Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib

BACKGROUND. A Phase I/II study was designed to show whether the addition of semisynthetic homoharringtonine (sHHT) would reduce the level of residual disease in patients with Ph-positive chronic myeloid leukemia who appeared to have achieved a suboptimal response to imatinib alone. METHODS. Patients with CML who had achieved a 35% Ph-negativity on imatinib were included. All patients had been treated with imatinib at a 400 mg/day for at least 2 years and had achieved a plateau in BCR-ABL transcripts denned by measuring BCR-ABL transcripts on at least 4 occasions over a minimum period of 1 year with the latest value not lower than the previous minimum value. Initially sHHT was given subcutaneously at a dose of 1.25 mg/m² twice daily for 1 day. Courses were repeated every 28 days. The dosage of sHHT was escalated by adding one day of treatment every two days. Efficacy was assessed by serial monitoring of blood levels of BCR-ABL transcripts. RESULTS. Of 10 evaluable patients, 7 had an appreciable decline in BCR-ABL transcript levels; in 5 cases the reduction was greater than 1 log. Asthenia (n = 10) and cytopenias (n = 3) were prominent side-effects, but the drug was generally well tolerated. Mutations in the P-loop of the BCR-ABL kinase domain were found in 2 of the patients who responded to the addition of sHHT. CONCLUSIONS. The addition of sHHT should be considered for patients on imatinib who fail to obtain low levels of minimal residual disease.