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Tyrosine Kinase Inhibitors in Ph+ Chronic Myeloid Leukemia Therapy: a Review

  • Shah, Krupa (Medicinal Chemistry & Pharmacogenomics, The Gujarat Cancer & Research Institute) ;
  • Parikh, Sonia (Dept. of Medical oncology, The Gujarat Cancer & Research Institute) ;
  • Rawal, Rakesh (Medicinal Chemistry & Pharmacogenomics, The Gujarat Cancer & Research Institute)
  • Published : 2016.07.01

Abstract

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. Deregulated BCR-ABL fusion tyrosine kinase activity is the main cause of CML disease pathogenesis, making BCR-ABL an ideal target for inhibition. Current tyrosine kinase inhibitors (TKIs) designed to inhibit BCR-ABL oncoprotein activity, have completely transformed the prognosis of CML. Interruption of TKI treatment leads to minimal residual disease reside (MRD), thought to reside in TKI-insensitive leukaemia stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML either as small molecule master TKIs or phytopharmaceuticals derived from nature to achieve chronic molecular remission. This review outlines the past, present and future therapeutic approaches for CML including coverage of relevant mechanisms, whether ABL dependent or independent, and epigenetic factors responsible for developing resistance against TKIs. Appearance of mutant clones along the course of therapy either pre-existing or induced due to therapy is still a challenge for the clinician. A proposed in-vitro model of generating colony forming units from CML stem cells derived from diagnostic samples seems to be achievable in the era of high throughput technology which can take care of single cell genomic profiling.

Keywords

Tyrosine kinase inhibitors;targeted therapy;minimal residual disease;colony forming units

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