title: Induced resistance to ofatumumab-mediated cell clearance mechanisms, including complement-dependent cytotoxicity, in chronic lymphocytic leukemia.
abstract: Ofatumumab (OFA), a human CD20-targeting mAb, kills B lymphocytes using the innate immune system including complement-dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients undergoing their first treatment for progressive CLL. As previously reported, OFA therapy rapidly decreased the absolute lymphocyte count, CD20 expression by CLL cells, and serum complement levels. We now show that after administration of the first dose of OFA, there was a modest rebound in the absolute lymphocyte count and serum complement levels, but substantial ongoing loss of CD20 expression by CLL cells. These post-OFA treatment CLL cells were highly resistant to OFA-mediated CDC but retained sensitivity to alemtuzumab-mediated CDC in vitro. Posttherapy serum OFA levels correlated inversely with both the amount of pretreatment circulating cell-bound CD20 and with the decrease in this value following treatment. In vitro OFA-mediated CDC did not predict clinical responses, and the patients with first-dose reactions to OFA did not have markers of increased complement activation in vivo. We propose that optimal efficacy of CD20- targeted therapy for CLL requires determining an mAb dose size and frequency that optimizes CLL killing without exceeding the capacity of the cytotoxic mechanisms and thus minimizes loss of CD20 expression in the surviving CLL cells.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Nisar A
authors.initials: NA
authors.lastname: Baig
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Taylor
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Lindorfer
authors.forename: Amy K
authors.initials: AK
authors.lastname: Church
authors.forename: Betsy R
authors.initials: BR
authors.lastname: LaPlant
authors.forename: Adam M
authors.initials: AM
authors.lastname: Pettinger
authors.forename: Tait D
authors.initials: TD
authors.lastname: Shanafelt
authors.forename: Grzegorz S
authors.initials: GS
authors.lastname: Nowakowski
authors.forename: Clive S
authors.initials: CS
authors.lastname: Zent
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000097:blood / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D015703:Antigens, CD / Q000096:biosynthesis; D018951:Antigens, CD20 / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D000074301:CD52 Antigen; D003165:Complement System Proteins / Q000378:metabolism; D003520:Cyclophosphamide / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D015649:Pentostatin / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; D015649:Pentostatin; D000074323:Alemtuzumab; D003520:Cyclophosphamide; D003165:Complement System Proteins; C527517:ofatumumab