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Natural killer (NK) cells play an important role in the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) by promoting engraftment, preventing acute graft-versus-host disease (GvHD), supporting immune reconstitution, and reducing the risk of leukemic relapse.1,2 Their activity is influenced by signaling via activating and inhibitory receptors.
Killer-cell immunoglobulin-like receptors (KIRs) upon binding to HLA class I epitopes can impede NK cell’s ability to recognize and eliminate malignant target cells. Therefore, a donor’s KIR gene haplotype influences the outcome of allo-HSCT for acute myeloid leukemia (AML). A transplant from donors with a KIR B haplotype has been reported to protect against relapse after myeloablative unrelated donor (MUD) allo-HSCT for AML.3,4
Previous reports suggest that conditioning regimen (reduced-intensity conditioning, RIC vs myeloablative conditioning, MAC) can affect NK cell reconstitution, that correlates with clinical outcomes.5 Although MAC MUD allo-HSCT has been shown to improve relapse protection and increase disease-free survival (DFS) in recipients of donors with KIR B haplotype, the impact of RIC in this setting has not been previously examined.5
A stronger protection from relapse for KIR B haplotype donors, has been demonstrated for recipients with the C1 epitope, and with a HLA-C-mismatched transplant, including HLA-C1/C2 mismatch.5
Daniel Weisdorf, University and Minnesota, US, and colleagues evaluated whether the impact of MUD KIR genotype on transplant outcome for patients with AML has changed due to improvements in transplant practice in recent years.6
Patient and donor demographics, transplant approach, and outcome data were collected between 2012–2016 from the prospective KIR DS trial7 and the contemporaneous cohort, through the Center for International Blood and Marrow Transplant Research. KIR genotypes for the contemporaneous cohort were collected retrospectively through the typing project of the National Marrow Donor Program.8 Donor KIR genotypes were used to assign KIR AA or Bx haplotypes. KIR haplotype is defined by the number and composition of activating and inhibitory genes. The KIR A haplotype is characterized by the presence of seven KIR genes, including six inhibitory and one activating. The KIR B haplotype is characterized by the presence of a varied number of KIR genes, with at least one activating KIR and two inhibitory genes. The impact of demographic and donor KIR genotype on relapse incidence, non-relapse mortality (NRM), DFS, and overall survival (OS) was evaluated in patients receiving MAC vs RIC.
Previous data showed a protective role of donor KIR B haplotype after myeloablative unrelated donor (MUD) allo-HCT for AML, with recipients having lower risk of relapsed. Transplant using KIR AB and BB vs AA haplotype donor, significantly reduced the risk of relapse (HR = 0.77; 95% CI, 0.62–0.97; p = 0.026) and increased DFS (HR = 0.84; 95% CI, 0.72–0.99; p = 0.038), especially in patients with the fully HLA-matched donors (Table 1).
CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; KIR, killer-cell immunoglobulin-like receptor |
||||
Factor | n | HR | 95% CI | p value |
---|---|---|---|---|
Relapse | ||||
Donor KIR haplotype AA Bx |
334 730 |
1 0.77 |
|
0.026
0.026 |
Cytogenetics | 0.0025 | |||
Disease status Early Advanced |
83 79 |
1 3.97 |
|
0.001
0.0003 |
DFS | ||||
HLA matched alleles 7/8 8/8 |
145 917 |
1 0.78 |
|
0.042
0.042 |
Cytogenetics | 0.0012 | |||
Disease status Early Intermediate Advanced |
836 218 8 |
1 1.18 3.01 |
1.22–7.4 |
0.022
0.085 0.017 |
Recipient CMV status | 0.035 |
There was a lower risk of relapse and a longer DFS with donor KIR Bx haplotypes in HLA-C1/x vs C2/C2 recipients (HR, 0.76; 95% CI, 0.61–0.97; p = 0.024 and HR, 0.85; 95% CI, 0.72–0.99; p = 0.04, respectively). Those patients also had greater OS (HR, 0.82; 95% CI, 0.68–0.98; p = 0.029).
The data demonstrated that transplants from KIR B haplotype donors where recipients expressed the C1 epitope of HLA-C offered a significantly reduced risk of leukemia relapse and improved DFS after RIC allo-HSCT. Conditioning using fully myeloablative regimens did not offer such benefits. The authors believe that the findings are important as RIC is commonly used in the current allo-HCT practice. Therefore, selection of KIR B donors for MUD allo-HSCT could offer significant relapse protection in patients with AML undergoing allo-HSCT.
Farag SS, Fehniger TA, Ruggeri L, Velardi A, Caligiuri MA. Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood. 2002;100(6):1935–1947. DOI: 10.1182/blood-2002-02-0350
Cooley S, McCullar V, Wangen R, et al. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood. 2005;106(13):4370–4376. DOI: 10.1182/blood-2005-04-1644
Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010;116(14):2411–2419. DOI: 10.1182/blood-2010-05-283051
Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Blood. 2009;113(3):726–732. DOI: 10.1182/blood-2008-07-171926
Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor killer cell Ig-like receptor B haplotypes, recipient HLA-C1, and HLA-C mismatch enhance the clinical benefit of unrelated transplantation for acute myelogenous leukemia. J Immunol. 2014;192(10):4592–4600. DOI: 10.4049/jimmunol.1302517
Weisdorf D, Cooley S, Wang T, et al. KIR B donors improve the outcome for AML patients given reduced intensity conditioning and unrelated donor transplantation. Blood Adv. 2020;4(4):740–754. DOI: 10.1182/bloodadvances.2019001053
Weisdorf D, Cooley S, Wang T, et al. KIR Donor Selection: Feasibility in Identifying better Donors. Biol Blood Marrow Transplant. 2019;25(1):e28–e32. DOI: 10.1016/j.bbmt.2018.08.022
Howard CA, Fernandez-Vina MA, Appelbaum FR, et al. Recommendations for donor human leukocyte antigen assessment and matching for allogeneic stem cell transplantation: consensus opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow Transplant. 2015;21(1):4–7. DOI: 10.1016/j.bbmt.2014.09.017
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