Monitoring minimal residual disease in BCR-ABL-positive chronic myeloid leukemia in the imatinib era

Abstract

The total number of leukemia cells in the body is reduced very substantially in patients with BCR-ABL-positive chronic myeloid leukemia (CML) responding to imatinib. This reduction is seen first as restoration of Ph negativity in blood and marrow and thereafter as decreasing BCR-ABL transcript levels assayed by quantitative polymerase chain reaction (PCR). Most patients with newly diagnosed chronic-phase CML who receive imatinib achieve complete cytogenetic remission (CCYR) and low levels of BCR-ABL transcripts, a status that seems to predict for relatively long survival compared with previous treatments. Patients treated with 400 mg daily who achieved a reduction in BCR-ABL transcript numbers equal or greater than 3 logs compared with a baseline value have a significantly better progression-free survival than those who achieved lesser degrees of response. The presence of Ph-positive subclones with point mutations in the ABL kinase domain correlates with "acquired" resistance to imatinib and some mutations are associated with greater resistance than others. Preliminary evidence suggests that P-loop mutations are especially likely to be associated with progression to advanced-phase disease. Patients with CML should be monitored routinely by serial cytogenetic analysis of bone marrow until Ph negativity is achieved. Thereafter serial quantitative-PCR studies should be undertaken at approximately 3-month intervals and probably also bone marrow cytogenetic studies at longer intervals. Routine studies for ABL kinase domain mutations may also be advisable. The observation of increasing quantities of residual leukemia or expansion of a mutated clone suggests the need to modify therapy.