title: Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution.
abstract: In vivo alemtuzumab reduces the risk of graft-versus-host disease (GVHD) and nonrelapse mortality after reduced intensity allogeneic transplantation. However, it also delays immune reconstitution, leading to frequent infections and potential loss of graft-versus-tumor responses. Here, we tested the feasibility of alemtuzumab dose deescalation in the context of fludarabine-melphalan conditioning and human leukocyte antigen (HLA)-identical sibling transplantation. Alemtuzumab was given 1-2 days before graft infusion, and dose reduced from 60 mg to 20 mg in 4 sequential cohorts (total n = 106). Pharmacokinetic studies were fitted to a linear, 2-compartment model in which dose reduction led to incomplete saturation of CD52 binding sites and greater antibody clearance. Increased elimination was particularly evident in the 20-mg group in patients who had CD52-expressing tumors at time of transplantation. The 20-mg dose was also associated with greater risk of severe GVHD (acute grade III-IV or chronic extensive) compared with > 20 mg (hazard ratio, 6.7; 95% CI, 2.5-18.3). In contrast, dose reduction to 30 mg on day -1 was associated with equivalent clinical outcomes to higher doses but better lymphocyte recovery at 12 months. In conclusion, alemtuzumab dose reduction to 30 mg is safe in the context of reduced intensity conditioning and HLA-identical sibling transplantation. This trial was registered at http://www.ncrn.org.uk as UKCRN study 1415.
authors.affiliation: Royal Free Hampstead National Health Service (NHS) Trust, London, United Kingdom. r.chakraverty@medsch.ucl.ac.uk
authors.forename: Ronjon
authors.initials: R
authors.lastname: Chakraverty
authors.forename: Guillermo
authors.initials: G
authors.lastname: Orti
authors.forename: Michael
authors.initials: M
authors.lastname: Roughton
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Adele
authors.initials: A
authors.lastname: Fielding
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Kottaridis
authors.forename: Donald
authors.initials: D
authors.lastname: Milligan
authors.forename: Matthew
authors.initials: M
authors.lastname: Collin
authors.forename: Charles
authors.initials: C
authors.lastname: Crawley
authors.forename: Peter
authors.initials: P
authors.lastname: Johnson
authors.forename: Andrew
authors.initials: A
authors.lastname: Clark
authors.forename: Anne
authors.initials: A
authors.lastname: Parker
authors.forename: Adrian
authors.initials: A
authors.lastname: Bloor
authors.forename: Ruth
authors.initials: R
authors.lastname: Pettengell
authors.forename: John
authors.initials: J
authors.lastname: Snowden
authors.forename: Andrew
authors.initials: A
authors.lastname: Pettitt
authors.forename: Richard
authors.initials: R
authors.lastname: Clark
authors.forename: Geoff
authors.initials: G
authors.lastname: Hale
authors.forename: Karl
authors.initials: K
authors.lastname: Peggs
authors.forename: Kirsty
authors.initials: K
authors.lastname: Thomson
authors.forename: Emma
authors.initials: E
authors.lastname: Morris
authors.forename: Stephen
authors.initials: S
authors.lastname: Mackinnon
mesh_terms: D000328:Adult; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000074301:CD52 Antigen; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000627:therapeutic use; D008875:Middle Aged; D035781:Siblings; D033581:Stem Cell Transplantation / Q000379:methods; D019172:Transplantation Conditioning; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; D006680:HLA Antigens; D000074323:Alemtuzumab; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan