Ofatumumab and Complement Replacement in Relapsed/Refractory Chronic Lymphocytic Leukemia

Abstract

Background While many humanized monoclonal antibodies utilize complement-dependent cytotoxicity, the complement depleting effects of these antibodies and the impact of complement replacement on treatment response are not well-described. Methods We conducted a phase 2 trial involving patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Patients were treated with ofatumumab with fresh frozen plasma (FFP) used as a source of complement replacement. The primary endpoint was objective response rate. Correlative endpoints included complement levels (C3 and C4) and complement activity (CH50) which was drawn at baseline and after ofatumumab with FFP administration. Results Among 12 enrolled patients, overall response rate was 83% with two patients (17%) achieving a complete response. While only two (17%) patients had low complement activity at baseline, eight (67%) developed low levels of complement activity after ofatumumab treatment with FFP replacement. The magnitude of complement depletion did not correlate with response. Adverse events were minimal. The combination of ofatumumab and FFP demonstrated tolerability and surprising activity in high-risk CLL patients. Conclusions The combination of ofatumumab and FFP demonstrated tolerability and surprising activity in high-risk CLL patients. Complement replacement should be studied further as a minimally toxic approach to improve efficacy of monoclonal antibody-based regimens.

The Role of Complement in the Mechanism of Action of Therapeutic Anti-Cancer mAbs

“…The demonstrated exhaustion of complement activity and of specific complement components after antibody infusion led to the suggestion that fresh frozen plasma could be used to replenish missing factors and overcome resistance due to complement exhaustion [ 138 ]. Fresh frozen plasma has been used in CLL patients treated with rituximab with some positive results [ 138 , 146 , 147 , 148 , 149 ]. Nonetheless the efficacy of such an approach may be limited by the downmodulation of CD20 expression that follows mAb infusion and take place mostly through trogocytosis of CD20, together with bound antibody from the tumor cell to phagocytes expressing FcγRs [ 134 , 150 , 151 , 152 , 153 , 154 ].…”

The Role of Complement in Cancer Immunotherapy

“…The demonstrated exhaustion of complement activity and of specific complement components after antibody infusion led to the suggestion that fresh frozen plasma could be used to replenish missing factors and overcome resistance due to complement exhaustion [138]. Fresh frozen plasma has been used in CLL patients treated with rituximab with some positive results [138, [146][147][148][149]. Nonetheless the efficacy of such an approach may be limited by the downmodulation of CD20 expression that follows mAb infusion and take place mostly through trogocytosis of CD20, together with bound antibody from the tumor cell to phagocytes expressing FcγRs [134, [150][151][152][153][154].…”