Targeted therapies in the treatment of adult acute myeloid leukemias: current status and future perspectives

Abstract

The rapid advancement of next-generation sequencing techniques and the identification of molecular driver events responsible for leukemia development are opening the door to new pharmacologic-targeted agents to tailor treatment of acute myeloid leukemia (AML) in individual patients. However, the use of targeted therapies in AML has met with only modest success. Molecular studies have identified AML subsets characterized by driver mutational events, such as NPM1, FLT3-ITD and IDH1-2 mutations, and have provided preclinical evidence that the targeting of these mutant molecules could represent a valuable therapeutic strategy. Recent studies have provided the first pieces of evidence that FLT3 targeting in FLT3-mutant AMLs, IDH1/2 inhibition in IDH-mutant AMLs and targeting membrane molecules preferentially expressed on leukemic progenitor/stem cells, such as CD33 and CD123, represent a clinically valuable strategy.

Keywords: acute myeloid leukemia; clinical trials; leukemia; leukemic progenitor/stem cells; molecular abnormalities; new drugs; targeted therapy.

Figure 1.. Molecular classification of acute myeloid leukemias according to the study of Papaemmanuil et al.

This classification was based on the results derived from the whole-genome sequencing of 1540 adult AMLs [4]. This analysis allowed to classify AMLs in 13 nonoverlapping molecular subtypes, characterized by a typical pattern of driver mutations: AML with NPM1 mutation, corresponding to about 27% of all AMLs (these AMLs frequently display DNMT3A, FLT3–ITD, NRAS, TET2 and PTPN11 mutations, in decreasing order); AML with mutated chromatin, RNA splicing genes such as RUNX1, MLL-PTD, ASXL1 and STAG2, corresponding to about 18% of all AMLs (these AMLs frequently display DNMT3A, NRAS, TET2 and FLT3–ITD mutations); AML with mutated chromatin, chromosomal and aneuploidy or both, including complex karyotype, -5/5q, -7/7q, TP53 mutations, -17/17p and -12/12p, corresponding to about 13% of all AMLs; AML with inv (16) (p13.1q22) or t(16;16) (p13.1; q22); CBFB-MYH11, corresponding to about 5% of all AMLs (these AMLs frequently display NRAS, KIT and FLT3–ITD mutations); AML with biallelic CEBPA mutations, corresponding to about 4% of all AMLs (these AMLs frequently exhibit NRAS, WT1 and GATA2 mutations); AML with t(15;17) corresponding to about 4% of all AMLs (these AMLs frequently exhibit FLT3–ITD and WT1 mutations); AML with t(8;21) (q 22; q 22); RUNX1–RUNX1T1, corresponding to about 4% of all AMLs (these AMLs frequently display KIT mutations, -Y and -9q); AML with MLL fusion genes; t(x;11) (x;q23), corresponding to about 3% of all AMLs (these AMLs frequently exhibit NRAS mutations); AML with inv (3) (q21q26.2) or t(3;3) (q 21; q26.2) ; GATA2, MECOM (EVI1), corresponding to about 1% of all AMLs (these AMLs frequently display -7 and KRAS, NRAS, PTPN11, ETV6, PHF66 and SF3B1 mutations), AML with IDH-R172 mutations, in the absence of other class-defining alterations, corresponding to about 1% of all AMLs (these AMLs frequently exhibit DNMT3A mutations and +8/8q); AML with t(6;9) (p23;q34); DEK-NUP214, corresponding to about 1% of all AMLs (these AMLs frequently display FLT3–ITD and KRAS mutations); AML with driver mutations, but no detected class-defining alteration (about 11% of all AMLs); AML with no detected driver mutation (about 4% of all AMLs); AML that meets criteria for ≥2 genomic subgroups (about 4% of all AMLs) [4]. These molecularly defined AML groups are prognostically relevant in that: among gene fusion groups, inv (16) and t(15;17) are associated with a good prognosis, t(8;21) with an intermediate prognosis and t(6;9), MLL fusion and inv (3) with a poor outcome. Among the AMLs with no gene fusions, CEBPA biallelic and IDH2-R172 had the best outcome, NPM1-mutated and intermediate risk and chromatin-spliceosome and TP53-aneuploidy a poor risk [4]. The outcome of NPM1-mutant AMLs was related to the presence of the concomitant DNMT3A and FLT3–ITD mutations: thus, the NPM1/DNMT3A, FLT3–ITD mutant subgroup had a clearly poorer survival than NPM1/DNMT3A-mutant AMLs [4]. AML: Acute myeloid leukemia. Data taken from [4].

Figure 2.. Clonal mutational evolution of acute myeloid leukemia.

The picture shows the sequential acquisition of somatic mutations occurring during leukemia development from a preleukemic condition until to leukemia relapse. Three different patterns of leukemic evolution are observed: founding mutations are enriched in epigenetic regulatory genes (DNMT3A, TET2, IDH1, IDH2, ASXL1), while late mutations occur preferentially at the level of genes involved in proliferative activated signaling (FLT3, KRAS/NRAS, NPM1); in other AMLs, founding mutations are represented by CBF and MLL rearrangements, which induce both epigenetic and transcription factor deregulation, and in these leukemias there is less requirement for additional genetic lesions; in other AMLs, founding mutations occur at the level of TP53 alone or together with an epigenetic gene (DNMT3A) and in these leukemia late events are represented by complex karyotype lesions and, less frequently, by NPM1, RAS and FLT3 mutations. HSC: Hematopoietic stem cell.