KIR Haplotype B Donors but Not KIR-Ligand Mismatch Result in a Reduced Risk of Relapse After Haploidentical Hematopoietic Stem Cell Transplantation Using Reduced Intensity Conditioning and a CD3/CD19 Depleted Graft.
Authors: Michaelis Sebastian , Mezger Markus , Bornhauser Martin , Trenschel Rudolf , Stuhler Gernot , Stelljes Matthias , Mueller Lutz P , Baurmann Herrad , Federmann Birgit , Oevermann Lena , Kanz Lothar , Handgretinger Rupert , Bethge Wolfgang A. 
Published: October 2019

Abstract
Abstract 3101
Natural killer (NK) cell alloreactivity, after allogeneic hematopoietic cell transplantation (HCT) is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and human leukocyte antigen (HLA) class I ligands on recipient cells. Recently, a positive influence of KIR haplotype B versus haplotype A donors on the outcome of HLA-matched allogeneic HCT was demonstrated (Cooley et al., Blood 2010). Previously, Ruggeri et al. (Science 2002) reported the positive influence of KIR-ligand mismatch (MM) on outcome of haploidentical HCT (HHCT). Here we investigated the influence of the donor KIR haplotype and KIR-ligand MM on relapse of 57 patients with hematologic malignancies receiving HHCT after reduced intensity conditioning and graft CD3/CD19 depletion. 36 patients with AML, eight with ALL, four with multiple myeloma, four with NHL and one with MCL, CML, CMML, MDS, CLL, respectively (median age 45 years, range 19–61 years) were evaluated. Patients were “high risk” because of relapse (n=8), prior HCT (n=23), refractory disease (n=20) or cytogenetic risk (n=6). At HHCT, 29 patients were in complete remission (CR) and 28 in partial remission (PR). 15 KIR genes were determined by real-time PCR as described (Vilches et al., Tissue Antigens 2007, Alves et al., Tissue Antigens 2009), and donors were assigned the A/A or B/x haplotype. Patients and donors were HLA-typed by high-resolution molecular methods. Of the 57 donors, 17 had KIR haplotype A (29.8%) and 40 KIR haplotype B (70.2%). A KIR-ligand MM was found in 34 of 57 patients (59.6%). Cumulative incidence adjusted for competing risk showed no difference between KIR haplotype A or B patients regarding non-relapse mortality (NRM) (Gray's test: p=0.200), but a significantly reduced incidence of relapse for patients with a haplotype B donor (p=0.001). In particular, patients in PR benefited more from a haplotype B graft (p=0.008) than patients in CR (p=0.297). This resulted in a trend in the Kaplan-Meier estimated event free (EFS) at 3 years of 26.8 % for KIR haplotype B and 11.7 % for KIR haplotype A (HR=1.33 [CI=0.66–2.70], log rank test: p=0.422). In detail, all patients in PR died within 1.2 years when haplotype A donor cells were transplanted whereas 25% of haplotype B recipients were still alive after 3 years (HR=1.27 [CI=0.49–3.30], p=0.631). In comparison, 16.6% of haplotype A and 28.1% of haplotype B recipients in CR survived for more than 3 years (HR=1.46 [CI=0.54–3.94], p=0681). Surprisingly, KIR-ligand MM cumulative incidence curves were not statistically different for relapse (p=0680) or NRM (p=0.579). In addition, KIR-ligand MM resulted in a trend for decreased EFS rate for MM patients (17.6%) in contrast to matched patients (33.7%; HR=1.47 [CI=0.89–2.75], p=0.230). These effects were even more pronounced when analyzing the patient cohort with AML. Of the 36 donors, 10 showed KIR haplotype A (27.8%), 26 KIR haplotype B (72.2%) and KIR-ligand MM was present in 25 patients (69.4%). EFS at 3 years was prolonged for KIR haplotype B graft recipients (EFS: HR=2.29 [CI=0.88–5.96], p=0.087). In addition, cumulative incidence adjusted for competing risk analysis revealed a reduced incidence of relapse for patients with a haplotype B donor (all AML patients: p=0.079, AML in PR: p=0.049), but not for NRM (all AML patients: p=0.806, AML in PR: p=0.674). Again, KIR-ligand MM cumulative incidence curves were not significantly different for both relapse (p=0.126) and NRM (p=0.535). In line, KIR-ligand MM led to decreased EFS rate for MM patients (16.0%) in contrast to matched patients (53.0%; HR=2.27 [CI=1.08–5.06], p=0.045). Taken together, in the setting of RIC and CD3/CD19 depleted HHCT we could not confirm the positive data with KIR-ligand MM but observed a significant lower risk of relapse with a KIR haplotype B donor. We therefore conclude from our results that a donor KIR B haplotype should be favored as donor for HHCT using RIC and CD3/CD19 depletion in patients with hematological malignancies, particularly if no complete remission has been achieved prior to HHCT.

Disclosures:
Off Label Use: off lable use of drugs for conditioning.