Examining complete molecular response to treatment with different doses of imatinib

This study examined the extent and effect of complete treatment response (on a molecular level) in patients treated with imatinib (Gleevac) for chronic myeloid leukemia (CML). Researchers reported that a high proportion of patients treated with imatinib reached complete molecular remission, particularly when given at a high dose. Complete molecular remission predicted survival better than complete cytogenetic remission.

Most people with CML have genetic abnormalities in certain chromosomes (cell structures that carry genetic information). In CML, part of the genetic material from one chromosome moves to another chromosome. This change results in an abnormally short chromosome that is called the Philadelphia chromosome. This chromosome carries a gene abnormality called BCR-ABL, which plays a role in the development of CML.

Patients who are no longer showing any cells with the Philadelphia chromosome in their blood or bone marrow after treatment are considered to have reached complete cytogenetic response. Patients who achieved complete cytogenetic remission have a similar life expectancy to that of the general population. An even stronger response to treatment is molecular remission (MR), when the amount of BCR-ABL gene in the blood is low or untraceable. Patients who reach a deep MR may be able to stop treatment.

Tyrosine kinase inhibitors, such as imatinib, are a type of targeted therapy that block enzymes called tyrosine kinases. These are often used to treat CML. Little is known about the proportion of patients who can achieve MR and the effect of high-dose imatinib on MR.

The aim of this study was to examine the effect of MR in patients treated with different doses of imatinib.

1,551 CML patients were included in this study. In these patients, CML was newly diagnosed and in the chronic (early) phase. Patients were randomly assigned to 5 different imatinib-based treatments. 406 patients were treated with low-dose imatinib (400 mg per day). 422 patients were treated with high-dose imatinib (800 mg per day after a 6-week run-in period with 400 mg per day). 434 patients were treated with imatinib (400 mg per day) in combination with interferon alfa (a type of biological therapy). 434 patients were treated with imatinib (400 mg per day) in combination with low-dose cytarabine (a chemotherapy drug). 131 patients were treated with imatinib (400 mg per day) after failure of interferon alfa treatment. The incidence of MR was followed over an average period of 67.5 months.

The overall survival rate (proportion who have not died from any cause since treatment) at 5 years was 90%. 87.5% of patients were progression-free at 5 years. The overall survival probability at 8 years was 86%.

Across all patients, the incidence of major MR after 9 years was 70%. 54% of patients reached complete MR. The average time to MR over all treatment groups was 4.9 years. MR was reached significantly faster (14 months faster on average) with high-dose imatinib compared to any other treatment except imatinib plus interferon alfa. High-dose imatinib was found to be an independent predictor of MR. Patients treated with imatinib after failure of interferon alfa achieved responses significantly later compared to the other treatment groups.

Complete MR at 4 years was associated with a significant survival benefit over complete cytogenetic remission, regardless of treatment group. 8-year overall survival for patients who achieved complete MR was 92%. This was 83% for patients who achieved complete cytogenetic remission. No patient with complete MR experienced disease progression during the study period. In contrast, 13 patients who reached complete cytogenetic remission experienced disease progression.

Researchers concluded that MR is achieved by the majority of patients treated with imatinib, particularly those treated with a high dose. MR predicts survival better than complete cytogenetic remission.