Killer-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic, and some KIR2DL1 alleles (ie, KIR2DL1-R245) encode receptors characterized by stronger signaling function than others (ie, KIR2DL1-C245). In a study reported in the Journal of Clinical Oncology, Rafijul Bari, PhD, of St. Jude Children’s Research Hospital, Memphis, and colleagues investigated whether outcomes of pediatric allogeneic hematopoietic stem cell transplantation are affected by donor KIR2DL1 polymorphism.1 They found that patients receiving a donor graft with the functionally stronger KIR2DL1-R245 allele had significantly improved overall survival and progression-free survival.
Study Details
The study involved 313 pediatric patients undergoing allogeneic hematopoietic stem cell transplantation at St. Jude Children’s Research Hospital between January 1, 2000, and January 1, 2010. Donor KIR2DL1 functional allele typing was retrospectively performed using a single nucleotide polymorphism assay. The functionally stronger KIR2DL1 allele has arginine at amino acid position 245 (KIR2DL1-R245), and the functionally weaker allele has cysteine at the same position (KIR2DL1-C245).
Patients had a median age of 9.9 years at transplantation (range, 1 month to 18.6 years). The primary diagnoses included 231 hematologic malignancies (lymphoid in 116 patients, myeloid in 115; total 74%), 25 solid tumors (embryonal tumors in 19 patients, bone sarcomas in 6; total 8%), and 57 nonmalignant diseases (marrow failure in 10 patients, genetic diseases in 47 patients; total 18%). Of 256 patients with cancer, 143 (56%) were in remission and 113 (44%) had persistent disease at the time of transplantation.
A total of 175 patients (56%) received a conditioning regimen including total-body irradiation. The majority (77%) of regimens were myeloablative, defined as total-body irradiation ≥ 5 Gy in single dose or ≥ 8 Gy fractionated, busulfan (Busulfex, Myleran) > 9 mg/kg, or melphalan > 150 mg/m2. Grafts were obtained from matched-sibling donors in 27% of recipients, matched-unrelated donors in 31%, and haploidentical donors in 41%.
Among the 313 donors, 215 (69%) were homozygous for KIR2DL1-R245 (RR; RR), 22 (7%) were homozygous for KIR2DL1-C245 (CC; CC), and 76 (24%) were heterozygous for KIR2DL1-R245/C245 (RC; RC). KIR2DL1-R245 was associated with centromeric A–containing haplotypes and KIR2DL1-C245 with centromeric B haplotypes (P < .00001). There was no significant difference among the three allelic groups for any other demographic or transplantation variables.
Survival
Compared with the patients who received a CC donor graft, the risk of death after hematopoietic stem cell transplantation was significantly lower in those who received an RR graft (hazard ratio [HR] = 0.4, P < .0001) or an RC graft (HR = 0.42, P = .0013), with the estimate of survival probability in patients receiving an RR or RC graft being significantly greater than that in patients receiving a CC graft (P = .0004). There was no difference in survival associated with RR vs RC grafts.
CC grafts were associated with the worst survival rates among 256 patients with malignancy (P = .001) and among 231 with hematologic malignancy (P = .0007). Patients with acute myeloid leukemia (AML) and those with acute lymphoblastic leukemia (ALL) had similar survival probabilities in all three donor KIR2DL1 allele groups (all P ≥ .71).
The effects of donor KIR2DL1 alleles were comparable in the sibling donor, unrelated donor, and haploidentical donor hematopoietic stem cell transplantation subgroups, in T-cell–depleted and T-cell–replete graft subgroups, and in the myeloablative hematopoietic stem cell transplantation subgroup. Differences between the RR and RC vs CC grafts were not significant in the nonmyeloablative subgroup.
In addition to donor KIR2DL1 polymorphism, primary disease, T-cell depletion, and conditioning intensity were also significantly associated with survival on univariate analysis. In multivariate analysis adjusting for these factors, survival remained significantly longer in patients receiving an RR (HR = 0.4, P < .0001) or RC graft (HR = 0.44, P = .0024) vs a CC graft.
Progression-Free Survival
On univariate analysis, progression-free survival in 256 patients with cancer was significantly greater in those with an RR (HR = 0.42, P = .0003) or RC graft (HR = 0.48, P = .0075) vs a CC graft, with no difference observed between RR and RC groups. RR and RC grafts were also associated with significantly prolonged progression-free survival among the 231 patients with hematologic malignancies (P = .01).
There was no significant difference in risk of progression between AML and ALL patients according to the three donor KIR2DL1 allele groups (all P ≥ .54). On multivariate analysis, progression-free survival remained significantly longer in the RR group (HR = 0.38, P= .0001) and RC group (HR = 0.45, P= .0049) vs the CC group.
Graft vs Host Disease
Grade II to IV graft-vs-host disease was present in 25% of the RR group, 32% of the RC group, and 27% of the CC group, with no significant correlation between graft-vs-host disease and donor KIR2DL1polymorphism.
Effects of Receptor-Ligand Mismatch
Among the 231 patients with hematologic malignancies, the 5-year survival rate was 48% in those in the RR or RC groups who were HLA-C receptor-ligand mismatched (P < .001 vs CC group), compared with 31% among those in the RR or RC groups who were not HLA-C receptor-ligand mismatched (P = .02 vs CC group) and 0% in the CC group with or without receptor-ligand mismatch. The cumulative incidence of disease progression was lowest in patients in the RR or RC groups who were HLA-C receptor-ligand mismatched (P < .001 vs CC group; P = .02 for RR or RC group patients who were not HLA-C receptor-ligand mismatched vs CC group).
The investigators concluded, “Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic [hematopoietic stem cell transplantation]. These findings have substantial implications for prognostication and donor selection.” ■
Disclosure: The study was supported in part by the National Institutes of Health, the Assisi Foundation of Memphis, and the American Lebanese Syrian Associated Charities. Drs. Bari and Wing Leung (also of St. Jude Children’s Research Hospital) hold the patent for the single nucleotide polymorphism assay used for killer-cell immunoglobulin-like receptor allele typing. Dr. Leung is the corresponding author for the Journal of Clinical Oncology article. For full disclosures of the study authors, visit jco.ascopubs.org.
Reference
1. Bari R, Rujkijyanont P, Sullivan E, et al: Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 31:3782-3790, 2013.
