Imatinib mesylate, an Abl kinase inhibitor, produces sustained complete hematologic responses (CHRs) in chronic myelogenous leukemia (CML) patients, but the sequence and timing of morphologic and cytogenetic changes in CML patients during prolonged imatinib mesylate treatment has not been described. In this report, we document sequential hematologic and bone marrow findings in 19 interferon-refractory/interferon-intolerant chronic phase CML patients on imatinib mesylate for at least 14 months. Patients treated at an effective oral dose (300 to 600 mg per day) were followed with peripheral blood (PB) counts, marrow examination, and cytogenetic studies at 0, 2, 5, 8, 11, and 14 months. By 2 months, 17 of 19 patients achieved CHR; 1 reached CHR by 5 months, and 1 at 11 months. Five of 19 patients developed cytopenias requiring treatment interruption and/or dose reduction, but all were able to continue in CHR on study. In contrast to interferon-alfa treatment, imatinib mesylate-treated CML patients achieved not only CHR but complete morphologic marrow response. Normalization of marrow lagged behind PB response; however, by 8 months, all marrows showed normal or reduced cellularity without morphologic evidence of CML. Eighteen of 19 patients continued in CHR and morphologic marrow remission at 14 months; 1 patient relapsed with chronic phase CML. Although hematologic and marrow responses were uniform, cytogenetic responses were variable. Complete cytogenetic responses occurred in 6 patients, with 4 also in remission by fluorescent in situ hybridization and/or reverse-transcription-polymerase chain reaction. Six of 19 had partial and 7 of 19 no cytogenetic response. Several patients acquired additional clonal cytogenetic abnormalities during therapy, a finding with significant implications for prognosis and laboratory monitoring in imatinib mesylate-treated CML patients.