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

August 1, 2004

The 14 reports in this special supplement discuss theuse of the cytoprotectant amifostine in patients withcancer of the head and neck, esophagus, lung, andcervix, as well as those with lymphoma and acutemyelogenous leukemia. Discussions focus on thepotential of this agent to both reduce radiation sideeffects such as xerostomia and permit doseescalation of chemotherapy and/or radiotherapy.Improvements in treatment outcome and quality oflife as a result of cytoprotection are examined.

PHILADELPHIA-"Elderlypatients with acute myelogeousleukemia (AML) are the group onewould like to treat most intensivelybut who tolerate intensive treatmentthe least well," observed DoloresGrosso, MSN, RN-C, CRNP.Ms. Grosso, of Thomas JeffersonUniversity Hospital in Philadelphia,reported that a phase II studyof CIA-cytarabine (Cytosar-U),idarubicin (Idamycin), and amifostine(Ethyol)-as inductiontherapy for patients with newly diagnosed,poor-risk AML will opensoon, based on promising resultsof a phase I study.Pretreatment Amifostine
Ms. Grosso said that this phase Istudy showed that amifostine pretreatmentallowed safe escalationof the idarubicin dose to 21 mg/m2, that antileukemic activity waspreserved with a suggestion of improvedefficacy at higher doses, andthat the 24 mg/m2 dose of idarubicinproduced unacceptable levelsof hematologic toxicity. "These resultswere obtained in a populationlargely consisting of older patients,"she reported."Planning therapy in AML is difficultbecause it is a heterogeneousdisease in terms of subtype and ofpatient age at time of diagnosis.Patients with poor-risk cytogeneticsand elderly patients often havepersistent disease. The frequencyof AML increases in the elderly,and AML in the elderly may bedifferent from the disease in youngerpatients-more like secondaryAML, therapy-related AML, orAML arising from myelodysplasticsyndrome," she added.In patients with good-risk cytogenetics,the complete response(CR) rate is 86% to 91%, but itdrops to 63% in those with poorriskcytogenetics. The phase I trialwas designed to examine whetheridarubicin could be safely doseescalatedin the presence of ami-fostine. Higher doses of idarubicinmay be more efficacious in thetreatment of AMLPhase I Protocol
The phase I trial included 34newly diagnosed, previously untreatedAML patients with a medianage of 65 years (range, 24-85).Nineteen had de novo AML, 3 hadsecondary AML, 9 had AML arisingfrom myelodysplastic syndrome(MDS), and 3 had AMLarising from myeloproliferativedisorders. There were no goodriskcytogenetics.The regimen included cytarabine100 mg/m2/d for 7 days, escalatingidarubicin doses over days 1to 8, amifostine 910 mg/m2 justprior to idarubicin, and amifos-tine 200 mg/m2 on days withoutadministration of idarubicin. Idarubicinwas dose-escalated in standardphase I fashion. "We hadthought we wouldn't get past 15mg/m2, but there were no problemsat 15 mg/m2 or at 17 mg/m2,so we increased idarubicin furtherwith a goal of 24 mg/m2, which isdouble the standard dose," Ms.Grosso said.Toxicity and Responses
Toxicity included one case ofsevere bradycardia, in an 85-yearoldpatient with undiagnosed sicksinussyndrome, who did well offstudyonce a pacemaker wasimplanted. Ms. Grosso said that76% of patients had little or nohypotension, and 24% requiredfluids for hypotension. One patientrequired dose-reduction ofamifostine, owing to hypotension.Fifteen percent of patients hadgrade 3 oral mucositis, all at idarubicindoses of 19 mg/m2 or higher."Sixty-four percent of patients hadno oral mucositis at all, includingsome patients at the 21 mg/m2 idarubicindose," Ms. Grosso noted.No diarrhea occurred in 64% ofpatients, 6% had grade 1 diarrhea,and 27% had grade 2 diarrhea.The overall CR rate was 61%(20 of 33 patients). Complete responserates were 56% with 12 to17 mg/m2 of idarubicin, 79% with19 to 21 mg/m2, and 0 at 24 mg/m2."All three patients treated at the 24mg/m2 level had grade 4 hematologictoxicity and died, so 21 mg/m2 is the upper-limit dose for idarubicin,"she said.Partial responses were seen in15% percent of patients, includingthose with the most stubborn typesof AML, she added. In patientswith AML arising from MDS, therewere six complete responses."This makes us very hopefulabout the phase II trial, which willbe opening soon," Ms. Grosso toldONI.