Evaluation of Donor KIR2DL1 Allelic Polymorphism in the Setting of T-Cell Repleted Haploidentical Transplantation

Introduction:  Killer-cell immunoglobulin-like receptors (KIRs) are highly polymorphic. Donor KIR2DL1-R 245 polymorphism has been associated with stronger signalling function than others. Our aim is to evaluate this donor polymorphism in the setting of T cell-repleted haploidentical hematopoietic stem-cell transplantation (HSCT) with post-infusion high-dose cyclophosphamide (PiCy).

Patients and Methods Thirty-nine adult patients who underwent T-cell repleted haploidentical HSCT with PiCy in a single centre were included.  Median age was 41 (r: 19-65). Diagnosis was: Hodking Lymphoma 11 (28%), Acute Myeloid Leukemia 14 (35%), Myelodisplastic Syndrome 3 (8%), Acute Lymphoblastic leukemia 4 (11%), Myeloproliferative Syndromes 1 (2%), Non-Hodking Lymphoma 4 (11%), Multiple Myeloma 2 (5%). Conditioning regimen was: myeloablative in 16 patients and reduced intensity in 23 patients. The donor-patient kinship was: father in 5 cases (5%), mother in 10 cases (26%), sibling in 17 cases (44%) and son/daughter in 7 cases (18%). Donor KIR2DL1 functional allele typing was retrospectively performed using single nucleotide polymorphism assay (Bari et al, Clinical Immunology 2011). KIR genotype was analyzed by PCR (KIR Typing, Miltenyi Biotec) using genomic DNA purified by the (Maxwell 16 Blood DNA Kit, Promega) from peripheral blood examples. KIR amplicons were visualized with ethidium bromide after agarose gel electrophoresis. HLA typing was used to identify HLA class I KIR ligands: HLA-C alleles with a Lys80 residue (C2 alleles), HLA-C with an Asn80 residue (C1 alleles), and HLA-B alleles with Bw4 and Bw6 specificity.

Results Donor KIR2DL1 polymorphism was: KIR2DL1-R 245 homozygous 26 (66.6%), KIR2DL1-R 245/C245 13 (33,3%), KIR2DL1-C 245 homozygous 0 (0%). Donor KIR haplotipe was A-A in 4 (12%) and Bx in 34 (87%). Patient haplotype was A-A in 7 (18%) and Bx in 32 (82%). Thirteen patients received a KIR2DL1-R 245 homozygous graft with HLA-C ligand-receptor mismatch, 13 patients received a KIR2DL1-R 245 graft with no HLA-C ligand-receptor mismatch and 12 patients received a KIR2DL1-R 245/KIR2DL1-C245 graft. We did not find event free survival (EFS) differences between patients who received a KIR2DL1-R 245 homozygous graft or a KIR2DL1-R 245/KIR2DL1-C245 graft (67% vs 68% p=0.37). However, patients who received a KIR2DL1-R 245 graft with HLA-C ligand-receptor mismatch had a marked tendency to better event free survival (EFS) compared with those who received a graft with KIR2DL1-R 245 and no HLA-C ligand-receptor mismatch, (80% vs 100%  respectively, p=0.057) one year after transplant

Conclusion Donor KIR2DL1-R 245 allelic polymorphism associated with KIR HLA-C ligand-receptor mismatch could affects recipient outcomes after T cell-repleted haploidentiacal HSCT with PiCy. These findings could have significant repercussion for donor selection.