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MSL-109 is a monoclonal antibody specific to the cytomegalovirus (CMV) glycoprotein H with high neutralizing capacity. In a prospective, randomized, double-blind study, allogeneic hematopoietic stem cell transplantation (HSCT) recipients with positive donor and/or recipient serology for CMV before transplantation received either 60 mg/kg MSL-109 (n = 59), 15 mg/kg MSL-109 (n = 60), or placebo (n = 60) intravenously every 2 weeks from day -1 until day 84 after transplantation. CMV pp65 antigenemia, CMV-DNA load in plasma, and viremia by culture were tested weekly. Primary end points were development of pp65 antigenemia at any level and/or viremia for which ganciclovir was given. There was no statistically significant difference in CMV pp65 antigenemia or viremia among patients in the 60-mg group (pp65 antigenemia, 47%; viremia, 15%), the 15-mg group (52%; 23%), and the placebo group (45%; 17%). There was also no difference in maximum levels of pp65 antigenemia, time to clearance of pp65 antigenemia after start of ganciclovir, CMV disease, invasive bacterial and fungal infections, time to neutrophil and platelet engraftment, acute graft-versus-host disease, days of hospitalization, and overall survival rate among the 3 groups. However, a subgroup analysis of CMV-seronegative recipients with a seropositive donor (D+/R-) showed a transiently improved survival rate by day 100 in MSL-109 recipients (mortality: 60-mg group, 1/13; 15-mg group, 1/12; placebo group, 6/10 [P = .02 for 60-mg versus placebo groups; P = .08 for 15-mg versus placebo groups]); by the end of follow-up, the difference was no longer statistically significant. The improved survival rate in D+/R- patients could not be attributed to a reduction in CMV disease; however, MSL-109 was associated with improved platelet engraftment and less grade III to IV acute graft-versus-host disease in this subgroup. In a subgroup analysis of CMV-seropositive recipients of MSL-109 (D+/R+ and D-/R+), overall mortality was increased compared to that of the placebo group (P = .12 for the 60-mg versus placebo groups, P = .05 for the 15-mg versus placebo groups, and P = .04 for the dose levels combined versus placebo). MSL-109 was well tolerated and no immune response to the drug was observed. Thus, MSL-109 was safe but did not reduce CMV infection in allogeneic HSCT recipients. The transient survival advantage seen early after transplantation in CMV D+/R- patients and the negative effect on survival in seropositive patients remain unexplained. Thus, there is no evidence that MSL-109 is beneficial in CMV-seropositive HSCT recipients.

s / Biol Blood Marrow Transplant 20 (2014) S128eS150 S146 virus (EBV) is a gammaherpes virus that is reactivated from latent to lytic cycle and can cause aggressive lymphomas known as post transplant lymphoproliferative disorder (PTLD) in immunocompromised hosts. We attempted to distinguish immune reconstitution profiles in double UCBT recipients who developed EBV viremia from those who did not. Thirty-one patients with hematologic malignancies received dUCBT with melphalan, fludarabine, ATG conditioning and tacrolimus plus sirolimus for GvHD prophylaxis. During the first 12 months after dUCBT, 14 of 31 (45%) patients developed EBV viremia and four (13%) developed PTLD. At one month after dUCBT, patients with EBV viremia displayed higher numbers of CD19+ B cells (p1⁄40.04) and CD4+CD25+ Treg cells (p1⁄40.03) compared with patients who never became viremic. Surprisingly, EBV viremia correlated with increased numbers of CD3+ (p1⁄40.04), CD4+ (p1⁄40.015) and CD8+ (p1⁄40.021) T cells, but this response was ineffective at controlling the virus. One explanation for this unexpected result might be skewing towards a late effector memory T cell phenotype, a stage in which T cells are incapable of mounting protective immune responses. We examined naive vs. memory T cell distribution and determined that patients who developed EBV reactivation had higher numbers of memory cell subsets (CD4+CD45RO+, p1⁄40.023; CD8+CD45RO+, p1⁄40.019) at two months after dUCBT. Analysis of repertoire diversity by deep-sequencing on PCR-amplified CDR3 regions of the TCRb gene using the ImmunoSEQ assay showed a more diverse TCR repertoire, as determined by higher entropy (p1⁄40.03) and lower clonality (p1⁄40.03), among patients who did not develop EBV reactivation. Assessment of SCF and IL-7, critical regulators of hematopoietic stem cell and naive T cell homeostasis, respectively, showed that patients without EBV viremia had higher levels of SCF (p1⁄40.0016) and IL-7 (p1⁄40.046) compared with patients who developed viremia and PTLD. Our findings suggest that control of EBV reactivation after dUCBT might be linked to the support of naive T cell homeostasis, which enables maintenance of a diverse TCR repertoire.