Chronic Myeloproliferative Neoplasms: Some Remaining Challenges

Following millennia of clinical medicine’s efforts to embrace standard daily dose of 400mg after 6 years due to either lack of personalized, more effective and kinder treatments, arguably, it is the lessons garnered from patients with chronic myeloid leukemia (CML) in the chronic phase (CP) that appear to be moving us closer to the prospect of precision cancer medicine. The BCRABL1 fusion gene encodes the oncoprotein BCR-ABL1 with a constitutive active tyrosine kinase activity that is the sole primary driver of the CP of CML. The discovery in 1996 that this kinase activity could be inhibited by imatinib mesylate (imatinib), a firstgeneration tyrosine kinase inhibitor (TKI) was pivotal. It established a new paradigm of targeted treatment for diverse cancers, in which relatively nonspecific and often toxic drugs are gradually being replaced by a cornucopia of safer, and in some cases, better targeted therapies and immunotherapies. Imatinib substantially and durably reduces the number of CML cells in the CP at a daily oral dose of 400mg, and the life expectancy of most patients now approaches that of the general population. The greatest advance is in those patients who achieve a complete cytogenetic response within 2 years of starting imatinib leading to life spans indistinguishable from the general population. These impressive results with imatinib therapy have had profound effects on the natural history of CML and its prevalence. Current estimates suggest that in the United States, where about 5500 new cases are diagnosed annually, the prevalence may well increase to about 120,000 by 2020 and to about 200,000 by 2050. However, imatinib is far from perfect, with only approximately 60% of patients remaining on the