Phase II Study of CIA Regimen in Poor-Risk AML to Open

PHILADELPHIA-"Elderly patients with acute myelogeous leukemia (AML) are the group one would like to treat most intensively but who tolerate intensive treatment the least well," observed Dolores Grosso, MSN, RN-C, CRNP. Ms. Grosso, of Thomas Jefferson University Hospital in Philadelphia, reported that a phase II study of CIA-cytarabine (Cytosar-U), idarubicin(Drug information on idarubicin) (Idamycin), and amifostine(Drug information on amifostine) (Ethyol)-as induction therapy for patients with newly diagnosed, poor-risk AML will open soon, based on promising results of a phase I study. Pretreatment Amifostine
Ms. Grosso said that this phase I study showed that amifostine pretreatment allowed safe escalation of the idarubicin dose to 21 mg/ m², that antileukemic activity was preserved with a suggestion of improved efficacy at higher doses, and that the 24 mg/m² dose of idarubicin produced unacceptable levels of hematologic toxicity. "These results were obtained in a population largely consisting of older patients," she reported. "Planning therapy in AML is difficult because it is a heterogeneous disease in terms of subtype and of patient age at time of diagnosis. Patients with poor-risk cytogenetics and elderly patients often have persistent disease. The frequency of AML increases in the elderly, and AML in the elderly may be different from the disease in younger patients-more like secondary AML, therapy-related AML, or AML arising from myelodysplastic syndrome," she added. In patients with good-risk cytogenetics, the complete response (CR) rate is 86% to 91%, but it drops to 63% in those with poorrisk cytogenetics. The phase I trial was designed to examine whether idarubicin could be safely doseescalated in the presence of ami- fostine. Higher doses of idarubicin may be more efficacious in the treatment of AML Phase I Protocol
The phase I trial included 34 newly diagnosed, previously untreated AML patients with a median age of 65 years (range, 24-85). Nineteen had de novo AML, 3 had secondary AML, 9 had AML arising from myelodysplastic syndrome (MDS), and 3 had AML arising from myeloproliferative disorders. There were no goodrisk cytogenetics. The regimen included cytarabine(Drug information on cytarabine) 100 mg/m²/d for 7 days, escalating idarubicin doses over days 1 to 8, amifostine 910 mg/m² just prior to idarubicin, and amifos- tine 200 mg/m² on days without administration of idarubicin. Idarubicin was dose-escalated in standard phase I fashion. "We had thought we wouldn't get past 15 mg/m², but there were no problems at 15 mg/m² or at 17 mg/m², so we increased idarubicin further with a goal of 24 mg/m², which is double the standard dose," Ms. Grosso said. Toxicity and Responses
Toxicity included one case of severe bradycardia, in an 85-yearold patient with undiagnosed sicksinus syndrome, who did well offstudy once a pacemaker was implanted. Ms. Grosso said that 76% of patients had little or no hypotension, and 24% required fluids for hypotension. One patient required dose-reduction of amifostine, owing to hypotension. Fifteen percent of patients had grade 3 oral mucositis, all at idarubicin doses of 19 mg/m² or higher. "Sixty-four percent of patients had no oral mucositis at all, including some patients at the 21 mg/m² idarubicin dose," Ms. Grosso noted. No diarrhea occurred in 64% of patients, 6% had grade 1 diarrhea, and 27% had grade 2 diarrhea. The overall CR rate was 61% (20 of 33 patients). Complete response rates were 56% with 12 to 17 mg/m² of idarubicin, 79% with 19 to 21 mg/m², and 0 at 24 mg/m². "All three patients treated at the 24 mg/m² level had grade 4 hematologic toxicity and died, so 21 mg/ m² is the upper-limit dose for idarubicin," she said. Partial responses were seen in 15% percent of patients, including those with the most stubborn types of AML, she added. In patients with AML arising from MDS, there were six complete responses. "This makes us very hopeful about the phase II trial, which will be opening soon," Ms. Grosso told ONI.