gms | German Medical Science

For many years, hematologic control and cytogenetic response have been the primary goals in the treatment of CML patients. In the imatinib era, high rates of complete cytogenetic remission, the availability of sensitive methods to detect residual disease, and strategies for treatment optimization are the basis to integrate regular molecular monitoring into the standards for the disease management. Several studies have shown that quantification of residual tumor cells significantly correlates with clinical outcome. Therefore, detection of minimal residual disease (MRD) is now becoming routinely implemented in protocols for guiding therapy and for evaluation of new treatment modalities. Treatment with imatinib in chronic phase CML patients is associated with a rapid and steady decrease of BCR-ABL transcript levels but only a minority of patients achieve complete molecular remission. Unfortunately, the lack of standardization of the methodology represents a major barrier in the comparison of data generated in different trials. Therapeutic response can be expressed in three ways: (i) Calculation of the ratio of mRNA transcripts of target to reference gene during therapy, e.g. ratio BCR-ABL/ABL, (ii) Individual calculation of the relative molecular response, i.e. comparison of the MRD level after therapy vs the pretherapeutic level, and (iii) use of a lab-specific reference point, e.g. a pool of diagnostic samples for calculation of the log reduction. In the IRIS trial, a three-log reduction after 12 months of imatinib therapy was accompanied by a 95% relapse free survival after 54 months and defined as major molecular response (MMR). The reference sample, however, is not available for widespread distribution. As an alternative, the calculation of the ratio BCR-ABL/ABL is a rational approach to express MRD levels and has been widely accepted to monitor patients after allogeneic stem cell transplantation, to optimize timing and dosage of donor lymphocyte infusions in case of molecular relapse, and to determine response and outcome prediction after therapy with interferon alpha. During imatinib therapy, BCR-ABL/ABL ratios <0.1% predict for long-term response. A minority of patients are either refractory to imatinib or eventually relapse. Relapse with imatinib frequently depends on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL–independent disease progression not amenable to imatinib inhibition. Sequencing of the BCR-ABL kinase domain revealed acquired mutations which lead to substitutions of amino acids which are important for specific binding of imatinib. In vitro analysis of the capacity of imatinib to inhibit mutated ABL protein demonstrated variable biological consequences of these mutations. These observations have established the rationale for strategies to avoid and overcome imatinib resistance in the management of CML patients. In conclusion, therapy surveillance by molecular methods has become a crucial part of the clinical management of CML patients. However, international standardization of the methodology is required to establish a basis for therapeutic decisions.