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

Abstract

Background: Although cytomegalovirus viral load is commonly used to guide pre-emptive therapy in the post-transplantation setting, few data are available correlating viraemia with clinical endpoints. We therefore investigated the association between cytomegalovirus viral load and mortality in the first year after haemopoietic stem cell transplantation.

Methods: In this retrospective cohort study, we included patients from the Fred Hutchinson Cancer Research Center, WA, USA, who received an allogeneic haemopoietic stem cell transplantation between Jan 1, 2007, and Feb 28, 2013, were cytomegalovirus seropositive or had a seropositive donor, and underwent weekly plasma cytomegalovirus monitoring by PCR through to day 100 post-transplantation. Cox proportional hazards models were used to estimate the association of cytomegalovirus viral load at different thresholds with overall mortality by 1 year post-transplantation, adjusting for the use of pre-emptive therapy and other factors such as neutropenia, and graft-versus-host disease.

Findings: Of the 1037 patients initially selected for inclusion in this cohort, 87 (8%) patients were excluded because of missing cytomegalovirus testing and 24 (2%) were excluded because of their participation in cytomegalovirus prophylaxis trials. In the remaining 926 patients included in this study, the cumulative overall mortality was 30·0% (95% CI 26·9-33·0) 1 year after haemopoietic stem cell transplantation. 95 patients developed cytomegalovirus disease; death was directly attributable to cytomegalovirus disease in three (1%) of 263 patients who died in the first year after transplantation. A cytomegalovirus viral load of 250 IU/mL or greater was associated with increased risk of early (day 0-60 post-transplantation) death (adjusted hazard ratio [HR] 19·8, 95% CI 9·6-41·1). The risk was attenuated after day 60 (adjusted HR 1·8, 95% CI 1·3-2·3). Similar associations were noted for higher cytomegalovirus viral load thresholds.

Interpretation: Cytomegalovirus viraemia is associated with an increased risk of overall mortality in the first year after haemopoietic stem cell transplantation, independent of the use of pre-emptive therapy, and with evidence of a positive dose-response relationship. These data indicate the suitability of viral load as a surrogate clinical endpoint for clinical trials for cytomegalovirus vaccines, biologics, and drugs.

Funding: Merck and Co, National Institutes of Health.

Figure 1. Cumulative incidence of: (a) CMV reactivation at different levels of viremia (any positive, >150 IU/ml, >500 IU/ml, and >1000 IU/ml); (b) Initiation of preemptive therapy^*; and (c) CMV disease by 1 year after HCT for all subjects

^*Preemptive antiviral therapy was initiated with either induction-dose ganciclovir (5 mg/kg intravenously every 12 hours), foscarnet (90 mg/kg intravenously every 12 hours), or valganciclovir (900 mg orally every 12 hours). Induction therapy was continued for at least one week followed by at least two weeks of maintenance (once daily) therapy until cessation of CMV viremia.

Figure 2. Adjusted HR and 95% CI from multivariable Cox proportional hazards models evaluating CMV viral load as a time-dependent risk factor for CMV disease by 1 year after HCT, stratified by use of preemptive therapy (n= 926)

Models each adjusted for CMV serostatus, HLA matching, cell source, underlying disease, HCT-CI, and disease risk.

Figure 3. Adjusted HR and 95% CI from multivariable Cox proportional hazards models evaluating CMV viral load as a time-dependent risk factor for overall mortality with (a) viral load as a categorical variable and (b) viral load as a threshold; and non-relapse mortality with (c) viral load as a categorical variable and (d) viral load as a threshold by 1 year after HCT (n=926)

Comparator group for categorical models (a and c) is patients with no CMV reactivation. Adjustment factors for overall mortality models: patient age,transplant year, underlying disease, disease risk, HCT-CI score, acute GVHD grade, neutropenia, and preemptive therapy. Adjustment factors for non-relapse mortality models: patient, HLA-matching, disease risk, HCT-CI score, acute GVHD, chronic GVHD, neutropenia, and preemptive therapy. Results of the categorical model for all factors are available in the appendix (page 2)

Figure 4. Cumulative incidence of (a) overall mortality and (b) non-relapse mortality by 1 year after HCT among day-100 survivors (n= 832) stratified by maximum CMV viral load before day 100 and (c) results from multivariable Cox proportional hazards models evaluating maximum CMV viral load before day 100 as a risk factor for overall and non-relapse mortality

Covariates for overall mortality models include: age, donor relation, transplant year, underlying disease, disease risk, HCT-CI score, neutropenia before day 100, CMV viremia after day 100 (time-dependent). Covariates for non-relapse mortality models include: age, donor relation, transplant year, disease risk, HCT-CI score, acute GVHD, chronic GVHD, neutropenia before day 100, CMV viremia after day 100 (time-dependent).