Quantifying Cytomegalovirus-Specific T Cell Responses Prior to Hospital Discharge Allows Risk Stratification for Late Viral Reactivation after Allogenic Hematopoietic Cell Transplantation

• Published in: Biology of blood and marrow transplantation Vol. 25; no. 3; pp. S362 - S363
• Main Authors: Kiener, Richard, Stevens-Ayers, Terry L, Xie, Hu, Wagner, Ralf, Boeckh, Michael J
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.03.2019
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2018.12.587

Cytomegalovirus (CMV) infection remains a significant complication after allogenic hematopoietic cell transplantation (HCT). In the first three months after HCT, close monitoring of patients associated with prophylactic or preemptive administration of ganciclovir effectively prevents CMV-related complications. However, once patients are discharged from cancer centers around day 100 after HCT their risk of late CMV reactivation remains high. Since virus-specific T cells are capable of controlling CMV replication, we assessed whether their quantification shortly before hospital discharge allows risk-stratification for late CMV reactivation. Allogeneic HCT recipients of all ages at the Fred Hutchinson Cancer Research Center who were CMV-seropositive or had a CMV-seropositive donor and participated in a prospective immune monitoring study were analyzed if they received at least 50% of weekly scheduled viral load (VL) PCR tests between days 100 and 180 after transplantation. CMV-specific cellular immunity was quantified via interferon-gamma ELISpot assay from cryopreserved peripheral blood mononuclear cells (PBMC) that were collected around day 90 after HCT. Cells were stimulated with peptide pools spanning the entire IE-1 and pp65 proteins (15mers with 11 amino acid overlap). Univariate Cox regression analysis was performed to determine hazard ratios (HR) for developing CMV reactivation at ≥50 IU, ≥500, ≥1000 IU/mL using different threshold levels (10, 50, or 100 spot-forming units (SFU) per 200,000 PBMC) for IE-1 and pp65. 13 out of 69 patients (18.8%) in this cohort showed clinically significant viral reactivation between days 100 and 180 after HCT, defined as having a viral load ≥1000 IU/ml at least once during the observational period (this level is commonly used to start preemptive treatment in the late setting). The best separation of risk was achieved by using a threshold of 10 SFU for both antigens: Individuals with less than 10 SFU for IE-1 or pp65 had an increased risk for CMV reactivation (HR 8.49, 95% CI, p=0.04) compared to patients with at least 10 SFU for both antigens. Correspondingly, the cumulative incidence of CMV reactivation was significantly higher in the group of patients with <10 SFU for IE-1 or pp65 compared to patients who showed at least 10 SFU for both antigens (Figure 1). Reactivation events ≥1000 IU/mL throughout the study period also occurred almost exclusively in patients with less than 10 SFU for IE-1 or pp65 (Figure 2). Quantification of CMV-specific cellular immune responses around day 100 can help identify patients that are at risk for developing clinically significant late CMV reactivation. Both IE-1 and pp65 are useful for predicting CMV reactivation. Further studies with larger cohorts should be performed to confirm the suggested threshold levels of immune protection.