Vaccine Therapy in Reducing the Frequency of Cytomegalovirus Events in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant

PRIMARY OBJECTIVES: I. To determine if cytomegalovirus (CMV) peptide(Pep)vaccine(Vax) (CMVpp65-A\*0201 peptide vaccine) increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated compared to placebo treated human leukocyte antigen (HLA) A\*0201 allogeneic CMV positive hematopoietic stem cell transplant (HCT) recipients (HCT-R+). (Entire cohort) II. To provide a preliminary evaluation of the incidence of CMV reactivation between day 56 and day 180 in patients who receive standard letermovir (Prevymis) prophylaxis (from day 14 through day 100), comparable to the evaluation of an expansion cohort in a pilot study, or the futility stage of a phase II trial. (Letermovir combination cohort) III. To determine if CMVPepVax increases levels, function and kinetics of CMV-specific T cell immunity in vaccinated HCT patients who receive standard Prevymis prophylaxis. (Letermovir combination cohort) SECONDARY OBJECTIVES: I. To determine, within the constraints of a pilot cohort, if CMVPepVax reduces the frequency of CMV events alone or in combination with Prevymis defined as reactivation or CMV disease in HLA A\*0201 allogeneic HCT-R+. II. To evaluate the safety and tolerability of CMVPepVax by assessing the following: non-relapse mortality (NRM) at 100 days post HCT, severe (grade 3-4) acute graft versus host disease (GVHD) (aGVHD), and grade 3-4 adverse events (AEs) (Common Terminology Criteria for Adverse Events \[CTCAE\] 4.0) probably or definitely related to the vaccination within 2 weeks from each vaccination. III. To characterize CMV reactivation and CMV disease in recipients of CMVPepVax compared to placebo by assessing time-to viremia (defined as number of days from transplantation to the date of \>= 500 CMV gc/mL), duration of viremia, recurrence of viremia, incidence of late CMV viremia/disease (\> 100 and =\< 360 days post HCT), use of antiviral drugs (triggered by clinically significant viremia), cumulative number of CMV specific antiviral treatment days. IV. To determine whether vaccination induces adaptive natural killer (NK) cell population changes, and increase in the highly cytotoxic memory NKG2C+ NK cells. V. To determine the impact of CMVPepVax on CMV immune reconstitution in patients who undergo treatment with antiviral agent Prevymis. VI. To explore GVHD biomarkers and compare between the vaccine and placebo groups. VII. To characterize CMV reactivation after day 180 OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive CMVpp65-A\*0201 peptide vaccine subcutaneously (SC) on days 28 and 56 after HCT. ARM II: Patients receive placebo SC on days 28 and 56 after HCT. After completion of study treatment, patients are followed up to day 365 after HCT.