Extending the duration of letermovir prophylaxis from 100 days to 200 days following HSCT is effective and safe in reducing clinically significant cytomegalovirus (CMV) infections.

An international phase 3 study, published in The Lancet Haematology [link here], randomised 220 adult patients at high risk of CMV infection or disease to either 100 days of letermovir or placebo in addition to the first 100 days of letermovir prophylaxis following HSCT.

The most common primary reasons for HSCT were AML, ALL and myelodysplastic syndrome.

The study found that extending the duration of letermovir prophylaxis to 200 days following HSCT was superior to 100 days of letermovir.

The proportion of participants with clinically significant CMV infection from randomisation at week 14 (approximately 100 days following HSCT) to the end of prophylaxis at week 28 was 3% with the extended duration of letermovir compared to 19% with the regular duration.

Beyond the treatment phase, the proportion of participants with clinically significant CMV infection was similar in both groups (13% v 19%).

“The rebound in the incidence of clinically significant cytomegalovirus infection after letermovir discontinuation was not entirely unexpected, given that letermovir use results in virological suppression, not cure.”

There was no difference between treatment arms in all-cause mortality.

The study said factors associated with continued risk of CMV reactivation include the type of transplantation, the degree of mismatch and relatedness between donor and recipient, the use of grafts depleted of T cells, and post-transplantation complications such as new-onset GVHD or other conditions requiring treatment with steroids.

Rates of adverse events were similar in both treatment arms with the most commonly reported being new-onset GVHD (30% v 31%), nausea (11% v 18%), diarrhoea (12% v 12%), pyrexia (9% v 12%) and decreased appetite (4% v 12%).

The study said the availability of letermovir for prophylaxis against late CMV infection and disease provided transplantation physicians with an attractive new option over active surveillance and pre-emptive therapy (PET) for viraemia and end-organ CMV disease.

“Other currently available anti-cytomegalovirus agents (eg, ganciclovir, valganciclovir, foscarnet, and cidofovir) used for PET are associated with clinically significant myelotoxicity, nephrotoxicity, or both; myelotoxicity is particularly relevant when treating HSCT recipients.”

An accompanying Comment in the journal [link here] by Australian infectious diseases physicians Dr Abby Douglas and Professor Monica Slavin said the findings had important implications for clinical practice.

“Reducing rates of clinically significant cytomegalovirus infection would reduce patient exposure to the often toxic cytomegalovirus therapies of valaciclovir, ganciclovir, foscarnet, and cidofovir.”

“This reduction could also translate to a downstream reduced risk of resistant or refractory cytomegalovirus.”

“Furthermore, reduced rates of clinically significant cytomegalovirus infection could reduce the risk of secondary infections, such as invasive fungal diseases.”

They said a cost-effectiveness analysis would be important to address whether the costs of implementing extended prophylaxis are offset by the reduced treatment costs of clinically significant CMV infection.