CMV Viral Load after Peripheral Blood Stem Cell Transplantation (PBSCT) and Posttransplant High-Dose Cyclophosphamide (PTCy)

Abstract

CMV viral load after allogeneic hematopoietic PBSCT is strongly associated with overall and non-relapse mortality. Recent studies suggest graft-versus-host-disease (GVHD) prevention with PTCy reduces GVHD risk through an immunomodulatory mechanism rather than T-cell ablation (Kanakry et al. Sci Transl Med 2013), which may preserve virus-specific adaptive immune responses. Lower rates of chronic GVHD with PTCy may also preserve thymic function and reduce cumulative corticosteroid use. We hypothesized that GVHD prophylaxis using PTCy leads to lower CMV viral load and disease compared to calcineurin-inhibitor (CNI) and methotrexate (MTX) or mycophenolate (MMF) GVHD regimens after PBSCT. We retrospectively analyzed subjects undergoing first HLA-matched unrelated or sibling donor PBSCT for hematologic malignancy between July 2007 and August 2017 at Fred Hutchinson Cancer Research Center. Inclusion criteria were CMV seropositive recipient and/or donor status and myeloablative or reduced-intensity conditioning. Subjects receiving ATG were excluded. We calculated the mean CMV viral load (obtained weekly posttransplant) for each subject divided by number of days survived through one year and compared these normalized average levels across patients using the Kruskal-Wallis test. A spline curve plotting the median viral load Log10 (CMV PCR +1) between the 3 groups was created for data visualization. Cox regression was used to compare cause-specific hazards of CMV reactivation at >0, ≥250 or ≥1000 IU/ml and CMV disease between groups, each modeled as a time-to-event outcome. 594 subjects met inclusion criteria (33 PTCy, 423 MTX, 138 MMF). Table 1 shows normalized median CMV viral load before and after day 70 in PTCy vs. MTX vs. MMF groups. The spline curve depicts median viral load across the 3 cohorts (Figure 1). The hazard ratios for CMV reactivation for MTX and MMF compared to PTCy at >0, ≥250 or ≥1000 IU/ml are shown in Table 2. CMV disease was not significantly different between PTCy vs. MTX and MMF: HR 1.13 (0.27-4.76, p = .87) and 0.93 (0.19-4.49, p = .93), respectively. While the time to first CMV reactivation at various levels and CMV disease was not statistically significantly different between the 3 groups, the kinetics of CMV viral load show initially higher, but later lower levels in subjects receiving PTCy compared to MTX or MMF regimens. This may be due to an initial period of T cell compromise associated with reduced viralimmunity in PTCy recipients, followed by rapid recovery of virus-specific T cells in the later posttransplant period. The net state of immunosuppression after PTCy may prove favorable for viral immunity and overall immune reconstitution posttransplant. Prospective randomized trials are underway.