Perspectives for therapeutic targeting of gene mutations in acute myeloid leukaemia with normal cytogenetics

Summary The acute myeloid leukaemia ( AML ) genome contains more than 20 driver recurrent mutations. Here, we review the potential for therapeutic targeting of the most common mutations associated with normal cytogenetics AML , focusing on those affecting the FLT 3 , NPM 1 and epigenetic modifier genes ( DNMT 3A , IDH 1/2, TET 2 ). As compared to early compounds, second generation FLT 3 inhibitors are more specific and have better pharmacokinetics. They also show higher anti‐leukaemic activity, leading to about 50% of composite complete remissions in refractory/relapsed FLT 3 ‐internal tandem duplication‐mutated AML . However, rapid relapses invariably occur due to various mechanisms of resistance to FLT 3 inhibitors. This issue and the best way for using FLT 3 inhibitors in combination with other therapeutic modalities are discussed. Potential approaches for therapeutic targeting of NPM 1 ‐mutated AML include: (i) reverting the aberrant nuclear export of NPM 1 mutant using exportin‐1 inhibitors; (ii) disruption of the nucleolus with drugs blocking the oligomerization of wild‐type nucleophosmin or inducing nucleolar stress; and (iii) immunotherapeutic targeting of highly expressed CD 33 and IL 3 RA ( CD 123) antigens. Finally, we discuss the role of demethylating agents (decitabine and azacitidine) and IDH 1/2 inhibitors in the treatment of AML patients carrying mutations of genes ( DNMT 3A , IDH 1/2 and TET 2 ) involved in the epigenetic regulation of transcription.