ASHA single dose of a radiolabeled murine anti-CD20 monoclonal antibody (IDEC-Y2B8) has produced responses in more than 80% of patients with relapsed or refractory low-grade or follicular non-Hodgkins lymphoma (NHL), Thomas E. Witzig, MD, of the Mayo Clinic, said in his presentation at the American Society of Hematology meeting in San Diego.
Rituximab(Drug information on rituximab) (Rituxan), a chimeric anti-CD20 monoclonal antibody, is the unlabeled, or cold, parent antibody of 2B8, and recently received FDA approval for use in patients with relapsed or refractory follicular or low-grade, CD20-positive, B-cell non-Hodgkins lymph-omas (see Patients Sought for Trial of Adoptive Immunotherapy). In the pivotal trials, rituximab, 375 mg/m2 for four doses, produced an overall response rate of 48%.
IDEC-Y2B8, the investigational agent used in the phase I/II study reported by Dr. Witzig, consists of a therapeutic radionuclide, yttrium-90, securely conjugated to the 2B8 murine antibody, which has a shorter half-life than rituximab.
An initial dosimetry study at the Mayo Clinic, presented at a poster session by Gregory Wiseman, MD, of the Department of Nuclear Medicine, showed that an imaging isotope (indium-111) conjugated with 2B8 could be used to assess tumor uptake of 2B8 and predict IDEC-Y2B8 radiation doses to other organs.
This study also settled on 250 mg/m2 as the optimum rituximab dose to be used as the unlabeled clearing antibody. Rituximab is given prior to indium-111 imaging and IDEC-Y2B8 treatment to clear B cells from the blood and bone marrow. This clearing optimizes the distribution of the radiolabeled antibody and may reduce the risk of human antimouse antibody (HAMA) development.
In the phase I dose escalation part of the study, patients received 0.2, 0.3, or 0.4 mCi/kg of IDEC-Y2B8 seven days after imaging with indium. No patient was found to be ineligible for treatment with IDEC-Y2B8 on day 8 due to predicted excess radiation to normal organs, Dr. Witzig said.
This study found that 0.4 mCi/kg was the maximum tolerated dose for use in the phase II portion of the trial. Since some patients with mild thrombo-cytopenia developed transient grade 4 hematologic toxicity, patients in the phase II section with platelet counts of less than 150,000 were given a reduced dose of 0.3 mCi/kg.
Interim Analysis of Response
An interim analysis of efficacy showed that at all three dose levels, the overall response rate was 65% (17/26), with 42% partial remissions and 23% complete remissions. Looking only at patients with low-grade or follicular disease, the response rate was 82% (14/17) (see Figures 1 and 2). Those with intermediate-grade lymphoma had a response rate of 50%, and none of the three patients with mantle cell disease responded to treatment.
Dr. Witzig further broke down the response rates of the 17 low-grade or follicular disease patients by dose: 50% at 0.2 mCi/kg, 83% at 0.3 mCi/kg, and 100% at the maximum dose, 0.4 mCi/kg, which will be used in phase III studies of IDEC-Y2B8 planned to begin in early 1998.
Dr. Witzig said that overall patient tolerance of the treatment was excellent. Toxicity was primarily hematologic, most often thrombocytopenia. Fortunately, there was no long-term cytopenias, and patients who have relapsed have been able to receive salvage therapy using anthra-cyclines without difficulty, he added.
To date, he added, no patient has developed human antimouse antibody (HAMA) or human antichimeric antibody (HACA).