Carboplatin alone or in combination in high-risk acute nonlymphoblastic leukemia

Abstract

The use of newly developed antileukemic agents is one of the therapeutic options available to overcome clinical resistance in refractory or other high-risk acute leukemias. Carboplatin is a second-generation platinum compound that has demonstrated significant activity against acute leukemia, particularly when administered via continuous intravenous infusion in phase I clinical trials. Based on the preliminary reports of these trials, we designed a phase II clinical trial to evaluate the efficacy and toxicity of carboplatin via continuous infusion (300 mg/m2/d for 5 days) for remission induction in adult patients with high-risk acute leukemia. Because of the significant antileukemic activity and the scarce extrahematologic toxicity noted in this trial, in order to increase the response rate, we were encouraged to try carboplatin in combination in a similar set of patients. A phase II study of carboplatin 300 mg/m2/d for 5 days in combination with etoposide 100 mg/m2/d for 3 to 4 days was designed by our group to treat patients with high-risk acute leukemia. This combination was chosen because (1) each drug has independent activity in acute nonlymphoblastic leukemia (ANLL) and (2) carboplatin/etoposide has been extensively tested in patients with small and non-small cell lung cancer, and therefore the toxicity and maximum tolerated dose are known. The complete remission rate achieved was somewhat higher (40%) than with carboplatin alone despite the increased incidence of extrahematologic toxicities, particularly gastrointestinal bleeding. At present, carboplatin should be considered as a new effective agent for the treatment of ANLL. Its myeloablative potential coupled with its scanty extrahematologic toxicity warrant the trial of carboplatin as a conditioning agent in bone marrow transplantation for myeloid malignancies. It could also be incorporated into front-line-regimens as part of intensive postremission therapy, and its role should be carefully addressed in high-risk myelodysplastic syndromes (refractory anemia with excess blasts [RAEB] and RAEB in transformation).