Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia

Sarah Cooley, Daniel J. Weisdorf, Lisbeth A. Guethlein, John P. Klein, Tao Wang, Chap T. Le, Steven G.E. Marsh, Daniel Geraghty, Stephen Spellman, Michael D. Haagenson, Martha Ladner, Elizabeth Trachtenberg, Peter Parham, Jeffrey S. Miller

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Abstract

Killer-cell immunoglobulin-like receptor (KIR) genes form a diverse, immunogenetic system. Group A and B KIR haplotypes have distinctive centromeric (Cen) and telomeric (Tel) gene-content motifs. Aiming to develop a donor selection strategy to improve transplant outcome, we compared the contribution of these motifs to the clinical benefit conferred by B haplotype donors. We KIR genotyped donors from 1409 unrelated transplants for acute myelogenous leukemia (AML; n = 1086) and acute lymphoblastic leukemia (ALL; n = 323). Donor KIR genotype influenced transplantation outcome for AML but not ALL. Compared with A haplotype motifs, centromeric and telomeric B motifs both contributed to relapse protection and improved survival, but Cen-B homozygosity had the strongest independent effect. With Cen-B/B homozygous donors the cumulative incidence of relapse was 15.4% compared with 36.5% for Cen-A/A donors (relative risk of relapse 0.34; 95% confidence interval 0.2-0.57; P < .001). Overall, significantly reduced relapse was achieved with donors having 2 or more B gene-content motifs (relative risk 0.64; 95% confidence interval 0.48-0.86; P = .003) for both HLA-matched and mismatched transplants. KIR genotyping of several best HLA-matched potential unrelated donors should substantially increase the frequency of transplants by using grafts with favorable KIR gene content. Adopting this practice could result in superior disease-free survival for patients with AML.

Original languageEnglish (US)
Pages (from-to)2411-2419
Number of pages9
JournalBlood
Volume116
Issue number14
DOIs
StatePublished - Oct 7 2010

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KIR Receptors
Natural Killer Cell Receptors
Donor Selection
Acute Myeloid Leukemia
Transplants
Genes
Transplantation
Survival
Tissue Donors
Haplotypes
Recurrence
Unrelated Donors
Confidence Intervals
Immunogenetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Grafts
Disease-Free Survival
Genotype
Incidence

Cite this

Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. / Cooley, Sarah; Weisdorf, Daniel J.; Guethlein, Lisbeth A.; Klein, John P.; Wang, Tao; Le, Chap T.; Marsh, Steven G.E.; Geraghty, Daniel; Spellman, Stephen; Haagenson, Michael D.; Ladner, Martha; Trachtenberg, Elizabeth; Parham, Peter; Miller, Jeffrey S.

In: Blood, Vol. 116, No. 14, 07.10.2010, p. 2411-2419.

Research output: Contribution to journalArticle

Cooley, S, Weisdorf, DJ, Guethlein, LA, Klein, JP, Wang, T, Le, CT, Marsh, SGE, Geraghty, D, Spellman, S, Haagenson, MD, Ladner, M, Trachtenberg, E, Parham, P & Miller, JS 2010, 'Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia', Blood, vol. 116, no. 14, pp. 2411-2419. https://doi.org/10.1182/blood-2010-05-283051
Cooley, Sarah ; Weisdorf, Daniel J. ; Guethlein, Lisbeth A. ; Klein, John P. ; Wang, Tao ; Le, Chap T. ; Marsh, Steven G.E. ; Geraghty, Daniel ; Spellman, Stephen ; Haagenson, Michael D. ; Ladner, Martha ; Trachtenberg, Elizabeth ; Parham, Peter ; Miller, Jeffrey S. / Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. In: Blood. 2010 ; Vol. 116, No. 14. pp. 2411-2419.
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abstract = "Killer-cell immunoglobulin-like receptor (KIR) genes form a diverse, immunogenetic system. Group A and B KIR haplotypes have distinctive centromeric (Cen) and telomeric (Tel) gene-content motifs. Aiming to develop a donor selection strategy to improve transplant outcome, we compared the contribution of these motifs to the clinical benefit conferred by B haplotype donors. We KIR genotyped donors from 1409 unrelated transplants for acute myelogenous leukemia (AML; n = 1086) and acute lymphoblastic leukemia (ALL; n = 323). Donor KIR genotype influenced transplantation outcome for AML but not ALL. Compared with A haplotype motifs, centromeric and telomeric B motifs both contributed to relapse protection and improved survival, but Cen-B homozygosity had the strongest independent effect. With Cen-B/B homozygous donors the cumulative incidence of relapse was 15.4{\%} compared with 36.5{\%} for Cen-A/A donors (relative risk of relapse 0.34; 95{\%} confidence interval 0.2-0.57; P < .001). Overall, significantly reduced relapse was achieved with donors having 2 or more B gene-content motifs (relative risk 0.64; 95{\%} confidence interval 0.48-0.86; P = .003) for both HLA-matched and mismatched transplants. KIR genotyping of several best HLA-matched potential unrelated donors should substantially increase the frequency of transplants by using grafts with favorable KIR gene content. Adopting this practice could result in superior disease-free survival for patients with AML.",
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AU - Weisdorf, Daniel J.

AU - Guethlein, Lisbeth A.

AU - Klein, John P.

AU - Wang, Tao

AU - Le, Chap T.

AU - Marsh, Steven G.E.

AU - Geraghty, Daniel

AU - Spellman, Stephen

AU - Haagenson, Michael D.

AU - Ladner, Martha

AU - Trachtenberg, Elizabeth

AU - Parham, Peter

AU - Miller, Jeffrey S.

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AB - Killer-cell immunoglobulin-like receptor (KIR) genes form a diverse, immunogenetic system. Group A and B KIR haplotypes have distinctive centromeric (Cen) and telomeric (Tel) gene-content motifs. Aiming to develop a donor selection strategy to improve transplant outcome, we compared the contribution of these motifs to the clinical benefit conferred by B haplotype donors. We KIR genotyped donors from 1409 unrelated transplants for acute myelogenous leukemia (AML; n = 1086) and acute lymphoblastic leukemia (ALL; n = 323). Donor KIR genotype influenced transplantation outcome for AML but not ALL. Compared with A haplotype motifs, centromeric and telomeric B motifs both contributed to relapse protection and improved survival, but Cen-B homozygosity had the strongest independent effect. With Cen-B/B homozygous donors the cumulative incidence of relapse was 15.4% compared with 36.5% for Cen-A/A donors (relative risk of relapse 0.34; 95% confidence interval 0.2-0.57; P < .001). Overall, significantly reduced relapse was achieved with donors having 2 or more B gene-content motifs (relative risk 0.64; 95% confidence interval 0.48-0.86; P = .003) for both HLA-matched and mismatched transplants. KIR genotyping of several best HLA-matched potential unrelated donors should substantially increase the frequency of transplants by using grafts with favorable KIR gene content. Adopting this practice could result in superior disease-free survival for patients with AML.

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