Pharmacotherapeutic Options for Philadelphia Chromosome-Positive CML

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative disorder of hematopoietic stem cells. Identifying the leading mutation in BCR-ABL that causes CML made it possible to develop a targeted approach against this vastly disseminating disease. The active tyrosine kinase protein of BCR-ABL was effectively blocked with an identified tyrosine kinase inhibitor (TKI), imatinib. Imatinib became the first targeted therapy licensed for patients with chronic-phase CML and its introduction was associated with substantial improvements in response and survival compared with previous therapies. However, drug resistance towards imatinib therapy soon emerged and hence limited the complete eradication of CML in patients receiving imatinib. This is primarily due to the mutations within the ABL kinase domain, and to a lesser degree, due to residual disease after treatment. Nilotinib and dasatinib were soon introduced and showed improved clinical outcomes in patients intolerant and resistant to imatinib treatment. However, the T315I mutant overcame these agents along with imatinib, rendering the treatment ineffective. Exploring the kinase domain of the BCR-ABL protein and identifying key components involved in the signal transduction pathways is crucial towards understanding the disease and developing better strategic approaches towards combating it. In this review, we broadly discuss the current treatment options available against Philadelphia chromosome (Ph) positive BCR-ABL CML.