New BCR-ABL inhibitors in chronic myeloid leukemia

Abstract

Abstract Despite outstanding progress achieved from the development of 3 generations of ATP-competitive TKIs with increasing BCR-ABL inhibitory potency, some unmet needs remain in chronic myeloid leukemia (CML). First, resistance to therapy and less frequently progression of the disease still occur despite the increasing use of 2nd generation TKIs upfront instead of imatinib and the salvage potential of 2nd or 3rd generation TKIs in refractory CML. Second, none of the currently available TKIs is absolutely safe and the widespread prescription of 2nd or 3rd generation TKIs is tempered by their toxicity, especially in fragile patients or those with comorbid illnesses. Third, at most 30 to 50% of patients obtain a sustained deep molecular response of the MR4.5 type after 5 years when given the 2nd generation TKIs dasatinib or nilotinib upfront and only half of them achieve a state called treatment-free remission (TFR). New agents are currently under development, among which 3 ATP-competitive TKIs and 1 allosteric inhibitor. PF-114, HQP1351 and K0706 are 3rd generation ATP-competitive TKIs capable to target native and mutated BCR-ABL including the T315I gatekeeper mutation like ponatinib. Asciminib (formerly ABL001), an allosteric BCR-ABL inhibitor, is the first compound of a totally new therapeutic class to be evaluated in humans in the setting of phase 1, 2 and 3 trials. During this lecture, preliminary results derived from ongoing studies will be presented, emerging advantages and disadvantages of each compound will be discussed as well as whether current treatment landscape and CML management may be modified by these emerging therapies in the near future.