title: Rapid immune reconstitution after a reduced-intensity conditioning regimen and a CD3-depleted haploidentical stem cell graft for paediatric refractory haematological malignancies.
abstract: The main obstacles to successful haploidentical haematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections and severe graft-versus-host disease (GvHD). We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin in order to expedite immune reconstitution after a CD3-depleted haploidentical stem cell transplant. This protocol was used to treat 22 paediatric patients with refractory haematological malignancies. After transplantation, 91% of the patients achieved full donor chimaerism. They also showed rapid recovery of CD3(+) T-cells, T-cell receptor (TCR) excision circle counts, TCRbeta repertoire diversity and natural killer (NK)-cells during the first 4 months post-transplantation, compared with those results from a group of patients treated with a myeloablative conditioning regimen. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.
authors.affiliation: Division of Bone Marrow Transplantation, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Chen
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hale
authors.forename: Raymond
authors.initials: R
authors.lastname: Barfield
authors.forename: Ely
authors.initials: E
authors.lastname: Benaim
authors.forename: Wing H
authors.initials: WH
authors.lastname: Leung
authors.forename: James
authors.initials: J
authors.lastname: Knowles
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Horwitz
authors.forename: Paul
authors.initials: P
authors.lastname: Woodard
authors.forename: Kimberly
authors.initials: K
authors.lastname: Kasow
authors.forename: Usman
authors.initials: U
authors.lastname: Yusuf
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Behm
authors.forename: Randall T
authors.initials: RT
authors.lastname: Hayden
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Shurtleff
authors.forename: Victoria
authors.initials: V
authors.lastname: Turner
authors.forename: Deo Kumar
authors.initials: DK
authors.lastname: Srivastava
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
mesh_terms: D000293:Adolescent; D001402:B-Lymphocytes / Q000276:immunology; D017252:CD3 Complex / Q000097:blood; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D019337:Hematologic Neoplasms / Q000276:immunology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D009894:Opportunistic Infections / Q000276:immunology / Q000517:prevention & control; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods*; D019562:Viral Load; D014766:Viremia / Q000276:immunology / Q000517:prevention & control
chemical_list: D017252:CD3 Complex; D016693:Receptors, Antigen, T-Cell, alpha-beta