The surface protein on the donor’s natural killer cells appeared to affect survival after hematopoietic stem cell transplant in children with leukemia, according to research published online in the Journal of Clinical Oncology.
In a study of KIR2DL1 functional allelotyping, children who received hematopoietic stem cell transplants were more likely to survive and to do so without experiencing progressive disease if the donor had an arginine-containing KIR2DL1 allele rather than a cysteine-containing KIR2DL1 allele.
Compared to patients who received donor grafts with two cysteine-containing alleles, the hazard ratio (HR) for the risk of death was 0.4 (P = .0001) when donor grafts had two copies of the arginine-containing allele and 0.42 (P = .0013) when donor grafts had one copy of the arginine allele and one copy of the cysteine-containing allele. Hazard ratio for progression-free survival were, respectively, 0.42 (P = .0003) and 0.48 (P = .0075).
Dr. Wing Leung
Functional allele typing should be included when selecting donors for hematopoietic stem cell transplants, advised Rafijul Bari, Ph.D., and his associates (J. Clin. Oncol. 2013 [doi: 10.1200/JCO.2012.47.4007]). "HLA and KIR typing can be performed using the same blood sample collected from potential donors during routine HLA matching," and the process would not slow down donor work-up. Further, KIR allele typing and KIR ligand typing can be performed simultaneously in a day using SNP assays.
Killer-cell immunoglobulin-like receptors (KIRs) regulate natural killer (NK) cell activity. The genes that encode these receptor proteins are found on chromosome 19 and are highly polymorphic, with at least 15 forms identified. KIR2DL1 is present in approximately 90%-95% of healthy individuals.
Dr. Bari and his coworkers at St Jude Children’s Research Hospital in Memphis, where the transplants were all performed, have previously found that a KIR2DL1 allele that contains arginine rather than cysteine in position 245 of the transmembrane domain encodes receptors that have stronger signaling function (Blood 2009;114:5182-90).
Their current study tested the hypothesis that the arginine-containing allele (KIR2DL1-R245) and the cysteine-containing allele (KIR2DL1-C245) would have different effects on the clinical outcomes of allogenic hematopoietic stem cell transplants.
Between 2000 and 2010, 313 children underwent allogenic hematopoietic stem cell transplants. DNA samples from their donors were obtained and KIR2DL1 functional allelotyping was retrospectively performed using a single nucleotide polymorphism assay developed by Dr. Bari and his colleague, Dr. Wing Leung. HLA typing also was performed.
The median age of the recipient children at transplant was 9.9 years. The reason for transplant varied, but the majority (n = 231; 73%) underwent the procedure for hematologic malignancies.
"The effect of KIR2DL1 allelic polymorphism on the patterns of survival estimates was similar in patients with childhood AML [acute myeloid leukemia] or ALL [acute lymphoblastic leukemia] among all allele groups," the researchers reported.
When donor grafts had the arginine-containing allele, patients fared better if the donor grafts were mismatched for the HLA-C receptor ligand. The 5-year survival rate was 48% for mismatched and 31% for matched grafts, respectively. "In contrast, patients who received a donor graft with the weak [cysteine] allele had poor survival, regardless of the presence or absence of receptor-ligand mismatch," the researchers wrote.
"The results presented thus far provide evidence that the capacity of inhibitory KIRs expressed by licensed NK cells to destroy cell targets lacking their cognate HLA ligands depends not only on the missing ligand but also on the signaling potential of the inhibitory KIR expressed," observed Dr. Richard J. O’Reilly, chief of the pediatric bone marrow transplant service at Memorial Sloan-Kettering Cancer Center (MSKCC), New York in an editorial (J. Clin. Oncol. 2013 Sept. 16 [doi:10.1200/JCO.2013.50.2138]).
"If confirmed, this introduces an important new variable in the analysis of NK-cell–mediated leukemia resistance," he said.
The research was supported by a grant from the National Institutes of Health, the Assisi Foundation of Memphis, and the American Lebanese Syrian Associated Charities. Dr. Bari and Dr. Leung hold the patent for the KIRs SNP assay used in the study. Dr. O’Reilly has received honoraria from and has provided expert testimony to Miltenyi Biotec, a company that produces a KIR-typing kit.