Donor killer-cell immunoglobulin-like receptor (KIR) genotype does not improve graft-versus-leukemia responses in chronic lymphocytic leukemia (CLL) after unrelated donor transplant: a CIBMTR analysis

Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with CLL leading to 40–45% long-term survival. The impact of donor KIR genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. Methods: We examined 573 adult (URD)-CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Results: Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved OS were reduced intensity conditioning (HR of death 0.76) and good performance status (HR 0.46), while allo-HCT in non-remission (HR 1.96) and mismatched donors (HR 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A vs B/x KIR haplotypes and those with KIR gene content scores of 0 vs 1 vs ≥2 yielded similar rates of non-relapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival (PFS) and overall survival (OS). Relapse risk was not different with grafts from donors with KIR3DL1 transplanted into HLA C1/1 vs C2 recipients. Conclusion: This large analysis failed to demonstrate an association between unrelated donor KIR genotype and transplant outcome for patients with CLL and thus KIR genotyping should not be used as a donor selection criterion in this setting. Stored donor samples were genotyped for the presence or absence of KIR genes. Outcome data were collected from the CIBMTR. Patient-related variables in the analysis included age, sex, coexistence of disease or organ impairment, Karnofsky and comorbidity scores, donor-recipient HLA match status and recipient HLA-based KIR ligands. Disease-related characteristics including presence/absence of chromosome 17p, immunoglobulin heavy-chain variable (IGHV) mutation status; Rai stage, lactate dehydrogenase levels, presence of bulky adenopathy at the time of HCT and fludarabine responsiveness were examined in the CIBMTR database; these variables were missing for many subjects and not included in the analysis. Disease status at transplantation was recorded by a center as complete response (CR), partial response (PR), partial response nodal (nPR), stable disease (SD) and progressive disease (PD). Transplant-related variables included the type of preparative regimen (myeloablative [MA], reduced-intensity conditioning [RIC], or non-myeloablative [NMA]), graft source (bone marrow versus peripheral blood), use of antithymocyte globulin and/or alemtuzumab, type of graft-versus-host disease (GVHD) prophylaxis, number of lines of therapy and transplant period. The study protocol was approved by the Institutional Review Board of the NMDP in accordance with the Declaration of Helsinki. Donor KIR genotyping was performed via gene specific or group specific multiplex polymerase chain reaction and next generation sequencing (Illumina, CA) for 16 individual killer immunoglobulin receptor (KIR) genes: KIR2DL1–5, KIR2DS1–5, KIR3DL1–3, KIR3DS1, KIR2DP1 and KIR3DP1. Sequences were analyzed using an American Society of Histocompatibility and Immunogenetics approved multiplex KIR typing algorithm developed by Histogenetics (using IMGT KIR database v2.6.0), and each KIR gene is defined as present or absent. We identified A and B KIR haplotypes and assigned donor genotypes (A/A or B/x). For B/x donors, we further determined whether their B-defining genes were in the centromeric or telomeric part of the KIR locus, or in both (Cen AA vs B/x, Tel AA vs B/x). 10 The KIR B–gene motifs content score (KIR B-score) for each donor was calculated as the sum of centromeric and telomeric gene-content motifs containing B haplotype–defining genes (values ranged from 0–4). 8