European guidelines recommend letermovir as CMV prophylaxis in HSCT recipients

Gerhard C. Hildebrandt, MD, FACP

Ljungman and colleagues — on behalf of the European Conference on Infections in Leukemia — provide us with an up-to-date, concise and extremely valuable manual for our toolbox to battle cytomegalovirus (CMV), a long known yet still besieged enemy. I suggest that you take 10 minutes out of your hectic day to read through their excellent work.

I feel compelled to mention a few key points from their recommendations that tend to slip the mind in our daily practice.

CMV infection frequently occurs among patients after allogeneic hematopoietic cell transplantation (HCT), and it is a significant cause of morbidity and mortality. Up to one in six patients develops CMV — mostly in the gastrointestinal tract — which often does not correlate with blood viremia. For CMV pneumonitis, no viral load threshold in bronchoalveolar lavage (BAL) fluid has been established, pulmonary viral latency clouds the interpretation of a positive BAL, and tissue polymerase chain reaction is not sufficient.

Weekly monitoring for CMV viremia is routinely done to guide us on whether and when to start pre-emptive antiviral therapy. Of note, the authors point out the importance that specific populations may benefit from prolonged monitoring beyond day 100 after allogeneic HCT. Following prophylaxis against CMV with letermovir, CMV reactivation has been observed as late occurrences, and prolonged monitoring may be considered. Mismatched, cord blood and haploidentical transplant recipients potentially benefit from prolonged monitoring, as do patients with a history of CMV reactivation.

For pre-emptive therapy, advances in management have been limited. Ganciclovir, foscarnet and valganciclovir remain the classical first-line options. IV ganciclovir is the preferred choice for treatment of CMV disease. Valganciclovir or foscarnet also may be considered for other manifestations.

Which drug to use is sometimes driven by patient variables. In the future,  maribavir (ViroPharma) may become an option to enhance our drug armamentarium, as it is being tested in a phase 3 trial (NCT 02931539). CMV-specific T cells potentially pave the way for immune cell therapy but, while the door is open, we cannot yet step through it entirely.

CMV not only troubles patients after allogeneic HCT. The use of fludarabine and cladribine resulting in T-cell reduction, the use of alemtuzumab — a CD52-directed monoclonal antibody — intensive chemotherapy, PI3 kinase inhibitors, tyrosine kinase inhibitors, chemotherapy-conjugated antibodies and monoclonal antibodies that target immune cells can increase the risk for CMV-related complications among nontransplant patients, as well.

CMV monitoring recommendations already exist for some of these cancer treatments. Fortunately, the last decade has brought tremendous progress to the care of patients with hematologic cancer, with around 20 drugs being approved between 2017 and 2019 alone. It is now up to those of us on translational research and clinical teams to not only determine the optimal cancer-directed use of these drugs, but also to evaluate and manage their side effects, with the increased risk for CMV reactivation potentially being one of them.

Reference:

CenterWatch. FDA-approved drugs for hematology. Available at: www.centerwatch.com/drug-information/fda-approved-drugs/therapeutic-area/6/hematology. Accessed on June 14, 2019.