Combination Antibody Therapy for Relapsed Lymphoma and Chronic Lymphocytic Leukemia

While recurrent non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are often responsive to therapy, they are rarely curable and disease control is the primary therapeutic goal. Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown single agent activity in these diseases and is currently approved for the therapy of recurrent indolent lymphoma. However, rituximab induces objective remission in at most 60% of cases with inevitable relapse. The 1D10 antigen, a subclass of the HLA-DR molecule, is expressed in a majority of cases of B-cell malignancy. Apolizumab is a humanized monoclonal antibody that targets this antigen. In a phase I dose escalation trial this antibody has shown clinical activity against B-cell NHL that express the 1D10 antigen. Acute infusional toxicity has been tolerable, and a maximum of 5 mg/kg has been given in each of 4 weekly doses. Preclinical in vitro data from Dr. George Weiner's laboratory suggests at least additive anti-tumor efficacy when cells are exposed to both antibodies simultaneously. This trial will pilot the use of combination therapy with rituximab and apolizumab in patients with tumors that express both antigens. Feasibility and tolerability of the regimen will be determined. Experimental endpoints will include pharmacokinetics of apolizumab, assessment of apoptosis in circulating CLL cells by FACS analysis with Annexin 5, assessment of T-and B-cell dynamics, and effects of rituximab and apolizumab on CLL mRNA as measured by cDNA microarray. Following the first 21 patients on trial, the administration sequence of rituximab and apolizumab was changed from rituximab first to apolizumab first to potentially reduce sensitization of apolizumab toxicity by rituximab.