In this study, we addressed the frequency and clinical impact of pre-engraftment CMVi. We noted that 26% of our patients had csCMVi before engraftment, and this event had a negative effect on time to engraftment and overall survival. In this study, we analyzed only csCMVi. In the study of CMV disease or CMVi that requires preemptive therapy, csCMVi is the preferred primary endpoint of studies reporting CMV post HCT. (9)
When quantitative PCR was not feasible, the documentation of CMV reactivation during neutropenia was a challenge. Episodes were mostly determined through tissue biopsy. (16, 17) Currently, the monitoring of CMVi by quantitative PCR is routine, including during the pre-engraftment HCT phase and early CMVi, as quantitative PCR can be easily performed. (8, 16) Therefore, many questions about pre-engraftment CMVi need answers, including the frequency of pre-engraftment CMVi, its clinical importance, and how to treat this condition.
Few studies have previously addressed pre-engraftment CMVi, and none have reported csCMVi. (18, 19) Two publications addressed pre-engraftment csCMVi in the last two years. (18, 19) In both, patients were closely monitored by quantitative PCR starting within the first week after HCT, but the incidence of pre-engraftment CMVi was in these studies was different: Solano and colleagues reported a pre-engraftment CMVi incidence of 19%, whereas Martin and colleagues reported an incidence of 6.5%. Our cohort had an overall csCMVi incidence (73%) that was similar to that of Solano et al. but a higher incidence of pre-engraftment csCMVi (26%), even when analyzing only csCMVi episodes. Several differences in terms of HCT population characteristics can be noted, including the frequency of CMV seropositivity in our recipients, transplant modality, and baseline disease. (4, 20) These differences probably contributed to the variation in pre-engraftment CMVi incidences.
Similar to Solano et al., we could not identify risk factors for pre-engraftment csCMVi by considering pre-HCT characteristics, the cellularity of donor progenitor infusion, conditioning strategy, or aGVHD prophylaxis. In addition, no differences in terms of viral features comparing pre- vs. postengraftment episodes were observed in Solano’s cohort and our cohort. In our study, the frequency of tissue-invasive CMV disease was higher than that in other studies, but the frequencies of pre- and postengraftment csCMVi were similar.
Our series observed that pre-engraftment csCMVi was associated with a delay in engraftment compared to postengraftment csCMVi. This could not be attributed to the myelotoxicity of therapy, as only 3 of 29 pre-engraftment csCMVi patients started the treatment before engraftment. All of them were treated during neutropenia with foscarnet. Anti-CMV therapy was delayed in pre-engraftment compared with postengraftment events. Martin and colleagues also observed a delayed start of CMV treatment in patients with pre-engraftment CMVi, but no difference in engraftment was observed between those who started therapy before engraftment and those who started therapy after engraftment. It is important to highlight that Martin and colleagues did not compare pre-engraftment to postengraftment events. We hypothesize that the virus had an important role in the engraftment delay in our cohort, as the adjusted model maintained the significance of pre-engraftment csCMVi as a risk factor, and CMV is a well-known myelotoxic pathogen. (21, 22)
Cytomegalovirus replication is a possible contributor to acute GVHD development, as demonstrated by Cantoni et al. (23) In our series, the frequency of aGVHD was not different in pre- and postengraftment events.
CMVi has been associated with higher nonrelapse mortality in Allo-HCT. (1, 5) Unlike Solano, we observed a negative impact of pre-engraftment csCMVi on overall survival, and this effect was sustained months after the csCMVi episode. Overall survival post HCT depends on several factors, but it is feasible that pre-engraftment csCMVi can serve as an indicator of high-risk patients.
Our study has limitations. The first is the retrospective and single-center design. As there is a lack of CMV treatment standardization and threshold viremia to indicate treatment, our results may not be extrapolated to other transplant centers.
This study described a potentially negative impact on outcome (engraftment delay and worse overall survival) in HCT patients who experienced pre-engraftment csCMVi. Close and early monitoring of CMV DNAemia after transplantation is needed to identify these patients. Prospective studies, including patients with letermovir prophylaxis, are necessary to define this population's standard in management and care. Currently, letermovir prophylaxis is the standard of care for high-risk patients (8, 24, 25), and an early start of prophylactic therapy could be an effective intervention to reduce pre-engraftment csCMVi, especially in the context of high incidences of csCMV.