A Study of the Drug Letermovir as Prevention of Cytomegalovirus Infection After Stem Cell Transplant in Pediatric Patients

Inclusion Criteria:

* \>= 2 years and \< 18 years at the time of enrollment
* Weight must be \>= 6 kg at the time of enrollment
* Planned allogeneic HCT (bone marrow, peripheral blood stem cell, or cord blood transplant)
* Patient must be CMV sero-positive (i.e., recipient CMV immunoglobulin G positive)

  * Note: If a patient has hypogammaglobulinemia but has previously been documented as CMV sero-positive, that is acceptable for study inclusion. For all patients already confirmed to be CMV IgG seropositive, repeat testing is not required within 7 days prior to enrollment. However, the laboratory data determining eligibility must be available in the patient's medical/research record for verification
* Patient is eligible for entry only if it is feasible for plasma CMV PCR testing to be sent and resulted within the protocol mandated time period

  * Reminder: To limit the likelihood of positive plasma CMV PCR post-enrollment and prior to start of study treatment period, it is recommended that patient enrollment proceed after patients start their transplant preparative regimen
* Patient must have a performance status corresponding to Lansky/Karnofsky scores \> 50

  * Note: Use Lansky for patients =\< 16 years of age and Karnofsky for patients \> 16 years of age. For further reference, see performance status scales scoring under the standard sections for protocols among protocol reference materials provided on the Children's Oncology Group (COG) member website: https://members.childrensoncologygroup.org/prot/reference\_materials.asp
* Estimated glomerular filtration rate \> 10 mL/min/1.73 m\^2 and not receiving dialysis
* Direct bilirubin =\< 2 mg/dL and serum glutamate-pyruvate transaminase (SPGT) (alanine transaminase \[ALT\]) =\<10 x upper limit of normal (ULN) for age

  * Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L

Exclusion Criteria:

* Expected inability to tolerate oral formulation of letermovir
* Hypersensitivity to letermovir or any component of the formulation
* History of CMV end organ disease within 6 months (180 days) prior to enrollment

  * Note: CMV end organ disease based on proposed definitions by Ljungman et al. and inclusive of proven, probable or possible disease
* Receipt of prior allogeneic HCT within one year of study enrollment
* Planned prophylactic administration of other anti-CMV medications or cellular products during the study, including:

  * High dose acyclovir (defined as doses \>= 1500 mg/m\^2 IV or \>= 3200 mg oral (patients \>= 40 kg) or \>= 2400 mg/m\^2 (patients \< 40 kg) per day)
  * High dose valacyclovir (defined as doses \>= 3000 mg/day in patients \> 20 kg)
  * Foscarnet
  * Ganciclovir
  * Valganciclovir
  * CMV-directed cytotoxic T lymphocytes
* Planned receipt of the following contraindicated medications during the study treatment period; contraindicated medications must be discontinued at least 14 days prior to Day +1

  * Contraindicated medications for all patients:

    * Pimozide
    * Ergot alkaloids
  * Contraindicated medications for patients planned to receive cyclosporine:

    * Bosentan
    * Pitavastatin
    * Simvastatin
* Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted in certain animal reproduction studies with letermovir. A pregnancy test is required for female patients of childbearing potential
* Lactating females who plan to breastfeed their infants
* Sexually active female patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their letermovir treatment and through at least 4 weeks after the last dose of letermovir.

  * Note: No contraception measures are needed specifically during letermovir treatment for male trial participants who have pregnant or non-pregnant female partner(s) of reproductive potential. Contraception measures may be required for other aspects of the HCT procedure.
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met