Analyzing molecular response in chronic myeloid leukemia clinical trials: pitfalls and golden rules

Clinical trials of chronic myeloid leukemia frequently rely on molecular markers as surrogates for clinical endpoints. Studies suggest that early molecular response (EMR) is a good indicator of a favorable prognosis and yet, to the authors' knowledge, the use of EMR as a robust surrogate marker for clinical response has yet to be fully explored. EMR to therapy appears to be affected by a variety of factors, including disease characteristics, risk score, adherence to treatment, and off-target effects of the treatment. Therefore, although molecular markers improve important research, they also bring with them important questions regarding their reliability. To be useful, markers must be must be easily measureable, capable of generating meaningful data, and clinically relevant. BCR-ABL1 is the hallmark marker in chronic myeloid leukemia. Nevertheless, investigators still struggle with how best to measure and interpret both high and very low BCR-ABL1 levels. Statistical models of BCR-ABL1 kinetics must address these concerns and account for the BCR-ABL1 variability between and within patients. Response models should also incorporate disease characteristics and other important parameters.