Patients with chronic myelogenous leukemia (CML) who have failed or cannot receive interferon alpha (IFN-alpha) based regimens or patients with advanced chronic myelomonocytic leukemia (CMML) have very limited current therapeutic options. Hence, there is a need to develop new strategies for these patients. This study was undertaken to determine the efficacy and toxicity of a chronic low-dose oral idarubicin regimen in these patients as positive data has been generated on this agent in shorter schedules given to patients with other hematological malignancies. Eighteen patients were treated on study. The starting dose of oral idarubicin was 2 to 5 mg/m2 daily depending in initial WBC count. This dose was escalated in the absence of Grade 4 myelosuppression or Grade 3 or 4 extramedullary toxicity. Oral idarubicin was given daily for 28 days followed by a 21 day break off treatment in repeated cycles until there was evidence of disease progression or intolerable toxicity. The dose of idarubicin was adjusted, at 2-week intervals, by 25% to maintain a white blood cell (WBC) count between 2 and 4x10(9)/L and a platelet count of >75x10(9)/L. The dose was reduced by 25% for grade 2 extramedullary toxicity and held until toxicity resolved to grade 2 or better for grade 3 toxicity. Oral idarubicin was then restarted at 75% of the initial dose. Five out of 14 CML patients achieved a complete hematologic remission. No CMML patient responded (median survival 3 months). The overall median survival was 24 months. CML patients had a median survival of 28 months. Major toxicities (myelosuppression, gastrointestinal, cardiac) were infrequent with a median cumulative dose of 1110 mg/m2 (range 54-9750). Five patients have received oral idarubicin for > 1 year with no overt cardiotoxicity, reaching median cumulative dose of 2756 mg/m2 (range 2550-9750) which is higher than those documented in prior studies. We conclude that oral idarubicin is sufficiently safe and active to warrant phase II studies investigating it as part of interferon-based regimens in patients with advanced CML.