title: Antithymocyte Globulin at Clinically Relevant Concentrations Kills Leukemic Blasts.
abstract: In contrast to cyclosporine or methotrexate, rabbit antithymocyte globulin (ATG) used for graft-versus-host disease (GVHD) prophylaxis with myeloablative conditioning does not increase the risk of relapse after hematopoietic cell transplantation. The reason for this is unknown. We hypothesized that ATG at concentrations achieved with our standard ATG dose of 4.5 mg/kg exerts antileukemic activity. We measured ATG-induced killing of leukemic blasts via complement-dependent cytotoxicity (CDC) and via complement-independent cytotoxicity (CIC) in marrow or blood from 36 patients with newly diagnosed acute leukemia. The median percentage of blasts killed by CDC was 0.3% at 1 mg/L ATG, 2.8% at 10 mg/L ATG, 12.6% at 25 mg/L ATG, and 42.2% at 50 mg/L ATG. The median percentage of blasts killed by CIC after a 4-hour incubation with ATG was 1.9% at 1 mg/L ATG, 7.15% at 10 mg/L ATG, 12.1% at 25 mg/L ATG, and 13.9% at 50 mg/L ATG. CIC appeared to represent a direct induction of apoptosis by ATG. There was a high variability in the sensitivity of the blasts to ATG; at 50 mg/L, the percentage of blasts killed ranged from 2.6% to 97.2% via CDC and from 1.4% to 69.9% via CIC. In conclusion, ATG at clinically relevant concentrations kills leukemic blasts in vitro. Some acute leukemias are highly sensitive to ATG, whereas others are relatively resistant. This finding could lead to personalized administration of ATG.
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address: rdabas@ucalgary.ca.
authors.forename: Rosy
authors.initials: R
authors.lastname: Dabas
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Maria Theresa
authors.initials: MT
authors.lastname: Servito
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Poonam
authors.initials: P
authors.lastname: Dharmani-Khan
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Alberta, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Modi
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Alberta Health Services, Alberta, Canada.
authors.forename: Tiffany
authors.initials: T
authors.lastname: van Slyke
authors.affiliation: Alberta Health Services, Alberta, Canada; Calgary Laboratory Services, Calgary, Alberta, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Luider
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Alberta, Canada.
authors.forename: Caylib
authors.initials: C
authors.lastname: Durand
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Alberta Health Services, Alberta, Canada.
authors.forename: Loree
authors.initials: L
authors.lastname: Larratt
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Alberta Health Services, Alberta, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Brandwein
authors.affiliation: Alberta Health Services, Alberta, Canada; Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Don
authors.initials: D
authors.lastname: Morris
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Alberta, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Daly
authors.affiliation: Alberta Health Services, Alberta, Canada; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada; Calgary Laboratory Services, Calgary, Alberta, Canada.
authors.forename: Faisal M
authors.initials: FM
authors.lastname: Khan
authors.affiliation: Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Health Services, Alberta, Canada.
authors.forename: Jan
authors.initials: J
authors.lastname: Storek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000961:Antilymphocyte Serum / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D001752:Blast Crisis / Q000097:blood / Q000188:drug therapy; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000517:prevention & control; D006801:Humans; D007938:Leukemia / Q000097:blood / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011817:Rabbits
chemical_list: D000961:Antilymphocyte Serum
keywords: Acute leukemia; Allogeneic hematopoietic cell transplantation; Antithymocyte globulin; Graft-versus-host disease; Relapse