Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study

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, EG G. Davies, Malcolm K. Brenner, Paul A. Veys, Persis Jal Amrolia

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

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 YTH24.5 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. Funding: None.

Original languageEnglish (US)
Pages (from-to)912-920
Number of pages9
JournalThe Lancet
Volume374
Issue number9693
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Medicine(all)

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