Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a randomized trial

Abstract

Background: Optimal prevention of late cytomegalovirus (CMV) disease is poorly defined.

Objective: To compare valganciclovir prophylaxis with polymerase chain reaction-guided preemptive therapy.

Design: Randomized, double-blind trial. (ClinicalTrials.gov: NCT00016068).

Setting: Multicenter trial.

Patients: 184 recipients of hematopoietic cell transplantation (HCT) who were at high risk for late CMV disease (95 patients received valganciclovir and 89 received placebo).

Intervention: 6 months of valganciclovir (900 mg/d) or placebo. Patients with polymerase chain reaction positivity at 1000 copies/mL or greater or a 5-fold increase over baseline were treated with ganciclovir or valganciclovir (5 mg/kg or 900 mg twice daily, respectively).

Measurements: The composite primary end point was death, CMV disease, or other invasive infections by 270 days after HCT. Secondary end points were CMV disease, CMV DNAemia, death, other infections, resource utilization, ganciclovir resistance, quality of life, immune reconstitution, and safety.

Results: The primary composite outcome occurred in 20% of valganciclovir recipients versus 21% of placebo-preemptive therapy recipients (treatment difference, -0.01 [95% CI, -0.13 to 0.10]; P = 0.86). There was no difference in the primary end point or its components 640 days after HCT. The incidence of a CMV DNAemia level of 1000 copies/mL or greater or a 5-fold increase over baseline was reduced in the valganciclovir group (11% vs. 36%; P < 0.001). Neutropenia was not significantly different at the absolute neutrophil count of less than 0.5 × 109 cells/L (P = 0.57); however, more patients received hematopoietic growth factors in the valganciclovir group (25.3% vs. 12.4%; P = 0.026). No significant differences were seen in other secondary outcomes.

Limitation: Some high-risk patients were not included.

Conclusion: Valganciclovir prophylaxis was not superior in reducing the composite end point of CMV disease, invasive bacterial or fungal disease, or death when compared with polymerase chain reaction-guided preemptive therapy. Both strategies performed similarly with regard to most clinical outcomes.

Primary funding source: Roche Laboratories.

Appendix Figure 1

Study design.

Appendix Figure 2

Analyses comparing the primary endpoint between study arms within subsets at day 270 (upper panel) and day 640 (lower panel). Reference=placebo. Each row of figure represents a subgroup.

Appendix Figure 3

Subset analyses comparing study arms for the neutropenia endpoints: absolute neutrophil counts < 1000/mm³ (upper panel) and < 500/mm³ (lower panel). Reference=placebo. Each row of figure represents a subgroup.

Figure 1

Study enrollment and randomization (Consort Diagram).

Figure 2

Cumulative incidence of the primary endpoint (CMV disease, invasive bacterial fungal infections or death) (panel A) and overall survival (panel B).

Figure 3

Cumulative incidence of CMV DNA positivity (A: > 1000/mL or 5× increase over baseline [study drug discontinuation], P=0.004; B: any PCR positivity, P=0.005; C: >10,000 copies/mL, P=0.025).

Figure 3

Cumulative incidence of CMV DNA positivity (A: > 1000/mL or 5× increase over baseline [study drug discontinuation], P=0.004; B: any PCR positivity, P=0.005; C: >10,000 copies/mL, P=0.025).

Figure 4

Virus-specific T cell reconstitution in Placebo vs Valganciclovir (VGCV) arms. Box-whisker plots show the first, second (median) and third quartiles, whiskers show the min and max. Upper panel: CD4+ T helper function by lymphoproliferation to CMV, HSV, and VZV in all patients. Stimulation index (SI) = (mean cpm antigen-stimulated cells/mean cpm unstimulated cells) shown on log-scale. Lower panel: Polyfunctional CD8+ CMV-specific cytotoxic T cell function in a subset of 20 patients with complete follow-up to day 640 as measured by production of cytokines interferon-gamma (IFNg, denoted by G on plots), tumor necrosis factor-alpha (TNFa) and interleukin 2 (IL-2) or degranulation marker CD107a. G columns indicate monofunctional CD8+ cells that produced IFNg alone; +1, +2, +3 columns indicate polyfunctional CD8+ cells that produced IFNg + 1, 2, or 3 additional markers.