title: Impact of T cell chimerism on clinical outcome in 117 patients who underwent allogeneic stem cell transplantation with a busulfan-containing reduced-intensity conditioning regimen.
abstract: Within the concept of reduced-intensity stem cell transplantation (RIST) there is a wide range of different regimens used, and little information is available on the clinical impact of chimerism status in patients conditioned with a busulfan-containing regimen. Therefore, we retrospectively reviewed lineage-specific chimerism and the subsequent clinical outcome in 117 patients (median age, 55 years; range: 29-68) who underwent busulfan-containing RIST. The conditioning regimen consisted of busulfan (oral 8 mg/kg or i.v. 6.4 mg/kg) and fludarabine (180 mg/m(2), n = 64) or cladribine (0.66 mg/kg, n = 53), with or without 2-4 Gy total-body irridiation (TBI) (n = 26) or antihuman T-lymphocyte immunoglobulin (ATG; 5-10 mg/kg; n = 31). Chimerism was evaluated with peripheral blood samples taken on days 30, 60, and 90 after transplantation by polymerase chain reaction (PCR)-based amplification of polymorphic short tandem repeat regions. The median follow-up of surviving patients was 1039 days (153-2535). The percent donor-chimerism was significantly higher in granulocyte than T cell fraction throughout the entire course, and the median (mean) values were, respectively, 100% (96%) versus 95% (83%), 100% (98%) versus 100% (89%), and 100% (98%) versus 100% (91%) at days 30, 60, and 90 after RIST. In a multivariate analysis, having received <2 types of chemotherapy regimens before RIST was the only factor that was significantly associated with low donor T cell chimerism (<60%) at day 30 (hazard ratio [HR]: 6.1; 95% confidence interval [CI], 2.1-18.4; P < .01). The median percentage of donor T cell chimerism at day 30 was 9% (0%-63%) in 5 patients who experienced graft failure, which was significantly lower than that (97%; 15%-100%) in the rest of the patients (P < .01). No correlation was found between the kinetics of T cell chimerism and the occurrence of acute or chronic GVHD (aGVHD, cGVHD). The stem cell source and the addition of TBI or ATG were not associated with the degree of T cell chimerism, overall survival (OS) or event-free survival (EFS). In a Cox proportional hazard model, low donor T cell chimerism of <60% at day 30 was associated with both poor OS (HR: 2.2; 95% CI, 1.1-4.5; P = .02) and EFS (HR: 2.0; 95% CI, 1.1-3.8; P = .02). In conclusion, we found that 43% of the patients retained mixed donor T cell chimerism (<90% donor) at day 30, whereas 92% achieved complete chimerism in granulocyte fraction. Low donor T cell chimerism of <60% at day 30 may predict a poor outcome, and a prospective study to examine the value of early intervention based on chimerism data is warranted.
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Bungo
authors.initials: B
authors.lastname: Saito
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan. Electronic address: tafukuda@ncc.go.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokoyama
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Saiko
authors.initials: S
authors.lastname: Kurosawa
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Fuji
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kinuko
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Sung-Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Mori
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Tanosaki
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Takaue
authors.affiliation: Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Heike
mesh_terms: D000328:Adult; D000368:Aged; D002066:Busulfan / Q000627:therapeutic use*; D006086:Graft vs Host Disease; D006098:Granulocytes; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods* / Q000401:mortality; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D016019:Survival Analysis; D013601:T-Lymphocytes; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods* / Q000401:mortality; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D002066:Busulfan