Donor KIR2DS1 reduces the risk of transplant related mortality in HLA-C2 positive young recipients with hematological malignancies treated by myeloablative conditioning

Abstract

Background Recognition of HLA-C2 group alleles on recipient cells by activating killer immunoglobulin like receptors, KIR2DS1 on donor natural killer cells may lead to increased graft-versus-leukemia effect or immunomodulation in patients treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) influencing disease free and overall survival (OS). Objective In the present study, 314 consecutive, allo-HSCT recipient and donor pairs were included with retrospective donor KIR-genotyping and clinical parameters analyzes. Results After a median follow-up of 23.6 months, recipients with HLA-C2 group allele (rC2) showed improved (p = 0.046) OS if transplanted with KIR2DS1 positive donors (d2DS1) compared to those without one or both of this genetic attribute. Within the myeloablative conditioning (MAC) subgroup (n = 227), rC2 homozygous+d2DS1 patients (n = 14) showed a 5 years OS of 93% followed by rC2 heterozygous+d2DS1 patients (n = 48, 65%) compared to rC2 and/or d2DS1 negatives (47%, p = 0.018). Multivariate analyses indicated rC2+d2DS1 positivity as an independent predictor of OS (HR:0.47, 0.26–0.86, p = 0.014) besides donor type, presence of CMV-reactivation or chemoresistant disease. Among MAC-treated patients, the combined rC2+d2DS1 presence was associated with a markedly decreased cumulative incidence of transplant related mortality (p = 0.0045). Conclusion The combination of rC2+d2DS1 may be a favorable genetic constellation in allo-HSCT with MAC potentially reducing transplant related mortality.

Influence of KIR and NK Cell Reconstitution in the Outcomes of Hematopoietic Stem Cell Transplantation

“…Cooley et al observed that patients with AML with KIR-B/x donors experienced a 30% improvement in RFS compared with those with A/A donors ( 40 ). Subsequently, many further investigations confirmed this beneficial effect of the KIR-B haplotype on relapse and survival in patients with hematological malignancies ( 50 , 51 , 57 , 67 , 72 , 76 , 79 , 81 , 85 , 88 – 92 , 96 , 98 , 101 – 104 ). Five of these studies reported that the protection effects mainly existed in the KIR Cen-B locus ( 67 , 88 , 91 , 92 , 96 ).…”

“…In addition to the technique of adoptive transfer, many studies have analyzed the effects of innate donor-recipient NK cell alloreactivity on GVHD in a clinical setting. The majority of studies did not report a significant association between these parameters ( 41 – 44 , 46 , 47 , 50 , 51 , 54 – 56 , 59 , 65 , 66 , 79 , 81 , 83 , 87 – 89 , 91 – 93 , 97 , 98 , 102 , 104 ), while some reported a protective effect ( 70 , 74 , 76 ). Moreover, several studies found that KIR ligand mismatch or receptor-ligand mismatch increased the risk of GVHD ( 45 , 57 , 60 , 64 , 68 , 80 ).…”

“…Babor et al further suggested that the presence of Cen-B with absence of Tel-B improved leukemia control in pediatric patients with ALL ( 97 ). At the genetic level, the KIR2DS2 gene, which is located on the Cen-B motif ( 72 , 76 , 79 , 90 , 92 , 96 ), and the KIR2DS1 gene, located on the Tel-B motif ( 51 , 72 , 82 , 98 ), were found to be related to a decreased relapse rate or an improved survival. However, several studies found that Cen-B donors indicated a lower OS ( 56 , 70 , 100 ).…”

“…Although CMV reactivation suggests an immune-compromised state, patients who experienced CMV reactivation had a lower relapse rate or better survival ( 70 , 98 , 99 , 164 ). This protective effect might be attributed to the rapid maturation of NK cells.…”

Decreased iKIR-HLA C Pair Confers Worse Clinical Outcomes for Patients With Myeloid Disease Receiving Antithymocyte Globulin-Based Haploidentical Hematopoietic Stem Cell Transplantation

“…In many European studies, aKIRs, especially KIR2DS1 ( 37 – 39 ) and KIR2DS2 ( 40 , 41 ), have been shown to be associated with improved survival or reduced relapse. Yet, as reported in several studies from East Asia ( 42 – 45 ), aKIRs were not found to grant any survival advantage or relapse protection to the patients in our cohort.…”