Advances in CMV Management: A Single Center Real-Life Experience

Abstract

CMV infection is a major challenge in allogeneic stem cell transplantation (allo-SCT). The changing landscape in CMV management includes the introduction of letermovir in prophylaxis of high-risk patients and the source of CMV DNA monitoring (plasma-PL vs. whole blood-WB), for pre-emptive therapy (PET) initiation. We report here how our real-life experience in CMV management evolved, following letermovir registration. We focus on: (i) the effects of systematic use of letermovir for CMV prophylaxis in high-risk patients, (ii) the results of a longitudinal comparison of CMV DNAemia monitoring in PL and WB. From December 2018 to April 2020, 60 allo-SCTs have been performed in our center (LET ERA), of whom 45 received letermovir in prophylaxis from day 0 to day + 100, because of recipient positivity of anti CMV IgG. These patients were compared with a cohort of 41 allo-SCTs performed between November 2017 and November 2018 (NO LET ERA). Firstly, the incidence of CMV clinically significant infections, CMV disease, bacterial infections, proven/probable fungal infections, hospital re-admissions after allo-SCT by day + 100 in the two ERA were 8 vs. 44% (p = 0.0006), 2 vs. 12% (p = 0.02), 37 vs. 56% (p = 0.05), 8 vs. 19% (p = 0.09), and 23 vs. 39% (p = 0.09), respectively. By day + 180 these differences were 17 vs. 68% (p < 0.00001), 2 vs. 12% (p = 0.02), 45 vs. 78% (p = 0.09), 8 vs. 22% (p = 0.05), and 40 vs. 66% (p = 0.01), respectively. Secondly, from February to May 2019, we comparatively measured CMV DNA from WB and PL and we confirmed that there is a linear correlation between CMV DNA level in WB and PL (Spearman's test r = 0.86). Moreover, CMV DNAemia at the time of PET in the 12 patients with a clinically significant CMV infection was higher in WB vs. PL (5.202 vs. 4.981 copies/ml, p = 0.1). Our real-life experience confirms that: (i) letermovir is highly effective, leading to a significant drop in CMV clinically significant infections and CMV-related complications by day + 100 and + 180 after allo-SCT; (ii) WB may be an effective alternative to PL as a source for CMV DNA monitoring, as a linear correlation of DNAemia was confirmed between WB and PL, even if the CMV DNAemia at PET initiation was comparable in the two sources.

Results of an Innovative Program for Surveillance, Prophylaxis, and Treatment of Infectious Complications Following Allogeneic Stem Cell Transplantation in Hematological Malignancies (BATMO Protocol)

“…This observation is of interest and may be related to the intensification of fungal prophylaxis in high-risk patients according to the BATMO protocol, with posaconazole instead of fluconazole (Table 1), in accordance with the risk score proposed by Stanzani et al (13). Finally, focusing on viral infections, the impact of CMV reactivations by day +100 (any level of DNA) significantly reduced moving from Cohort A to Cohort B (51% in Cohort A vs. 15% in Cohort B; p=0.00001; Supplementary Figure S4B), and this is in line with our recently published study (26). This reflects the efficacy of letermovir prophylaxis, but the issue of CMV is not completely resolved, as the OS of patients with a CMV reactivation is significantly impaired in comparison to those without this event (Supplementary Figure 4B).…”

New trends in the management of cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a survey of the Infectious Diseases Working Party of EBMT

“…On the other hand, several factors may have slowed down this policy such as the variable time interval for the authorization of letermovir prescription at different European countries, the costs of the drug prophylaxis and the need for every allogeneic-HCT unit to reformulate the annual budget and approve the costs for letermovir, and the attitude of the centres and hematologists to utilise in the routine practice the indications coming from a clinical trial. Retrospective data from "real world" use and cost-effectiveness model analysis, con rmed that anti-CMV primary prophylaxis with letermovir is associated with a reduction of CMV infections, shorter hospitalizations, reduced costs and improvement of hematological and renal parameters [21][22][23] . In this regard, our interpretation of existing data support that a broader use of letermovir primary prophylaxis in the next future may result into an improvement of the overall transplant outcomes, as suggested by a post-hoc analysis on overall mortality conducted on the patient recruited in the phase III trial of letermovir versus placebo 24 .…”

Letermovir Prophylaxis for Cytomegalovirus Infection in Allogeneic Stem Cell Transplantation: A Real-World Experience

“…Other real-world experiences have also been published. An Italian study compared 45 patients undergoing prophylaxis with LET with a retrospective cohort that did not receive prophylaxis ( 38 ). Results showed that prophylaxis was highly effective and safe in reducing the incidence of CSCI when administered from day 0 to day +100.…”