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

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

 

 

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: n=3; level 2: n=3; level 3: n=6). At enrollment, overall chronic GVHD was moderate (n=7) or severe (n=5), with diverse organ involvement (skin: n=8; mouth: n=8; eye: n=8; lung: n=4; GI: n=3; liver: n=5; genital: n=2; joint/fascia: n=5), and both overlap (n=7) and classic (n=5) sub-types were represented. KPS was ≥ 80% in 11/12, median platelet count was 164 (range 92-287), 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 (n=27), possibly related AE (n=3) 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 (n=1), PR (n=7), or SD (n=1), 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. 

Figure: Ofatumumab therapy depletes total CD19+ B cells and IgG

*CD19+ B cell comparison (3mo vs. baseline): p=0.02; all other comparisons: p=NS.