Risk Factors for Progression of CMV Viremia to CMV Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction:

Cytomegalovirus (CMV) causes significant morbidity and mortality after allogeneic hematopoietic stem cell transplant (allo-HSCT). Factors associated with progression from CMV viremia to disease despite pre-emptive CMV treatment are poorly defined. We sought to identify risk factors among adult allo-HSCT recipients. 

Methods:

Retrospective single-center case-control study. The McGill University Health Centre SCT Program database was used to identify adults receiving a first allo-HSCT between January 1, 2006 and February 12, 2013, and who experienced ≥1 episode of CMV viremia detected by polymerase chain reaction (PCR). Medical records of cases (CMV disease) and controls (without disease) were reviewed for the following data: characteristics of recipient, donor, stem cell graft, transplant procedure, viremic episodes, steroid use post-transplant, and occurrence of acute and/or chronic GVHD post-transplant. For analysis, Fisher’s exact test or Wilcoxon Rank Sum test (for categorical and continuous variables, respectively) was used. Variables were selected for multivariate analysis using the LASSO approach to logistic regression analysis.

 Results:

Of 134 allo-HSCTs, 29 (21.6%) patients experienced CMV viremia. Among these patients, median age was 51 years (range 27-67), with 48 episodes of viremia. Nine (31%) viremic patients developed CMV disease.

CMV disease occurred at a median of 124 days post HSCT (range 61-322). Patients with CMV disease had a median of 2 viremic episodes before disease (range 1-4). Disease occurred at a median of 33 days from the start of the last viremic episode, and 75 days from the start of the first episode of viremia.

On univariate analysis, factors associated with progression to CMV disease were: steroid-refractory acute GVHD (60 vs. 20%, p=0.028); number of episodes of viremia >1x10³ copies/mL (mean 2.4 vs 1.1, p=0.016); longer duration of viremia (mean 38 vs. 22 days, p=0.01); higher peak viral load (mean 4.49x10⁵ vs. 8.31x10³copies/mL, p<0.001); and failure of pre-emptive ganciclovir therapy (50 vs. 10%, p=0.015). On multivariate analysis, no factors were significantly associated with progression to CMV disease.

CMV-related mortality was 33%. All-cause mortality was significantly higher in patients developing CMV disease (100 vs. 35%, log rank test p=0.0027).

Conclusions:

In adult allo-HSCT recipients experiencing ≥1 episode of CMV viremia, we found by univariate analysis that patients who developed CMV disease were more likely to have steroid refractory acute GVHD, more episodes of viremia >1x10³ copies/mL, a longer duration of viremia, and to have failed first-line pre-emptive ganciclovir therapy. This study, while limited, suggests that these risk factors may be predictive of CMV disease. Larger, prospective studies are needed to confirm these risk factors, some of which may be amenable to more aggressive anti-viral therapy.