Early CMV viremia is associated with impaired viral control following nonmyeloablative hematopoietic cell transplantation with a total lymphoid irradiation and antithymocyte globulin preparative regimen

Abstract

The reconstitution of immune function after hematopoietic cell transplant (HCT) plays an important role in the control of viral infections. Both donor and recipient cytomegalovirus (CMV) serostatus has been shown to contribute to effective immune function; however, the influence of a nonmyeloablative preparative (NMA) regimen using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) on antiviral immune reconstitution has not yet been described. In 117 recipients of NMA HCT patients following ATG and TLI, not unexpectedly, CMV viremia was seen in approximately 60% of the seropositive patients regardless of donor serostatus, and recipient seropositivity significantly increased the odds of CMV viremia after transplant in a multivariate analysis. The administration of ATG and TLI resulted in a strikingly earlier viremia in the posttransplant period when compared to the previously reported timing of viremia following myeloablative preparative regimens, especially for transplant recipients who were seropositive for CMV with seronegative donors. Furthermore, early viremia in the setting of a CMV naïve donor was associated with a delay in functional antiviral control. These observations demonstrate the dynamic nature of immunity in relation to CMV antigen exposure in the complex environment resulting from NMA conditions where both donor and residual recipient immune response affect viral control.

Figure 1

Weekly CMV PCR measurements in the first 100 days posttransplant, separated by serology group and by number of reactivations. CMV PCR results are shown (y-axis), graphed against time after transplantation in days (x-axis). Each patient is represented by a different symbol and color; the left-hand column displays results falling within 0 to 15,000 copy number, and those with 15,000 to 150,000 copy number are displayed in the right-hand column. (A) Patients experiencing single viremia episodes separated by serology group. (B) R+/D+ and R+/D− patients experiencing multiple viremia episodes. No patients in the R−/D+ experienced multiple episodes of viremia, and no patients in the R+/D− group had multiple viremia episodes in the 15,000 to 150,000 range.

Figure 2

Area under the curve (AUC) of CMV PCR viremia by serology group. AUC was calculated for each patient by summing the areas generated using the time between CMV PCR results as “length” and the CMV PCR copy number as “height.” Patients in the R−/D+ serology group are indicated by circles, R+/D+ by triangles, and R+/D− by squares. Break in y-axis scale is indicated by a double line. Mann-Whitney U comparison between all 3 groups was statistically significant (P =.005) as was the comparison between the R+/D+ and R−/D+ serotypes (P = .049). Red horizontal bars on scatterplot graph indicate means for each serology group; asterisks (*) indicate statistically significant comparisons.

Figure 3

Percentage of patients experiencing CMV viremia and days to first episode by serology group. (A) Percentage of patients with either 0, 1, or >1 episodes of CMV viremia within each serology group are indicated by white, gray, and black bars, respectively. A maximum of 2 episodes of viremia per patient were seen in the R+/D+ group, and a maximum of 3 episodes of viremia per patient were seen in the R+/D− group. The number of episodes by serology type was statistically significantly different between all 3 groups (P = .002, Fisher’s exact test). Median time in days to reactivation is indicated below the bar graph. There was a trend toward shorter time to reactivation in the R−/D+ group (P = .11) compared with the other 2 serology groups. Range of days to reactivation was 38 to 74 days in the R−/D+ group, −4 to 53 days in the R+/D+ group, and −11 to 46 days in the R+/D− groups. (B) Sixty-six patients who experienced 1 or more episodes of CMV viremia were grouped by single versus multiple episode status (regardless of serology group). Horizontal bars within the scatter plot indicate the median number of days to first detectable CMV PCR, which was significantly different between the 2 groups (P =.008). The median day to first episode of viremia was 17 (range: −4 to 74) in the single episode of viremia group (n = 53), versus 10 (range: −11 to 31) in the multiple episode group (n = 13). Asterisk (*) indicates statistically significant comparisons.

Figure 4

Flow cytometry results by day after transplant and serology group. Means 6 standard error of absolute cell count for each cell type are graphed with absolute lymphocyte (ALC) in black, CD3⁺ with dots (CD3⁺), CD4⁺ in lines (CD4⁺), and CD8⁺ in gray (CD8⁺) at day 28, day 56, and day 90 after transplant. The number of patients with evaluable results within each serology group are shown below. Patient results were not included if the patient had a diagnosis of CLL as their underlying disease or if they experienced documented relapse prior to day 56 posttransplant. Means that were statistically significantly higher than the other groups are indicated by single asterisk (*); means that were statistically significantly than the 2 R− groups are indicated by a double asterisk (**). Statistical analysis performed using the Mann-Whitney U test. Pound sign (#) indicates a mean that was statistically significantly higher than the R+/D− group.

Figure 5

Mean cell count by cell type and experience of CMV viremia. Mean cell counts are indicated by squares with flanking standard error bars for each cell type at days 28, 56, and 90 posttranplantation. Means of cell counts from patients who experienced 1 or more episodes of CMV viremia are shown by black squares; those without CMV viremia in the first 100 days after transplant are shown by open squares. Y-axis scale is smaller for the CD4⁺ and CD19⁺ values compared with the other cell types. Asterisks indicated statistically significant difference by Mann-Whitney U test.