H&O How common is CMV infection among patients undergoing allogeneic hematopoietic stem cell transplant?
MB Cytomegalovirus (CMV) reactivation occurs in approximately 50% to 70% of seropositive patients undergoing allogeneic transplant. The rate varies depending on the diagnostic method that is used to identify reactivation. Among settings in which the donor is seropositive and the recipient is negative, the incidence is 20% to 25% (Figure).
H&O What risk factors have been identified for CMV reactivation and the development of CMV infection?
MB The CMV serostatus is important, with CMV seropositivity of the recipient being the highest-risk setting. CMV donor serostatus can affect the severity of CMV infection among seropositive recipients. However, even if both the donor and the recipient are seronegative and “CMV-safe” blood is used, CMV infection occurs in approximately 1% of patients. The conditioning regimen, including T-cell depletion, can affect the risk of reactivation, the viral load kinetics, and the time to first reactivation, as well.
H&O Is there a viral threshold for treatment of CMV reactivation?
MB The exact threshold for treatment is still an area of controversy. Different thresholds have been used at different sites and clinical trials, and vary according to the severity of immunosuppression. For example, the recently completed phase 3 trials of letermovir and brincidofovir both used 137 IU/mL in high-risk patients. In low-risk patients, however, the thresholds were 274 IU/mL in the letermovir trial and 1000 IU/mL in the brincidofovir trial.
H&O How is CMV monitored in allogeneic transplant patients?
MB The most common approach to monitoring is to perform a polymerase chain reaction (PCR) assay once or twice a week to identify the virus during the high-risk period and then to use an antiviral agent if the test becomes positive at a certain level. Then treatment will be administered for several weeks until the PCR assay becomes negative. This strategy is called “preemptive therapy.” The first 3 months after allogeneic transplant are considered the high-risk period, and some patients require prolonged treatment of up to 1 year.
H&O What signs or symptoms indicate CMV infection after allogeneic transplant?
MB The overwhelming majority of patients with blood reactivation are asymptomatic. When symptoms do occur, they vary depending on the part of the body that is affected. Gastrointestinal symptoms include nausea and epigastric pain when the infection is in the stomach or duodenum, and severe diarrhea and cramps when it is located in the lower gastrointestinal tract. Infection in the lungs can lead to signs and symptoms of pneumonia, such as cough and shortness of breath. If the eyes or central nervous system are infected, changes in vision or signs of encephalitis may occur.
H&O What is the morbidity associated with CMV infection after allogeneic transplant?
MB The morbidity includes direct and indirect effects. The direct effects are those just mentioned: gastrointestinal disease, pneumonia, and retinitis or encephalitis. The virus also has a profound impact on the immune reconstitution of the stem cell transplant recipient and increases the risk of other infections, especially fungal infections. These sequelae are termed indirect effects. All effects combined lead to a survival disadvantage that is observed in seropositive recipients.
H&O What are the management approaches?
MB Management includes the use of antiviral agents or CMV-specific T cells. CMV-specific T cells are in an earlier phase of development and usually reserved for more serious infections. As I mentioned, when CMV is detected in the blood, preemptive therapy will involve administration of an antiviral drug for 2 to 3 weeks or until the virus becomes undetectable. These treatment courses are repeated as needed during the high-risk period after transplant.
When patients already have signs and symptoms of end-organ disease, antivirals are given but usually at higher doses and for longer periods, sometimes in combination with immunoglobulin (eg, in patients with CMV pneumonia). For more complicated situations, such as refractory infections or resistant disease, therapy sometimes consists of antivirals given in combination or T-cell products. However, to date, no good evidence from randomized trials exists that demonstrates which of these approaches is superior.
In addition to the early treatment of disease, there is also a prophylactic approach, in which an antiviral drug or a vaccine is given up front to all seropositive transplant recipients. For this approach, there is a strong need for the treatment to be very well-tolerated and nontoxic. With the currently available drugs, this strategy is not frequently used. It is an option, however, when justified by the risk-benefit ratio, for example, in situations when PCR testing is not available and/or the CMV disease risk is very high owing to the transplant protocol that is used. Newer drugs and vaccines under development may be more suited for prophylaxis.
Disclosure
Dr Boeckh has received research funding from Astellas, Shire, Merck, and Chimerix Inc. He is a consultant for Astellas, Shire, Merck, Chimerix Inc, Oxford Immunotec, Microbiotix, Artemis Therapeutics, and Helocyte.
Suggested Readings
Boeckh M, Leisenring W, Riddell SR, et al. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood. 2003;101(2):407-414.
Green ML, Leisenring W, Stachel D, et al. Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18(11):1687-1699.
Green ML, Leisenring W, Xie H, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 2016;3(3):e119-e127.
Hakki M, Riddell SR, Storek J, et al. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood. 2003;102(8):3060-3067.
Marty FM, Ljungman PT, Chemaly RF, et al. A phase III randomized, double-blind, placebo-controlled trial of letermovir (LET) for prevention of cytomegalovirus (CMV) infection in adult CMV-seropositive recipients of allogeneic hematopoietic cell transplantation (HCT). Abstract presented at: the BMT Tandem Meetings; February 23-26, 2017; Orlando, FL. Abstract LBA2.
Marty FM, Winston DJ, Chemaly RF, et al. Brincidofovir for prevention of cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT) in CMV-seropositive patients: a randomized, double-blind, placebo-controlled, parallel-group phase 3 trial. Biol Blood Marrow Transplant. 2016;22(suppl 3):S23.
Nakamae H, Kirby KA, Sandmaier BM, et al. Effect of conditioning regimen intensity on CMV infection in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15(6):694-703.
Pergam SA, Xie H, Sandhu R, et al. Efficiency and risk factors for CMV transmission in seronegative hematopoietic stem cell recipients. Biol Blood Marrow Transplant. 2012;18(9):1391-1400.
Zhou W, Longmate J, Lacey SF, et al. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood. 2009;113(25):6465-6476.