Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis

Abstract

Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R- patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.

Keywords: CIMBTR; CMV; MARROW AND STEM CELL TRANSPLANTATION; haploidentical; organ specific toxicity: infectious; outcomes; posttransplant cyclophosphamide.

Graphical abstract

Figure 1.

Univariate analysis of the cumulative incidence of CMV DNAemia comparing HaploCy, SibCy, and SibCNI allogeneic HCT. The incidence of CMV DNAemia was significantly higher among both cohorts receiving PTCy compared with that which did not (P < .0001). Cumulative incidences of CMV DNAemia by day 100 were 40% (99% CI, 35-45), 36% (99% CI, 30-42), and 21% (99% CI, 18-24) for HaploCy, SibCy, and SibCNI, respectively; and by D180 were 42% (99% CI, 37-46), 37% (99% CI, 31-43), and 23% (99% CI, 20-26), respectively. The median times to CMV infection (days) were 38 (range, 2-176), 32 (range, 5-136), and 42 (range, 4-176; P < .001).

Figure 2.

Univariate dynamic landmark analyses demonstrate that those with CMV DNAemia by D100 have worse nonrelapse mortality at day 100, 1 year, and 2 years after HCT. Landmark time points were based on median time to CMV infection and interquartile ranges.

Figure 3.

Multivariate analyses of the combined impact of CMV serostatus, donor source, and PTCy. Impact on nonrelapse mortality (A), overall survival (B), relapse (C), and chronic GVHD (D). Notable pairwise comparisons from multivariable analysis are also presented in supplemental Table 5.

Figure 4.

Multivariate analyses of the combined impact of CMV infection by day 180, donor source, and PTCy. Impact on nonrelapse mortality (A), overall survival (B), relapse (C), and chronic GVHD (D). Notable pairwise comparisons from multivariable analysis are also presented in supplemental Table 5.