Real-life experience with CMV prophylaxis in patients undergoing an allogeneic stem cell transplantation

In order to validate the promising effects of prophylactic letermovir on the development of cytomegalovirus (CMV) in patients who underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT), the Heidelberg University Hospital conducted a real-world retrospective analysis in 164 allo-HSCT patients. These real-life results confirmed the safety and efficacy of letermovir, with an impressive 71% reduction in the cumulative incidence of clinically significant CMV infections and indicated that letermovir reduces the use of pre-emptive therapy, resulting in an important saving in resources.

Cytomegalovirus (CMV) viral load is known to be a time-dependent risk factor for mortality during the first year after an allogeneic stem cell transplantation (allo-HCT). Therefore, it is of utmost importance to lower the incidence of CMV infections and its associated non-relapse mortality. As of the nineties, CMV monitoring and pre-emptive treatment have become the standard of care to mitigate the CMV-related risks in transplanted patients. Unfortunately, antiviral options such as ganciclovir and foscarnet can cause severe toxicities, including bacterial and fungal infections and renal failure. Moreover, many patients eventually become drug resistant, which further limits the use of pre-emptive therapy. More recently, prophylaxis with letermovir resulted in a significantly lower risk of clinically significant CMV infection as compared to placebo-treated patients (cumulative rate of clinically significant CMV infection of 18.9% vs. 44.3%, p= 0.0005). In addition, the cumulative rate of all-cause mortality (9.8% vs. 15.9%) and the non-relapse mortality (6.5% vs. 10.6%) at week 24 in patients without detectable CMV DNA at randomisation were markedly improved in patients receiving letermovir prophylaxis.^1,2

Real-world letermovir data

After the positive results obtained with prophylactic letermovir in clinical trials, the Heidelberg University Hospital conducted a real-world retrospective analysis in 164 allogeneic hematopoietic stem cell transplanted patients. In total, 82 patients received letermovir after engraftment until day +100, while patients in the control cohort received no CMV prophylaxis. Patient’s characteristics such as age, sex, CMV-status, diagnosis, HLA matching and donor type were well balanced between the letermovir and control cohort.¹

In the letermovir cohort, a significant 71% reduction in the cumulative incidence of clinically significant CMV infection (HR[95%CI]: 0.29[0.15-0.57], p< 0.001) was seen. This translated into a 25% reduction in the risk of death, compared to the control cohort (HR[95%CI]: 0.75[0.43-1.30], p= 0.306) with 12-month overall survival rates of 72% and 84% for the control and letermovir groups, respectively. Interestingly, the researchers also observed a trend for an improved non-relapse mortality (NRM) in the letermovir cohort (9% vs. 12% NRM, HR[95%CI]: 0.60[0.28-1.32], p= 0.19).¹

In addition, letermovir prophylaxis also resulted in a reduced use of pre-emptive valganciclovir (- 56%) and forcarnet, which in turn reduced the number of hospitalisations from nine in the placebo arm to only two in the letermovir group. Finally, only half as many deaths were encountered in the letermovir arm before day 100 as compared to the control arm (4 vs. 8 deaths). Letermovir prophylaxis did not lead to relevant side effects, particularly no myelotoxicity or renal toxicity. As such, letermovir prophylaxis can save important resources such as the use of pre-emptive drugs and hospital beds, which then become available to other HSCT patients.¹

To wrap up his presentation, Prof. Schmitt discussed two exemplary case reports underscoring that not only CMV infection on its own can be dangerous, but that also the treatment for CMV reactivation with myelotoxic drugs comes with important risks. For example, patients with neutropenia and/or lymphopenia are more prone to other opportunistic infections, which can potentially cause pneumonia, multi-organ failure or even death. Also for these reasons, good prophylactic treatment is of utmost importance.¹

Conclusions

The real-life experience with letermovir confirms the safety and efficacy previously reported in a randomised, controlled study. In this real-life data set, prophylactic use of letermovir also led to a reduction in the use of pre-emptive therapy, with a trend for a possible reduction of mortality until day +100. As a result, Prof. Schmitt concluded that letermovir should be considered as a game changer in allo-HSCT.¹

References

1. Schmitt M. Real-life experience with CMV prophylaxis in allogeneic stem cell transplantation. Presented at EBMT 2020; Session IS20-3.
2. Duarte R. CMV prophylaxis in allogeneic HSCT; how to optimize clinical care? Presented at EBMT 2020; Session IS20-2.