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In the context of chronic myeloid leukemia (CML) resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL1 tyrosine kinase domain (TKD) mutations still remain the sole biological marker that directly condition therapeutic decision. These recommendations aim at updating the use of BCR-ABL1 mutation testing with respect to new available therapeutic options and at repositioning different testing methods at the era of next generation sequencing (NGS). They have been written by a panel of experts from the French Study Group on CML (Fi-LMC), after a critical review of relevant publications. TKD mutation testing is recommended in case of treatment failure but not in case of optimal response. For patients in warning situation, mutation testing must be discussed depending on the type of TKI used, lasting of the treatment, kinetic evolution of BCR-ABL1 transcripts along time and necessity for switching treatment. The kind and the frequency of TKD mutations occasioning resistance mainly depend on the TKI in use and disease phase. Because of its better sensitivity, NGS methods are recommended for mutation testing rather than Sanger's. Facing a given TKD mutation, therapeutic decision should be taken based on in vitro sensitivity and clinical efficacy data. Identification by sequencing of a TKD mutation known to induce resistance must lead to a therapeutic change. The clinical value of testing methods more sensitive than NGS remains to be assessed.

In the context of chronic myeloid leukemia (CML) resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL1 tyrosine kinase domain (TKD) mutations still remain the sole biological marker that directly condition therapeutic decision. These recommendations aim at updating the use of BCR-ABL1 mutation testing with respect to new available therapeutic options and at repositioning different testing methods at the era of next generation sequencing (NGS). They have been written by a panel of experts from the French Study Group on CML (Fi-LMC), after a critical review of relevant publications. TKD mutation testing is recommended in case of treatment failure but not in case of optimal response. For patients in warning situation, mutation testing must be discussed depending on the type of TKI used, lasting of the treatment, kinetic evolution of BCR-ABL1 transcripts along time and necessity for switching treatment. The kind and the frequency of TKD mutations occasioning resistance mainly depend on the TKI in use and disease phase. Because of its better sensitivity, NGS methods are recommended for mutation testing rather than Sanger's. Facing a given TKD mutation, therapeutic decision should be taken based on in vitro sensitivity and clinical efficacy data. Identification by sequencing of a TKD mutation known to induce resistance must lead to a therapeutic change. The clinical value of testing methods more sensitive than NGS remains to be assessed.

Second-generation tyrosine kinase inhibitors (TKI 2) represent a recent important improvement in the treatment of Philadelphia positive leukemias. These agents are a suitable major option if resistance or significant imatinib intolerance occurs in chronic and accelerated phase CML. They are now introduced as first line therapy in chronic phase CML where they induce cytogenetic and molecular response rates never seen to date, which is promising for long-term survival. We propose here an analysis of the main current data available for the use of TKI 2 in CML.

Second-generation tyrosine kinase inhibitors (TKI 2) represent a recent important improvement in the treatment of Philadelphia positive leukemias. These agents are a suitable major option if resistance or significant imatinib intolerance occurs in chronic and accelerated phase CML. They are now introduced as first line therapy in chronic phase CML where they induce cytogenetic and molecular response rates never seen to date, which is promising for long-term survival. We propose here an analysis of the main current data available for the use of TKI 2 in CML.

The treatment of chronic myeloid leukemia (CML) has considerably evolved since imatinib mesylate has been introduced as a new therapeutic weapon for this disease. The 5-year updated results of the IRIS study confirmed that imatinib mesylate is the best first line therapy for chronic phase CML with an overall survival of 90%. Responses improve with time and complete cytogenetic and major molecular levels reach 87 and 70% respectively at 5 years. However, despite these remarkable improvements, new problems arise as sub-optimal responses, imatinib-resistances with recently identified BCR-ABL protein point mutations, responsible for a variety of therapeutic consequences : imatinib dose increase, alternative treatments with second generation tyrosine kinase inhibitors (TKIs : dastinib, nilotinib) or allogeneic stem cell transplantation. The treatment of accelerated and blastic phases relies on imatinib +/- conventional chemotherapy, ideally followed by allogeneic stem cell transplantation, as newly developed TKIs are currently evaluated within this frame. Finally, BCR-ABL(T315I) mutations remain a new therapeutic critical challenge as none of the three TKIs (imatinib, nilotinib, dasatinib) can efficiently control such diseases.