High-dose carboplatin in the treatment of hematologic malignancies.

Carboplatin is a second-generation platinum complex developed to be less ototoxic and nephrotoxic than cisplatin. The major toxicity was found to be myelosuppression; thus, it was tried in acute leukemia. When given by daily bolus injection for 5 days, carboplatin exhibited some activity but was associated with additional nonhematologic toxicity as well. When administered by continuous infusion, responses were higher and toxicity less. The Eastern Cooperative Oncology Group (ECOG) conducted a phase II study of carboplatin 315 mg/m2 daily given by continuous infusion for 5 days to adults with refractory and relapsed acute leukemia. A second course was given if the bone marrow on day 14 revealed persistent leukemia. Those achieving a complete remission (CR) were given an additional course as consolidation. The median age was 49 years among acute myelogenous leukemia (AML) patients and 46 years in acute lymphoblastic leukemia (ALL) patients. Of 46 eligible patients enrolled in the study (36 AML and 10 ALL), 8 (17%) achieved a CR (6 AML and 2 ALL). Remissions were observed in 2 of 10 primary refractory patients (1 AML and 1 ALL). When treated in first relapse, 5 of 14 patients (36%) achieved a CR. In 38 instances marrow specimens were examined after treatment; 10 (26%) showed no change, 16 (42%) were hypoplastic, and 12 (32%) were hypoplastic with residual leukemic cells. Of the 18 deaths that occurred on study, 14 were due to infection, 2 due to infection and bleeding, 1 due to uncontrolled gastrointestinal bleeding and 1 due to graft-versus-host disease in a patient who had relapsed after bone marrow transplantation. Marrow suppression was usually prolonged. Nonhematologic toxicity was mild. Gastrointestinal toxicity consisted of easily controlled nausea and vomiting. Three patients had grade 3 diarrhea. Grade 3 or more renal toxicity was observed in 8 patients, all of whom had received nephrotoxic antibiotics for treatment of bacterial or fungal infections. One patient died of renal failure that developed near the end of a second induction course. Ototoxicity was observed in 11 patients (24%) and was grade 2 or less in all but 3. These results indicate that carboplatin is an active agent in leukemia. Further studies are under way in combination with other agents such as etoposide, mitoxantrone, 5-azacytidine, and daunorubicin in treatment of acute leukemia and in combination with ifosfamide and etoposide in refractory lymphomas.