Document Detail

Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study.
MedLine Citation:
PMID:  19729196     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Stem-cell transplantation can cure primary immunodeficiencies. However, in patients with pre-existing organ toxicity, patients younger than 1 year, and those with DNA or telomere repair disorders, chemotherapy-based conditioning is poorly tolerated and results in major morbidity and mortality. We tested a novel antibody-based minimal-intensity conditioning (MIC) regimen to assess whether this approach allowed curative donor stem-cell engraftment without non-haemopoietic toxicity.
METHODS: 16 high-risk patients underwent stem-cell transplantation for primary immunodeficiencies with an MIC regimen consisting of two rat anti-CD45 monoclonal antibodies YTH 24.5 and YTH 54.12 for myelosuppression, and alemtuzumab (anti-CD52) and fludarabine, and low dose cyclophosphamide for immunosuppression. Donors were matched siblings (n=5), and matched (9) and mismatched (2) unrelated donors.
FINDINGS: Antibody-based conditioning was well tolerated, with only two cases of grade 3 and no grade 4 toxicity. Rates of clinically significant acute (n=6, 36%) and chronic graft-versus-host disease (GVHD) (n=5, 31%) were acceptable. 15 of 16 patients (94%) engrafted, of whom 11 (69%) achieved full or high-level mixed chimerism in both lymphoid and myeloid lineages, and three achieved engraftment in the T-lymphoid lineage only. One patient needed retransplantation. At a median of 40 months post-transplant, 13 of 16 patients (81%) in this high-risk cohort were alive and cured from their underlying disease.
INTERPRETATION: Monoclonal antibody-based conditioning seems well tolerated and can achieve curative engraftment even in patients with severe organ toxicity or DNA repair defects, or both. This novel approach represents a shift from the paradigm that intensive chemotherapy or radiotherapy, or both, is needed for donor stem-cell engraftment. This antibody-based conditioning regimen may reduce toxicity and late effects and enable SCT in virtually any primary immunodeficiency patient with a matched donor.
Karin C Straathof; Kanchan Rao; Matthias Eyrich; Geoff Hale; Prudence Bird; Eleanor Berrie; Lucinda Brown; Stuart Adams; Paul G Schlegel; Nicholas Goulden; H Bobby Gaspar; Andrew R Gennery; Paul Landais; E G Davies; Malcolm K Brenner; Paul A Veys; Persis Jal Amrolia
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Publication Detail:
Type:  Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-09-02
Journal Detail:
Title:  Lancet     Volume:  374     ISSN:  1474-547X     ISO Abbreviation:  Lancet     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-14     Completed Date:  2009-09-24     Revised Date:  2013-05-27    
Medline Journal Info:
Nlm Unique ID:  2985213R     Medline TA:  Lancet     Country:  England    
Other Details:
Languages:  eng     Pagination:  912-20     Citation Subset:  AIM; IM    
Great Ormond Street Children's Hospital, London, UK.
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MeSH Terms
Antibodies, Monoclonal / therapeutic use*
Antibodies, Monoclonal, Humanized
Antibodies, Neoplasm / therapeutic use
Antigens, CD45 / antagonists & inhibitors*
Child, Preschool
Cyclophosphamide / therapeutic use
Disease-Free Survival
Follow-Up Studies
Graft vs Host Disease / epidemiology,  etiology,  prevention & control
Hematopoietic Stem Cell Transplantation / adverse effects,  methods*
Immunologic Deficiency Syndromes / therapy*
Immunologic Factors / therapeutic use*
Immunosuppressive Agents / therapeutic use
Kaplan-Meier Estimate
Transplantation Chimera
Transplantation Conditioning / adverse effects,  methods*,  mortality
Treatment Outcome
Vidarabine / analogs & derivatives,  therapeutic use
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Antibodies, Neoplasm; 0/Immunologic Factors; 0/Immunosuppressive Agents; 3A189DH42V/alemtuzumab; 50-18-0/Cyclophosphamide; 5536-17-4/Vidarabine; EC, CD45; P2K93U8740/fludarabine
Comment In:
Lancet. 2009 Sep 12;374(9693):856-8   [PMID:  19729197 ]

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