CMA-676 (gemtuzumab zogamicin) is an antibody-targeted chemotherapeutic agent consisting of a humanized anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. This agent was designed to effectively deliver cytotoxic chemotherapy to acute myelogenous leukemia (AML) cells, while limiting nonhematopoietic toxicity.
In a phase II trial, CMA-676 was administered intravenously (IV) at a dose of 9 mg/m² every 2 weeks for two doses. Eligible patients had AML in first relapse following an initial remission of at least 6 months; those with secondary AML or preceding myelodysplastic syndromes were excluded.
A total of 59 patients entered the study prior to December 31, 1998. Median age was 53 years (range, 22 to 81 years). Of the 59 patients, 20 (34%) achieved a remission (characterized by < 5% blasts in the marrow, 1,500/µL neutrophils, and platelet transfusion independence prior to any additional post-remission therapy).
Median survival for all patients was 161 days, while that of patients achieving remission was not reached by the data cutoff date of March 15, 1999. Of the 20 patients who achieved remission, 12 remained relapse free, with a median follow-up of 238 days (range, 21 to 608 days).
Post-remission therapy was administered to 15 of the 20 patients (bone marrow transplantation [BMT] in 12 patients, chemotherapy in 3). Of the 15 patients, 1 died during a complete response (CR) due to transplant complications and 1 relapsed following allogeneic BMT. Two patients experienced a relapse following autologous BMT, with 1 patient expiring from progressive AML and 1 patient relapsing after receiving chemotherapy. Of the 5 patients who did not receive post-remission therapy, 3 relapsed and 2 remain leukemia free 4.5 and 3.5 months, respectively, after the first dose of CMA-676.
Overall, CMA-676 was well tolerated, as indicated by hospitalization for £ 1 week for 15 patients during treatment (ending 28 days after the last dose of CMA-676; excluding patients who expired during the same period). Severe (National Cancer Institute [NCI] grade 3-4) mucositis was not observed with CMA-676 treatment.
Adverse events following CMA-676 infusion frequently included self-limited fever, chills, and infrequently consisted of hypotension and shortness of breath. Almost all patients experienced grade 4 neutropenia and thrombocytopenia. Transient grade 3-4 increases in bilirubin and/or hepatic transaminases occurred in 9 patients. Individual patients experienced severe bone pain, intussusception, diabetes insipidus, seizures, exacerbation of disseminated intravascular coagulation, and intracerebral bleeding.
CONCLUSION: Antibody-targeted chemotherapy of AML cells via administration of CMA-676 as a single agent is associated with an acceptable safety profile while achieving