title: Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.
abstract: 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.
authors.affiliation: Fred Hutchinson Cancer Research Center and University of Washington, Seattle 98109, USA. mboeckh@FHCRC.org
authors.forename: M
authors.initials: M
authors.lastname: Boeckh
authors.forename: R A
authors.initials: RA
authors.lastname: Bowden
authors.forename: B
authors.initials: B
authors.lastname: Storer
authors.forename: N J
authors.initials: NJ
authors.lastname: Chao
authors.forename: R
authors.initials: R
authors.lastname: Spielberger
authors.forename: D K
authors.initials: DK
authors.lastname: Tierney
authors.forename: G
authors.initials: G
authors.lastname: Gallez-Hawkins
authors.forename: T
authors.initials: T
authors.lastname: Cunningham
authors.forename: K G
authors.initials: KG
authors.lastname: Blume
authors.forename: D
authors.initials: D
authors.lastname: Levitt
authors.forename: J A
authors.initials: JA
authors.lastname: Zaia
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D000914:Antibodies, Viral / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000175:diagnosis / Q000188:drug therapy / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D010919:Placebos; D011446:Prospective Studies; D015996:Survival Rate; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000998:Antiviral Agents; D010919:Placebos; C409204:sevirumab