The Association of HLA-E Ligand and NKG2 Receptor Variation with Relapse and Mortality after Haploidentical Related Donor Transplantation

Effie W Petersdorf; Caroline McKallor; Mari Malkki; Katherine Hsu; Meilun He; Stephen R Spellman; Theodore Gooley; Philip Stevenson

doi:10.1016/j.jtct.2025.01.004

The Association of HLA-E Ligand and NKG2 Receptor Variation with Relapse and Mortality after Haploidentical Related Donor Transplantation

Transplant Cell Ther. 2025 Jan 9:S2666-6367(25)00005-3. doi: 10.1016/j.jtct.2025.01.004. Online ahead of print.

Authors

Effie W Petersdorf¹, Caroline McKallor², Mari Malkki², Katherine Hsu³, Meilun He⁴, Stephen R Spellman⁴, Theodore Gooley⁵, Philip Stevenson⁵

Affiliations

¹ Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA; University of Washington School of Medicine, Seattle, WA. Electronic address: epetersd@fredhutch.org.
² Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA.
³ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
⁴ Center for International Blood and Marrow Transplant Research, National Marrow Donor Program/Be The Match, Minneapolis, MN.
⁵ Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA.

PMID: 39798802
DOI: 10.1016/j.jtct.2025.01.004

Abstract

Background: Recurrence of blood malignancy is the major cause of mortality after hematopoietic cell transplantation. NKG2 receptor/HLA-E ligand complexes play a fundamental role in the surveillance and elimination of transformed cells but their role in the control of leukemia in transplantation is unknown.

Objective: We tested the hypothesis that gene variation of patient and/or donor HLA-E ligand and donor NKG2C-NKG2A receptors are associated with the risks of relapse and mortality (primary endpoints) and GVHD and non-relapse mortality (secondary endpoints) after haploidentical transplantation.

Study design: We retrospectively defined donor NKG2 receptor haplotypes and patient HLA-E ligands in 1629 haploidentical related transplantations. HLA-E residue 107 was genotyped in patients and donors. Single nucleotide polymorphisms descriptive of NKG2C and NKG2A haplotypes were characterized in donors. Overall mortality, relapse, non-relapse mortality and chronic GVHD were studied using Cox regression models. Acute GVHD was studied by logistic regression.

Results: The hazard of relapse for patients transplanted from NKG2C-del/del donors was 51% lower than that from wt/wt donors (hazard ratio, HR, 0.49 [95% confidence interval, CI, 0.26-0.89) contributing to a HR for mortality of 0.62 (95% CI, 0.38-1.02). The HR of mortality among patients transplanted from a donor with 2 vs. 0 copies of the NKG2A rs35909400-rs2734440-rs12824474 CCC haplotype was HR 2.28 (95% CI, 1.34-3.86). The HRs of mortality for ArgArg and ArgGly patients compared to GlyGly patients were 1.42 (95% CI, 1.11-1.82) and 1.43 (95% CI, 1.13-1.81), respectively. Hazard ratios for non-relapse mortality for patients with ArgGly or ArgArg genotypes compared to patients with GlyGly genotype were HR 1.60 (95% CI, 1.06-2.41) and HR 1.79 (95% CI, 1.21-2.66), respectively. Assessment of donor receptor/patient ligand pairings showed that among Arg-positive patients, the HR of mortality from donors with any wt-CCC/CCC haplotype was HR 2.52 (95% CI, 1.45-4.38) relative to donors with any wt-non CCC/CCC haplotype.

Conclusions: The success of haploidentical transplantation may be defined by the cumulative effects of donor NKG2 receptor and patient HLA-E ligand polymorphisms. Patient HLA-E ligand and donor NKG2C-NKG2A receptor haplotypes shed new light on their role in the control of malignancy.

Keywords: HLA-E ligand; NKG2 receptor; haploidentical transplantation; haplotypes; relapse; survival.