TREATMENT OF LEUKEMIA AND LYMPHOMA USING ANTIBODY LABELED WITH HIGH-DOSES OF I-131

Although the use of radiolabeled antibodies has led to objective responses in the treatment of patients with hematologic malignancies, it has not been possible to deliver curative doses of radiation to these patients due to myelosuppression. We have, however, initiated studies using radiolabeled antibodies in combination with autologous or allogeneic bone marrow transplantation in an attempt to deliver higher, potentially curative, doses of radiation to patients with leukemia or lymphoma. In studies of lymphoma we have initiated a Phase I trial of high-dose I-131-labeled antibodies against B-cell associated antigens. In 13 of 27 patients in whom we studied the biodistribution of trace-labeled antibody, the antibody delivered greater estimated absorbed doses of radiation to tumor as compared to liver, lung or kidney ("favorable biodistribution"). This favorable biodistribution was found only in patients with a relatively small tumor burden. Eleven patients received therapeutic amounts of I-131-labeled antibody. All patients responded, with nine patients achieving complete remissions lasting 4 to 29 + months. All patients experienced myelosuppression and seven received an infusion of autologous marrow cells. We have not yet observed significant toxicity in non-hematopoietic organs following delivery of up to estimated doses of 2025 rads to lung, liver, or kidney, suggesting that future radiation doses may be substantially escalated. In studies of leukemia, patients receive radiolabeled antibody followed by high dose cyclophosphamide and 1200 rads total body irradiation with autologous or allogeneic bone marrow transplantation. Using an anti-CD33 antibody labeled with trace amounts of I-131, 3 patients were estimated to receive greater estimated absorbed doses to marrow compared to lung, liver or kidney. These patients were treated with the antibody labeled with an amount of I-131 calculated to deliver estimated absorbed doses of 175 rads to normal organs and greater amounts to marrow. No unexpected toxicity has occurred and engraftment has been prompt. Dose escalation studies are proceeding.