engleski

Monitoring CML patients responding to treatment with tyrosine kinase inhibitors with real-time quantitative polymerase chain reaction

Historically, chronic myeloid leukemia (CML) had many revolutional advances in therapy implementation. Discovery of new improved drugs like imatinib mesylate (IM) requires advances in technology in order to enable more precise assessment of response to therapy. Real-time quantitative polymerase chain reaction (RQ-PCR) provides an accurate measure of the total leukemia-cell mass and the degree of BCR-ABL transcripts reduction which correlates with progression-free survival. The aim of the study was to quantitate BCR-ABL transcripts in CML patients and to monitor response to treatment with tyrosine kinase inhibitors. The study included total of 25 patients treated with IM. RNA was isolated from bone marrow or peripheral blood cells. RQ-PCR was performed according to EAC protocol using TaqMan technology (LightCycler, Roche) with ABL as housekeeping gene and BCR-ABL/ABL ratio was calculated. Majority of patients tested were pretreated with hydroxyurea for different period of time but the baseline for each patient that was established prior to IM implementation (400 mg/day) was used for calculation of log reduction. Patients were divided according to calculated log reduction of BCR-ABL/ABL ratio: group I - 1 log reduction, group II - 2 log reduction and group III – equal to or more than 3 log reduction. Group I included 9 patients monitored on average for 53 months (range: 10-81 months) with no more than one log reduction in BCR-ABL/ABL ratio. Because of inadequate response to therapy, the change in treatment occured. Three patients proceeded with higher dose of IM (600 mg/day) ; one patient achieved 2 log reduction in 16 months but the other two did not have significant changes in BCR-ABL/ABL ratio. Treatment with nilotinib was started in other three patients. Two of them achieved 2 log reduction in 6 months while the third patient is in follow-up as well as two patients who started with dasatinib therapy. The patient without any response to IM therapy underwent bone marrow transplantation with undetectable BCR-ABL transcript 6 months later. Group II included 5 patients whose 2 log reduction was achieved in 16 months on average (range: 12-24 months). This group was monitored on average for 31 months (range: 12-56 months) with no significant variation in BCR-ABL/ABL ratio. Only 11 patients (group III) achieved 3 log reduction in 14 months (range: 3-32 months) and fulfilled the criteria for major or complete molecular response. Our results show that RQ-PCR is mandatory for careful monitoring of response to treatment with tyrosine kinase inhibitors in order to ensure that an individual patient receives the proper treatment and to decide if and when a therapy should be changed.

CML; tyrosine kinase inhibitors; real-time quantitative polymerase chain reaction

doi:10.1016/S0145-2126(07)70376-4