We analyzed the impact of recipient CMV serostatus and the consequences of CMV reactivation on transplant associated outcomes using 332 patients with hematological malignancies undergoing myeloablative or RIC followed by transplantation with either one or two UCB units. When compared to CMV seronegative patients, CMV seropositive recipients had similar outcomes. CMV reactivation did not alter TRM, GVHD, relapse or survival, however patients that developed CMV disease had higher TRM and lower OS, but relapse and cGVHD were unaffected.
Previous reports have found that CMV reactivation in the post-UCB setting varies between 21% and 100%.[11
] CMV reactivation post-bone marrow (BM) and peripheral blood (PB) transplant have ranged from 12.8% to 22% in study groups containing both CMV seronegative and seropositive donors and recipients and 52% to 69% in CMV seropositive donors and recipients.[11
] The rate of CMV reactivation in this study was 51% and there was no difference for patients undergoing RIC or myeloablative conditioning. We and others have shown that the rate of CMV reactivation after UCB transplantation is not different when compared to more traditional hematopoietic cell sources such as BM or PB.[11
To date, only five studies have focused on CMV reactivation following UCB transplantation.[3
] The largest of these studies included 140 Japanese adults, all of whom received reduced intensity conditioning.[3
] Similar to our findings, CMV reactivation (antigenemia) occurred in 55% of patients at a median of day +35. These investigators observed that a low CD34+
cell dose was a risk factor for CMV reactivation. In contrast, we found no impact of either total mononuclear, CD34+
cell dose on CMV reactivation. Tomonari evaluated 101 Japanese adults, all of whom received myeloablative conditioning.[36
] Sixty-five percent of these patients had CMV reactivation. There was no significant difference between CMV seronegative and CMV seropositive patients with respect to TRM, aGVHD and cGVHD, leukemia relapse and OS, similar to our findings.
Our findings show that CMV seropositivity pre-transplant and CMV reactivation do not negatively impact transplant outcomes. This is in contrast to prior studies where UCB transplant recipients had inferior outcomes following CMV reactivation.[3
] Although in our study TRM was not significantly different between CMV seronegative and CMV seropositive recipients, CMV seropositive recipients did show a trend toward greater day 100 TRM (p=0.07). Curiously, CMV reactivation was not associated with higher TRM.
In this analysis, follow-up was limited to day +100 because patients are typically transitioned to their home institution at that time. As a result, data regarding CMV reactivation after this time point was not available. However, late CMV reactivation is increasingly being reported and a recent study found late CMV reactivation to be as high as 31% [38
]. In addition, data for this study, including patient characteristics and outcomes, was collected prospectively, however the outcome analysis was done retrospectively. Perhaps a larger prospective study which captures late CMV reactivation events and progression to CMV disease could help determine whether the trend toward increased TRM among CMV seropositive recipients becomes significant with longer follow-up. However, a subset analysis of this study revealed very few CMV reactivation events beyond day +100 (not shown).
High dose acyclovir prophylaxis, as used in this study, has been shown to be equivalent to ganciclovir in preventing CMV antigenemia and disease while having a lower side effect profile with respect to neutropenia and bacterial infections.[39
] Prophylactic ganciclovir has toxicities such as myelosuppression and increased risk of infection.[33
] Moreover, ganciclovir may cause delayed recovery of CMV-specific T-cell immunity resulting in increased late CMV disease.[40
] Perhaps the use of high dose acyclovir prophylaxis, rather than ganciclovir, impacted the severity and consequence of CMV reactivation in our patients.
We found that CMV disease developed in 13.8% of CMV seropositive patients and among 27.1% of those who reactivated. These findings are similar to previous UCB transplant studies which have reported disease rates of 12% to 13% among seropositive UCB recipients and 23% to 29% for patients with CMV reactivation.[3
] As would be expected, we found a lower OS and higher TRM among patients with CMV reactivation who experienced disease compared to those who did not develop CMV disease.
Previously investigators have found CMV to be associated with GHVD [3
], and the immune suppression used for GVHD treatment may diminish graft vs. leukemia reactions. Interestingly, two recent studies showed a reduction in leukemia relapse rate in pediatric CMV seropositive donors and recipients, particularly in children where prophylaxis was omitted and only pre-emptive therapy was used.[37
] There was no association between CMV and GVHD or disease recurrence in our study however; we did not use the above approach.
Absolute lymphocyte count (ALC) at day +30 post-transplant is predictive of survival in patients with a number of malignant diseases including ALL, AML, myeloma, Hodgkin’s disease and Non-Hodgkin’s lymphoma following autologous or allogeneic transplantation.[42
] While studies have varied in their ALC cut-off and day of analysis, patients with low ALCs (<1.75–3.0 ×108
/L) early after transplant (day +21–30) showed inferior survival compared to patients with higher ALCs.[43
] In a subsequent study, ALC <2.0 was found to be predictive of CMV infection in adult UCBT patients in univariate analysis.[33
] In contrast, we found that an ALC <2.0 at day +28 was associated with a lower incidence of CMV reactivation (37% vs. 61%, p=0.02). However, the competing risk of death among patients with ALC <2.0 was much higher (27%) than that for patients with ALC ≥2.0 (4%).
KIRs are a polymorphic family of surface receptors expressed by NK cells and some T cells. Depending upon the individual receptor, KIR can either positively or negatively regulate lymphocyte activation and function. Individuals vary in the number of KIR genes contained within their genome and have been referred to as either haplotype A or B, depending upon the relative absence or presence of activating KIR, respectively.[49
] Prior studies show that donor KIR haplotype may be associated with CMV reactivation. More specifically, recipients of HCT from a donor with a KIR B/X haplotype [50
] or those that express KIR2DS2 [51
] have a decreased incidence of CMV reactivation. In our study, donor KIR haplotype did not appear to influence recipient CMV reactivation (p=0.83), however KIR haplotype was only available for a subset of patients.
In summary, we could not identify a relationship between either CMV serostatus or reactivation following UCBT and transplantation outcomes. As well, the rate of CMV reactivation in this study is similar to that reported for other HSC sources.[11
]. Further studies are required to elucidate whether the trend toward greater day 100 TRM among CMV seropositive recipients following UCB transplant reaches significance, especially in the setting of late reactivation Perhaps, current CMV prophylaxis and vigilant pre-emptive treatment strategies have reduced the historical significance of pretransplant CMV serostatus for most UCB transplant recipients, given the similar TRM, relapse, OS, aGVHD, and cGVHD. However, some patients still develop CMV disease, which continues to be associated with higher TRM and lower OS.