Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation

Abstract

Purpose: Killer-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic. Some KIR2DL1 alleles encode receptors that have stronger signaling function than others. We tested the hypothesis that the clinical outcomes of allogeneic hematopoietic stem-cell transplantation (HSCT) could be affected by donor KIR2DL1 polymorphism.

Patients and methods: All 313 pediatric patients received allogeneic HSCT at a single institution. Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay.

Results: Patients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R(245)) had better survival (P = .0004) and lower cumulative incidence of disease progression (P = .001) than those patients who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C(245)). The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia or acute lymphoblastic leukemia among all allele groups (P ≥ .71). Patients who received a KIR2DL1-R(245)-positive graft with HLA-C receptor-ligand mismatch had the best survival (P = .00003) and lowest risk of leukemia progression (P = .0005) compared with those who received a KIR2DL1-C(245) homozygous graft.

Conclusion: Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic HSCT. These findings have substantial implications for prognostication and donor selection.

Fig 1.

Survival of patients stratified by donor KIR2DL1 functional allelic groups. Shown are the overall survival of (A) the entire cohort of 313 transplantation recipients, (B) the 256 patients with malignant disease, (C) the 231 patients with a hematologic malignancy, and (D) the patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) displayed separately after receiving a KIR2DL1-R²⁴⁵ homozygous (RR), KIR2DL1-R²⁴⁵/C²⁴⁵ heterozygous (RC), or KIR2DL1-C²⁴⁵ homozygous (CC) graft. P_RR/RC, P value between RR and RC group; P_RR,RC/CC, P value comparing RR and RC groups with CC group; ALL:RR, patients with ALL who received an RR donor graft; ALL:RC, patients with ALL who received an RC donor graft; ALL:CC, patients with ALL who received a CC donor graft; AML:RR, patients with AML who received an RR donor graft; AML:RC, patients with AML who received an RC donor graft; AML:CC, patients with AML who received a CC donor graft; P×RR,RC/CC, P value when comparing RR and RC groups with CC group for patients with the diagnosis of AML or ALL as indicated; P_RR, P_RC, and P_CC, P values when comparing ALL and AML patients who received a similar RR, RC, or CC donor graft.

Fig 2.

Cumulative incidence of disease progression after transplantations stratified by donor KIR2DL1 functional allelic groups. Shown are the cumulative incidence (CI) of disease progression or relapse in (A) 256 patients with malignancy, (B) 231 patients with hematologic malignancy, and (C) patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) displayed separately after receiving a KIR2DL1-R²⁴⁵ homozygous (RR), KIR2DL1-R²⁴⁵/C²⁴⁵ heterozygous (RC), or KIR2DL1-C²⁴⁵ homozygous (CC) graft. Deaths unrelated to disease were considered competing events. ALL:RR, patients with ALL who received an RR donor graft; ALL:RC, patients with ALL who received an RC donor graft; ALL:CC, patients with ALL who received a CC donor graft; AML:RR, patients with AML who received an RR donor graft; AML:RC, patients with AML who received an RC donor graft; AML:CC, patients with AML who received a CC donor graft; P_RR,RC/CC, P value when comparing RR and RC groups with CC group; P_RR/RC, P value between the RR and RC groups; P_RR, P_RC, and P_CC indicate the P values when comparing ALL and AML patients who received a similar RR, RC, or CC donor graft.

Fig 3.

Survival and cumulative incidence (CI) of disease progression stratified by donor KIR2DL1 allelic groups and the presence of HLA-C receptor-ligand mismatch. Shown are the (A) overall survival probability and (B) CI of disease progression or relapse among different groups of patients with hematologic malignancy. Group 1, patients with a KIR2DL1-R²⁴⁵ homozygous (RR) or KIR2DL1-R²⁴⁵/C²⁴⁵ heterozygous (RC) donor and HLA-C receptor-ligand mismatch; group 2, patients with a KIR2DL1 RR or RC donor but not HLA-C receptor-ligand mismatched; group 3, patients who received a KIR2DL1-C²⁴⁵ homozygous (CC) graft with or without HLA-C receptor-ligand mismatch. P_{group 1/group 3}, P value between group 1 and group 3; P_{group 2/group 3}, P value between group 2 and group 3.

Fig A1.

Overall survival stratified by donor KIR2DL1 functional allelic groups. (A) Survival of patients who received a graft from a haploidentical (H), sibling (S), or unrelated (U) donor. (B) Survival of patients who received a T cell depleted (yes) or replete (no) graft. (C) Survival of patients who received a myeloablative (yes) or nonmyeloablative (no) conditioning. CC, KIR2DL1-C²⁴⁵ homozygous graft; P_RR, P_RC, and P_CC, P values when comparing patients who received a similar RR, RC, or CC donor graft, respectively; P×_RR, _RC/CC, P value when comparing the RR and RC groups with the CC group in the corresponding subset; RC, KIR2DL1-R²⁴⁵/C²⁴⁵ heterozygous graft; KIR2DL1-R²⁴⁵ homozygous graft.