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


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
None.
Straathof
Karin C
KC
Great Ormond Street Children's Hospital, London, UK.
Rao
Kanchan
K
Eyrich
Matthias
M
Hale
Geoff
G
Bird
Prudence
P
Berrie
Eleanor
E
Brown
Lucinda
L
Adams
Stuart
S
Schlegel
Paul G
PG
Goulden
Nicholas
N
Gaspar
H Bobby
HB
Gennery
Andrew R
AR
Landais
Paul
P
Davies
E G
EG
Brenner
Malcolm K
MK
Veys
Paul A
PA
Amrolia
Persis Jal
PJ
D000074323:Alemtuzumab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000628:therapy*; D007155:Immunologic Factors / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D053208:Kaplan-Meier Estimate; D017493:Leukocyte Common Antigens / Q000037:antagonists & inhibitors*; D008297:Male; D051381:Rats; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; D003520:Cyclophosphamide; D017493:Leukocyte Common Antigens; D014740:Vidarabine; C024352:fludarabine