CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality involving the Bcr-Abl protein. After a slow, chronic phase of production of too many white blood cells, CML typically evolves to more aggressive phases (i.e., “accelerated” phase or “blast crisis”). Treatment with Bcr-Abl inhibitors is initially effective but frequently results in the emergence of Bcr-Abl mutations that confer drug resistance. The T315I mutant of Bcr-Abl currently accounts for 15-20 percent of all drug resistance in CML. First-generation therapies for CML, such as imatinib, and second-generation therapies for CML, such as dasatinib and nilotinib, are not able to inhibit this mutated protein and thus are not effective against all forms of CML—indicating a key unmet medical need.
