Favorable Molecular Responses to Imatinib in CML Patients in Early Chronic Phase in Comparison to Late Chronic Phase Patients after Treatment with Hydroxyurea and Interferon.

Peripheral blood samples from 70 patients treated with imatinib were regularly sent to us for the determination of bcr-abl transcript levels by a standardized quantitative real-time PCR (TaqMan®). 45 patients with early chronic phase CML were treated with imatinib as a first line therapy and 25 patients in late chronic phase received imatinib as a second line therapy after hydroxyurea plus interferon. The median pre-treatment time with hydroxyurea plus interferon in these late chronic patients was 43 months (6 – 130). The median follow-up was 18.4 months (1–51) for first line patients and 18.0 months (1–48) for second line patients. Patients received a median dosage between 400–600 mg imatinib in both groups.

At the time of diagnosis the median bcr-abl/abl ratio was 248 % (26–460%, SD: 148%) in patient receiving imatinib as a first line treatment. Patients receiving imatinib as second line treatment had a median bcr-abl/abl ratio of 24,84% (1–256%, SD: 78%) just before the imatinib treatment was initiated.

Early chronic phase CML patients treated with imatinib as a first line therapy showed a strong biphasic decay of their bcr-abl transcript with a fast reduction between 1-2-log during the first 6–9 months followed by a slower rate of reduction afterwards. A bcr-abl/abl ratio <0.1% could be observed in 19/51 (37%) patients and in 12/51 (23%) patients a bcr-abl/abl ratio < 0.01% was found. After 18 months of therapy the median reduction of bcr-abl was about 2.5-log, after 36 months about 3-log. 12/51 (23%) patients showed a suboptimal response or had a subsequent increase of their bcr-abl transcript levels. Best responding patients could be identified by a >2-log reduction after 6 months and > 3-log reduction after 18 months of therapy.

In late chronic phase CML patients pre-treated with hydroxyurea and interferon the overall median decrease of bcr-abl transcript levels was about 1-log after a median follow-up of 18 as well as after 36–48 months. Obviously, there are at least three subgroups of patients with a different molecular response. We identified 7/25 (28%) patients with no significant reduction of bcr-abl transcripts after 18 months as well as after 36 months of imatinib therapy. In contrast, another group of 4/25 (16%) patients showed a 2-log reduction of bcr-abl/abl ratio after 18 months with a subsequent reduction of 3-log after 36 months. Within the largest group of 14/25 (56%) patients a 1-log reduction after 18 months and a 1-2-log reduction after 36 months was observed. No patient had > 3-log reduction within the whole group of 25 late chronic phase patients.

The reduction of bcr-abl transcript levels as a result of imatinib therapy is significantly superior in CML patients receiving imatinib as first line treatment for CML in early chronic phase compared to patients treated with imatinib after a long term pre-treatment with hydroxyurea and interferon.