Second line small molecule therapy options for treating chronic myeloid leukemia

Introduction: Approximately 33% of chronic myeloid leukemia (CML) patients discontinue treatment with imatinib in the long-term due to resistance and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) have added complexity to the treatment paradigm for this disease.

Areas covered: Second generation TKIs, approved as second-line treatment in all phases of the disease, are highly effective in patients resistant to and/or intolerant to imatinib and are extremely active against all the resistant BCR-ABL1 mutations, with the exception of T3151. Ponatinib, active against all BCR-ABL1 mutants including T315I, became widely used for resistant patients in all phases of disease after previous therapies. Other drugs, such as ABL001, which targets the myristoyl pocket of the ABL1 kinase, are currently in development, to offer therapeutic alternatives for resistant patients to ATP-binders.

Expert opinion: In this review, we summarize the efficacy of second line small molecules available. Specific safety profiles have emerged for each drug from sponsored clinical trials in the long-term. Stratification of patients according to comorbidities and cardiovascular risk is now needed to individualize second line treatment. Combinations of different drugs with different mechanisms of action will be used in the future to decrease the incidence of resistance.