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.
Authors: Schüler Frank , Leithäuser Malte , Kiefer Thomas , Richter Saskia , Dolken Gottfried 
Published: April 2020

Abstract
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 &lt;0.1% could be observed in 19/51 (37%) patients and in 12/51 (23%) patients a bcr-abl/abl ratio &lt; 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 &gt;2-log reduction after 6 months and &gt; 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 &gt; 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.