Molecular Responses in Newly Diagnosed Chronic Myelocytic Leukemia (CML) Patients Treated with 800 mg Imatinib Daily: An Update from the RIGHT Trial Study Group.

Recent long term clinical outcome data have now established 400 mg/d of imatinib as the first line treatment for newly diagnosed patients with CML. We report here the kinetics of molecular response in newly diagnosed CML patients initially treated with a higher dose of 800 mg daily of imatinib. The RIGHT trial is a multicenter study conducted in academic and community practices across the US using 800 mg daily of imatinib as initial therapy in patients with newly diagnosed CML. 115 patients, median age 50y (19y–81y), were followed for both molecular and cytogenetic responses for up to 18 mo. As of May 16, 2006, all patients on study had reached at least 12 mo of follow up, and 51 pt have reached 18 mo, with median follow up of 16 mo. Bone marrow for cytogenetics and PCR were done at baseline and 12 mo, and peripheral blood (PB) for PCR was obtained every 3 mo. As of June 27, 2006, 89 patients were still on study or reached the end of the study period. 10 patients came off study for adverse events and 10 patients withdrew consent. Within the first 12 months, 6 patients (5%) had documented progression of disease and 1/51 patients (1%) treated beyond 12 mo also progressed. One of the 7 patients who progressed showed a BCR-ABL mutation (E255V), while all other patients with mutation analysis had wild type BCR-ABL. PB sampling for PCR showed that the kinetics of major molecular response (MMR), defined as ≥3 log reduction in BCR-ABL/ABL, for these patients was rapid with 50/115 patients (44%) on treatment achieving a MMR by 6 mo. This differs from the previous IRIS study in which 400 mg daily of imatinib resulted in 21% MMR at the 6 mo time point. At 12 mo, MMR rate remained at 44% with 50/115 patients showing at least a 3 log reduction. There appeared to be a relationship between Dose Intensity (DI) and the kinetics of response. The 50 patients with a MMR at 12 mo had a median DI of 98.5% (39–100%). The 8 patients with slower response who failed to obtain both a 2 log reduction in BCR-ABL/ABL at 6 mo and MMR by 12 mo had a median DI of 79% (72–98). The median DI for the patients who progressed on study was 85%. Tolerability of the higher dose of imatinib did not differ significantly in this study for those over or under age 65. DI for the younger and older age groups was 98% (39–100%) and 91% (33–100%) respectively. No difference was noted in the types of AEs for either of the age groups. The most frequent AEs included myelosuppression, rash, fatigue, and musculoskeletal symptoms. 1/115 pt with previous cardiac history had Gr 4 CHF following a second myocardial infarct. We conclude that 800 mg of imatinib daily results in more rapid reduction in tumor burden than 400 mg daily. Tolerability of imatinib was sustainable in both older (>65y) and younger (<65y) pt and did not result in either a significantly greater rate of AEs or a different AE profile in older pt. Further follow up will be needed to determine if the rapid reduction in CML cells implied by the kinetic response to 800 mg imatinib will reduce later rates of progression over time.