Ofatumumab in Combination with Glucocorticoids for Primary Therapy of Chronic Graft Vs. Host Disease

Abstract

s / Biol Blood Marrow Transplant 21 (2015) S322eS354 S344 Teresa Field , Linda Kelley , Mohamed Kharfan-Dabaja , Frederick L. Locke , Asmita Mishra , Michael L. Nieder , Taiga Nishihori , Jose-Leonel Ochoa-Bayona , Lia Elena Perez , Marcie L. Riches , Claudio Anasetti . 1 Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2 Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Standard primary therapy for chronic graft vs. host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I-II trial examining the combination of standard ( 1mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti-CD20 monoclonal antibody, for primary chronic GVHD therapy (NCT01680965). We here report the results of the phase I trial. Patients age 18 with NIH Consensus moderate-severe chronic GVHD newly requiring 1mg/kg/day prednisone were treated at three escalating dose levels (300mg, 700mg, and 1,000mg) of IV ofatumumab on day 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by the following: grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade 3 organ toxicities, and grade 4 neutropenia lasting >14 days. Secondary endpoints included: adverse events, infectious complications, clinical response to therapy including reduction in prednisone dose, and serial measures of lymphocyte subsets and immunoglobulins. A total of 12 patients (median age 54, range 25-72) were treated (dose level 1: n1⁄43; level 2: n1⁄43; level 3: n1⁄46). At enrollment, overall chronic GVHD was moderate (n1⁄47) or severe (n1⁄45), with diverse organ involvement (skin: n1⁄48; mouth: n1⁄48; eye: n1⁄48; lung: n1⁄44; GI: n1⁄43; liver: n1⁄45; genital: n1⁄42; joint/fascia: n1⁄45), and both overlap (n1⁄47) and classic (n1⁄45) sub-types were represented. KPS was 80% in 11/12, median platelet count was 164 (range 92287), and median bilirubin 0.6 (range 0.2-0.9). Infusion of ofatumumab was well tolerated: Two infusion reactions (grades 2 and 3) occurred, resolved with supportive care, and all patients completed d1 and 14 infusions. No DLT was observed. From the total number of adverse events (n1⁄427), possibly related AE (n1⁄43) included grade 1 fatigue, grade 1 transaminitis, and grade 3 hand/foot cramping. Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy (PML). At 3 months after therapy initiation, overall clinical response among evaluable patients was CR (n1⁄41), PR (n1⁄47), or SD (n1⁄41), and responses were sustained at 6 months (including one conversion from PR to CR). Encouraging reduction in prednisone dose was observed at 3 (median 89%, range 57-100%) and 6 months (median 93%, range 71-100%). Therapy produced significant B-lymphopenia (figure). Ofatumumab in combination with prednisone is safe, and phase II examination of efficacy is ongoing.