Low number of donor activating killer immunoglobulin-like receptors (KIR) genes but not KIR-ligand mismatch prevents relapse and improves disease-free survival in leukemia patients after in vivo T-cell depleted unrelated stem cell transplantation.
BACKGROUND
The effect of natural killer (NK) cell alloreactivity on outcome of unrelated stem cell transplantation (SCT) remains controversial. Killer immunoglobulin-like receptors (KIRs) recognize human leukocyte antigen C and B epitopes on target cells, thereby regulating NK cell activity. The KIR genes are polymorphic and two broad haplotypes exist: KIR-haplotype A mainly encode for inhibitory receptors and only for one activating (KIR2DS4), whereas the group B haplotype encodes more for activating KIRs (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5 und KIR3DS1).


METHODS
The impact of KIR ligand mismatch on the number of activating and inhibitory donor KIR genes and on KIR-haplotype was studied on outcome of 142 patients with leukemia, who received standard myeloablative conditioning followed by in vivo T-cell depleted (ATG) unrelated SCT.


RESULTS
In a multivariate analysis KIR ligand mismatch had significantly higher treatment related mortality (RR 2.206, P = 0.03), resulting in reduced overall (RR 2.015, P = 0.02) and disease-free survival (RR 1.924, P = 0.03). In contrast, SCT from donors with group A haplotype (P = 0.003) or with low number of activating KIR genes (P = 0.005) resulted in reduced relapse rate with improved disease-fee survival (P = 0.04). This effect was seen only in acute myeloid leukemia/myelodysplastic syndrome and to a less extent in chronic myeloid leukemia. No effect was seen for acute lymphoblastic leukemia.


CONCLUSIONS
After in vivo T-cell depleted (ATG) unrelated stem cell transplantation with donors carrying low number of activating KIR genes (group A KIR haplotype), the risk of relapse is reduced and resulted in a significantly better disease-free survival.
Kröger
Nicolaus
N
Bone Marrow Transplantation, University Hospital Hamburg, Hamburg, Germany. nkroeger@uke.uni-hamburg.de
Binder
Thomas
T
Zabelina
Tatjana
T
Wolschke
Christine
C
Schieder
Heike
H
Renges
Helmut
H
Ayuk
Francis
F
Dahlke
Joachim
J
Eiermann
Thomas
T
Zander
Axel
A
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D000939:Epitopes / Q000737:chemistry; D005260:Female; D006086:Graft vs Host Disease / Q000378:metabolism; D006650:Histocompatibility Testing; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry* / Q000235:genetics; D007223:Infant; D007938:Leukemia / Q000276:immunology* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000378:metabolism; D054340:Receptors, KIR; D054349:Receptors, KIR3DS1; D012306:Risk; D033581:Stem Cell Transplantation / Q000379:methods*
D000939:Epitopes; D007136:Immunoglobulins; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054349:Receptors, KIR3DS1