Donor IFNL4 Genotype Is Associated with Transplant-Related Mortality after Unrelated Donor Myeloablative Hematopoietic Cell Transplantation in Patients with Acute Leukemia

Introduction. Interferon Lambda 4 gene (IFNL4) encodes IFN-λ4 protein, a new member of the type-III interferon family. IFNL4 genotype (rs368234815-dG allele), defines the genetic ability to produce IFN-λ4 and has been associated with reduced clearance of hepatitis C virus (HCV) infection. Given antiviral activity and immune modulation properties of IFN-λ4, we hypothesized that IFNL4 genotype of recipient and/or donor may modulate post-transplant survival outcomes, possibly through control of viral infections, and/or alloreactivity.

Methods. From the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we randomly selected 627 patients who received unrelated hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML, N=449) or acute lymphocytic leukemia (ALL, N=178). The patients had to match the following criteria: 1) HCT between 2004 and 2012, 2) available pre-HCT blood sample for the donor and recipient, 3) 8/8 HLA matching, and 3) myeloablative conditioning. IFNL4 genotyping was completed for 619 donors and 522 recipients using a custom-designed TaqMan assay for rs368234815. Multivariable Cox proportional hazard models were used for statistical analyses. Follow-up ended in November 2017.

Results. Median age at HCT was 40 years (range=<1-68). Most patients (66%, N=411) were in first complete remission, had a Karnofsky Performance Score (KPS) between 90-100% (70%, N=436), and received peripheral blood stem cell grafts (70%, N=439). The median post-HCT follow-up was 68 months (range=5-122). Donor IFNL4 genotype was associated with risk of transplant-related mortality (TRM); with 5 years probabilities=19%, 27%, and 30% for donor TT/TT (n=286), TT/dG (n=267), and dG/dG (n=64) genotypes, respectively, p=0.02. The results remained significant in multivariable analysis (p=0.002); compared with patients receiving HCT from donors with TT/TT genotype, with the HR=1.59 (95% CI=1.13-2.23, p=0.007) for TT/dG donors and HR=1.95 (95% CI=1.18-3.23, p=0.009) for dG/dG donors. The data suggested that donor IFNL4 genotype may also predict risk of disease-free survival (DFS; HR=1.43, 95% CI=1.02-2.00, p=0.03), and overall survival (OS; HR=1.40 (95% CI=0.98-1.99, p=0.06) for donor dG/dG genotype (Table1). No association between recipient genotype and any survival outcome was observed (p>0.05 for OS, DFS, and TRM)

Conclusions. Donor IFNL4 genotype is associated with risk of transplant-related mortality in patients with acute leukemia. The data suggest that avoiding donors with dG/dG genotype will improve HCT outcomes without limiting the potential donor pool. A validation study is needed; if confirmed, IFNL4 genotype may provide an added value to donor selection criteria.

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