Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study

Abstract

SummaryBackgroundWhile 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).MethodsThis 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.FindingsAmong 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.InterpretationCMV 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.FundingMerck & Co., Inc., National Institute of Health (K23-AI097234, K24HL093294, HL088021, CA78902, CA18029, HL122173)

Sirolimus exposure and the occurrence of cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation

“…These models were implemented as shown in Equation 4: where k a is the activation rate constant, k a_0 is the activation rate constant when tacrolimus and sirolimus concentrations are 0, θ T is the parameter quantifying the effect of tacrolimus concentration, C T is the concentration of tacrolimus, θ S is the parameter quantifying the effect of sirolimus concentration, and C s is the concentration of sirolimus. A negative exponential model was used to describe the effect of sirolimus on k a , preventing k a, values from becoming negative at high sirolimus concentrations.…”

“…[10][11][12][13][14] Allo-HSCT is also characterized by shorter sirolimus exposure times (the scheduled reduction of immunosuppressant drugs promotes the immunotolerance phenomena), the more common use of drugs with potential drug-drug interactions (ie, triazoles), and with conditions related to variable absorption capacities (mucositis, nausea, vomiting, and/or diarrhea associated with conditioning regimens, drugs, or graft-versus-host disease [GvHD]) that produce large concentration fluctuations and/ or treatment interruptions. However, CMV DNAemia is a common and complex phenomenon after allo-HSCT (>70% of the recipients) 4,12 and its analysis is particularly challenging. Exposure-response analyses are of utmost importance because exposure variability results in different anti-CMV activity patterns for different drugs.…”

Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6

“…High-level CMV reactivation was defined as more than 1000 CMV DNA copies/ mL plasma or more than 10 pp65 antigen-positive cells per 200 000 peripheral blood leukocytes. 22,23 Overall mortality was defined as mortality occurring for any reason. Nonrelapse mortality (NRM) was defined as mortality occurring for reasons other than relapse in patients receiving myeloablative HCTs or for reasons other than relapse or progression of underlying disease in patients receiving nonmyeloablative HCTs.…”

Co-Infections by Double-Stranded DNA Viruses after Ex Vivo T Cell–Depleted, CD34+ Selected Hematopoietic Cell Transplantation

“…An association between CMV viral load with lower survival has been recently reported 25 and corroborated in the prospective study of CMV prevention with letermovir 18 . A larger sample size or longer follow up may have demonstrated significant differences in TCD recipients.…”