CMV Viral Load and Mortality after Hematopoietic Cell Transplantation: A Cohort Study in the Era of Preemptive Therapy

BACKGROUND: While CMV viral load (CMV-VL) is commonly used to guide preemptive therapy in the post-transplant setting, there is little data correlating viremia with clinical endpoints. We therefore investigated the association of CMV-VL with mortality in the first year after hematopoietic cell transplantation (HCT). METHODS: This cohort study included patients who received an allogeneic HCT between 01 January 2007 and 28 February 2013, were CMV seropositive or had a seropositive donor, and underwent weekly plasma CMV monitoring by PCR through day 100 post-transplant. Cox proportional hazards models were used to estimate the association of CMV-VL at different thresholds with overall by 1 year post-transplant, adjusting for the use of preemptive therapy and other factors such as neutropenia, and graft-versus-host disease. Secondary endpoints were non-relapse mortality and CMV end organ disease by 1 year post-transplant. FINDINGS: Among 926 patients, the cumulative overall mortality was 30·0% (95% CI 26·9–33·0) by 1 year. CMV-VL of ≥250 IU/ml was associated with increased risk of early (day 0–60 post-transplant) death (adjusted HR 18·1, 95% CI 8·8–37·4). The risk was attenuated after day 60 (adjusted HR 1·8, 95% CI 1·4–2·4). Similar associations were observed for higher CMV-VL thresholds. CMV-VL was also associated with increased risk of non-relapse mortality and demonstrated a dose-response relationship. The adjusted HR (95% CI) for CMV-VL of any positive CMV-VL below 500, 501–1000, and >1000 IU/ml were 1·4 (0·9–2·1), 2·6 (1·3–4·9), and 5·0 (3·1–8·1), respectively. INTERPRETATION: CMV viremia is associated with increased risk of overall and non-relapse mortality in the first year after HCT, independent of the use of preemptive therapy and with evidence of a postitive dose-response relationship. These data establish the suitability of viral load as a surrogate clinical endpoint for clinical trials for CMV vaccines, biologics, and drugs. FUNDING: Merck & Co., Inc., National Institute of Health (K23-AI097234, K24HL093294, HL088021, CA78902, CA18029, HL122173)