Impact of KIR/HLA Incompatibilities on NK Cell Reconstitution and Clinical Outcome after T Cell–Replete Haploidentical Hematopoietic Stem Cell Transplantation with Posttransplant Cyclophosphamide

Abstract

Little is known regarding the effect of KIR/HLA incompatibilities (inc.) in the setting of T-replete haploidentical allogeneic hematopoietic stem cell transplantation using posttransplant cyclophosphamide (PTCy). In this retrospective study, the impact of KIR/HLA inc. on clinical outcomes and NK cell reconstitution was studied in a cohort of 51 consecutive patients receiving a T cell–replete haploidentical allogeneic hematopoietic stem cell transplantation after a reduced-intensity conditioning using peripheral blood stem cells as the source of the graft and PTCy as graft-versus-host disease (GvHD) prophylaxis. The NK cell repertoire reconstitution was examined by multiparameter flow cytometry in 34 of these 51 patients from day 0 to day 100 posttransplant. Genetic KIR2DL/HLA inc. were found to be significantly associated with more GvHD (81.2 versus 45.7%, p = 0.01) and less relapse (6.2 versus 42.8%, p = 0.008) in this context. GvHD is associated with increased levels of differentiated and activated NK cells. A significant loss of KIR2DL2/3+ NK cells was observed at day 30 in patients with inhibitory KIR/HLA inc., suggesting that responsive KIR NK cells are particularly targeted by the immunosuppressive PTCy treatment. Further investigations are needed from a larger cohort with an identical clinical approach to consolidate these results and to identify the NK cell subsets that may be beneficial for the graft-versus-leukemia effect observed. Because many haploidentical donors can be identified in a family, the prediction of KIR NK cell alloreactivity could be of crucial importance for donor selection and patient outcome.

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

“…Moreover, the potency of the relapse protection positively correlated with the number of receptor-ligand mismatch pairs ( 39 ). Subsequently, the protective effect of receptor-ligand mismatch has been confirmed by many investigations ( 58 , 59 , 66 , 69 , 71 , 73 , 76 , 79 , 80 ). Moreover, a survival advantage was also observed in patients with receptor-ligand mismatch compared with receptor-ligand matched pairs ( 59 , 66 , 69 – 71 , 73 , 76 , 79 ).…”

“…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 ). Accordingly, two studies performed in China that applied the ‘Peking protocol’ for HSCT using the granulocyte-colony stimulating factor (G-CSF)-mobilized graft containing a high dose of T cells observed promotive effects of NK cell alloreactivity on GVHD ( 48 , 49 ).…”

Prospective phase 2 trial of ixazomib after nonmyeloablative haploidentical peripheral blood stem cell transplant

“…We hypothesized that this might promote improved engraftment, maintain the low GVHD and NRM rates inherent in this regimen, and augment NK cell-mediated cytotoxicity, which is believed to be important in HIDT-associated GVM effects. [24][25][26] Although the study failed to meet our statistically predefined goal of decreasing relapse risk, it did show durable engraftment in all patients, which was unexpected, given the historical experience of 10% graft failure with NMA HIDT-PTCy and a PBSC graft. Furthermore, NRM was low (12% at 3 years posttransplant) confirming the safety of this regimen.…”

Report from the Eleventh Killer Immunoglobulin‐like Receptor (KIR) Workshop: Novel insights on KIR polymorphism, ligand recognition, expression and function

“…Phenotypic analysis of NK cell repertoire reconstitution suggested that alloreactive NK cells can be activated and proliferate, but become particularly targeted by PTCy. She discussed the hypothesis that this activated context might promote the differentiation/activation of NK cells associated with GvL . Lena‐Marie Martin evaluated the relevance of maternal fetal microchimerism (FM) as donor criteria to select optimal haploidentical donor to cure pediatric leukemic patients.…”