In the JournalsPerspective

European guidelines recommend letermovir as CMV prophylaxis in HSCT recipients

Rafael de la Camara, MD
Rafael de la Camara

Updated clinical practice guidelines prepared by the European Conference on Infections in Leukemia recommend the use of letermovir for the prevention of cytomegalovirus in adults undergoing allogeneic hematopoietic stem cell transplant, or HSCT. The guidance was published in The Lancet Infectious Diseases.

“Cytomegalovirus (CMV) is one of the most common opportunistic infections that affects the outcome of adult patients undergoing stem cell transplant,” Rafael de la Camara, MD, from the department of hematology at the Hospital de la Princesa in Madrid, told Infectious Disease News. “It is also an important cause of morbidity and mortality in these patients. This updated guideline provides evidence-based and expert recommendations for screening, diagnosis, prevention and treatment of CMV in this population that will inform the management of CMV now and in the future.”

Recently, letermovir given as prophylaxis was shown to reduce the risk of clinically significant CMV infection, but the treatment of resistant or refractory CMV infection and disease remains to be a major therapeutic challenge, according to de la Camara and colleagues.

The FDA approved letermovir in 2017 for CMV prophylaxis in patients who have undergone HSCT. CMV is common, with more than 50% of U.S. adults having been infected by age 40, according to the CDC. It is a common complication in HSCT patients.

From 2000 to 2015, the proportion of patients who underwent HSCT who were aged 60 years or older tripled, from less than 10% in 2000 to 2006, to around 30% in 2015, according to the researchers. This resulted in an increased number of patients who were CMV seropositive undergoing HSCT over the same period, they wrote.

De la Camara and colleagues analyzed studies related to CMV in patients who have undergone HSCT published before June 30, 2017, and their recommendations were graded on the amount of evidence and strength of the recommendation according to the European Society of Clinical and Infectious Diseases (ESCMID) grading system, they wrote. Letermovir received an A1 grade, meaning that ESCMID strongly supported the recommendation for use, and there was evidence from at least one properly designed randomized, controlled trial, according to the review.

“[CMV] replication itself has been associated with increased nonrelapse mortality in patients who have undergone allogeneic HSCT,” de la Camara and colleagues wrote. “Therefore, prevention of [CMV] replication by systemic prophylaxis would be logical.”

However, they noted two “possible caveats” concerning the use of CMV prophylaxis. First, not all patients will reactivate CMV and may receive antiviral drugs unnecessarily, exposing them to side effects. Second, late CMV disease can occur after discontinuation of the prophylaxis, they wrote. – by Joe Gramigna

Reference:

CDC. Cytomegalovirus (CMV) and congenital CMV infection. https://www.cdc.gov/cmv/index.html. Accessed June 11, 2019.

Disclosures: Ljungman reports personal fees from AiCuris and grants from Merck, Shire, Oxford Immunotech and Astellas. Please see the study for the other authors’ relevant financial disclosures.

Rafael de la Camara, MD
Rafael de la Camara

Updated clinical practice guidelines prepared by the European Conference on Infections in Leukemia recommend the use of letermovir for the prevention of cytomegalovirus in adults undergoing allogeneic hematopoietic stem cell transplant, or HSCT. The guidance was published in The Lancet Infectious Diseases.

“Cytomegalovirus (CMV) is one of the most common opportunistic infections that affects the outcome of adult patients undergoing stem cell transplant,” Rafael de la Camara, MD, from the department of hematology at the Hospital de la Princesa in Madrid, told Infectious Disease News. “It is also an important cause of morbidity and mortality in these patients. This updated guideline provides evidence-based and expert recommendations for screening, diagnosis, prevention and treatment of CMV in this population that will inform the management of CMV now and in the future.”

Recently, letermovir given as prophylaxis was shown to reduce the risk of clinically significant CMV infection, but the treatment of resistant or refractory CMV infection and disease remains to be a major therapeutic challenge, according to de la Camara and colleagues.

The FDA approved letermovir in 2017 for CMV prophylaxis in patients who have undergone HSCT. CMV is common, with more than 50% of U.S. adults having been infected by age 40, according to the CDC. It is a common complication in HSCT patients.

From 2000 to 2015, the proportion of patients who underwent HSCT who were aged 60 years or older tripled, from less than 10% in 2000 to 2006, to around 30% in 2015, according to the researchers. This resulted in an increased number of patients who were CMV seropositive undergoing HSCT over the same period, they wrote.

De la Camara and colleagues analyzed studies related to CMV in patients who have undergone HSCT published before June 30, 2017, and their recommendations were graded on the amount of evidence and strength of the recommendation according to the European Society of Clinical and Infectious Diseases (ESCMID) grading system, they wrote. Letermovir received an A1 grade, meaning that ESCMID strongly supported the recommendation for use, and there was evidence from at least one properly designed randomized, controlled trial, according to the review.

“[CMV] replication itself has been associated with increased nonrelapse mortality in patients who have undergone allogeneic HSCT,” de la Camara and colleagues wrote. “Therefore, prevention of [CMV] replication by systemic prophylaxis would be logical.”

However, they noted two “possible caveats” concerning the use of CMV prophylaxis. First, not all patients will reactivate CMV and may receive antiviral drugs unnecessarily, exposing them to side effects. Second, late CMV disease can occur after discontinuation of the prophylaxis, they wrote. – by Joe Gramigna

Reference:

CDC. Cytomegalovirus (CMV) and congenital CMV infection. https://www.cdc.gov/cmv/index.html. Accessed June 11, 2019.

Disclosures: Ljungman reports personal fees from AiCuris and grants from Merck, Shire, Oxford Immunotech and Astellas. Please see the study for the other authors’ relevant financial disclosures.

    Perspective
     Gerhard C. Hildebrandt

    Gerhard C. Hildebrandt

    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.


    • Gerhard C. Hildebrandt, MD, FACP
    • HemOnc Today Editorial Board Member
      Markey Cancer Center
      University of Kentucky

    Disclosures: Hildebrandt reports stock or other ownership interests in, consultant/advisory roles with, research funding from, or travel, accommodations or expenses from AbbVie, Aetna, Astellas, Bluebird Bio, Bristol-Myers Squibb/Medarex, Cardinal Health, Celgene, Cellectis, Clovis Oncology, CRISPR Therapeutics, CVS Health, Endocyte, Falk Foundation, GW Pharmaceuticals, IDEXX Laboratories, Immunomedics, Incyte, Insys Therapeutics, Jazz Pharmaceuticals, Johnson & Johnson, Juno Therapeutics, Kite Pharma, Novartis, Pfizer, Pharmacyclics, Procter & Gamble, Sangamo Therapeutics, Takeda and Vertex.