched blood CD34(+) cells from a mismatched haploidentical donor are a feasible alternative source of stem cells, but do not appear to ensure engraftment. Because none of the patients who were administered DLI survived, the therapeutic efficacy and safety of periodic DLI, as an integrated part of such transplants, needs to be clarified in further studies.
authors.affiliation: Department of Pediatrics, University of Tokushima, Tokushima; National Cancer Center Hospital, Tokyo; the Department of Pediatrics, University of Akita, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawano
authors.forename: Y
authors.initials: Y
authors.lastname: Takaue
authors.forename: A
authors.initials: A
authors.lastname: Watanabe
authors.forename: O
authors.initials: O
authors.lastname: Takeda
authors.forename: K
authors.initials: K
authors.lastname: Arai
authors.forename: E
authors.initials: E
authors.lastname: Itoh
authors.forename: Y
authors.initials: Y
authors.lastname: Ohno
authors.forename: T
authors.initials: T
authors.lastname: Teshima
authors.forename: M
authors.initials: M
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: T
authors.initials: T
authors.lastname: Kajiume
authors.forename: T
authors.initials: T
authors.lastname: Matsushita
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: M
authors.initials: M
authors.lastname: Endo
authors.forename: Y
authors.initials: Y
authors.lastname: Kuroda
authors.forename: S
authors.initials: S
authors.lastname: Asano
authors.forename: R
authors.initials: R
authors.lastname: Tanosaki
authors.forename: K
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: P
authors.initials: P
authors.lastname: Law
authors.forename: J D
authors.initials: JD
authors.lastname: McMannis
mesh_terms: D000293:Adolescent; D018952:Antigens, CD34 / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D002678:Chimera; D003586:Cytomegalovirus Infections / Q000453:epidemiology; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000209:etiology; D016179:Granulocyte Colony-Stimulating Factor; D006239:Haplotypes; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000401:mortality; D006504:Hepatic Veno-Occlusive Disease / Q000209:etiology; D006648:Histocompatibility; D006801:Humans; D007223:Infant; D000078224:Lenograstim; D017710:Lymphocyte Transfusion; D008297:Male; D009679:Nuclear Family; D010290:Parents; D011994:Recombinant Proteins; D012074:Remission Induction; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology* / Q000401:mortality; D016896:Treatment Outcome
chemical_list: D018952:Antigens, CD34; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000078224:Lenograstim