Surrogate end points for long-term outcomes in chronic myeloid leukemia.

The natural history of the chronic phase (CP) of chronic myeloid leukemia (CML) and the high response rates achieved with BCR-ABL inhibitor therapy necessitate long-term evaluation of survival-based outcome measures. Prior to the availability of long-term BCR-ABL inhibitor data, short-term surrogate end points predictive of longer-term outcomes have been identified using data from clinical trials of patients with CML-CP treated with interferon-α-based therapy and approved BCR-ABL inhibitors. In patients with newly diagnosed CML-CP treated with imatinib, achieving a complete cytogenetic response (CCyR) by 12 months has been associated with more favorable outcomes, and both CCyR and major cytogenetic response have been used as surrogate end points for regulatory approval. Following approval of second-generation BCR-ABL inhibitors in the first-line setting (nilotinib, dasatinib), which have significantly faster and deeper response rates than imatinib, molecular-based surrogate markers at earlier time points of 3 and 6 months are also being explored, although longer follow-up is needed. As patients who achieve early responses show the greatest long-term benefit, these end points may help to identify patients with suboptimal responses early in treatment who might benefit from switching to a different, more effective therapy.