Treatment-free remission after third-line therapy with asciminib in chronic myeloid leukemia with an atypical e19a2 BCR::ABL1 transcript and T315I mutation
Philipp Ernst, Jenny Rinke, Georg‐Nikolaus Franke, Frank Dicker, Torsten Haferlach, Thomas Ernst, Andreas Hochhaus
Abstract
Chronic myeloid leukemia (CML) is characterized by a reciprocal translocation between chromosome 9 and 22 in the hematopoietic stem cell that results in formation of the Philadelphia chromosome (Ph), encoding the BCR::ABL1 fusion gene [ 1 ]. The formation of the corresponding BCR::ABL1 oncoprotein causes the depletion of the N-terminal cap of Abelson murine leukemia viral oncogene homolog 1 (ABL1), which under physiological conditions binds in the myristoyl pocket of the C-terminal lobe of the kinase domain and thereby negatively regulates its activity [ 2 ]. Loss of ABL1 autoregulation contributes to the constitutive activation of BCR::ABL1, driven by homo-oligomerisation of BCR::ABL1 mediated by the coiled-coil domain of the breakpoint cluster region (BCR) protein [ 3 ], which in turn induces uncontrolled proliferation and survival of leukemia stem cells. Apart from the typical BCR::ABL1 transcripts e13a2 and e14a2, less than 2% of patients express atypical transcripts such as e1a2, e8a2, or e19a2. In these cases, however, reliable monitoring by routine real-time quantitative polymerase chain reaction (RT-qPCR) is not feasible, therefore an assessment of the individual molecular response with specific RT-qPCR primers is recommended [ 4 , 5 ].