Next Generation Sequencing in AML-On the Way to Becoming a New Standard for Treatment Initiation and/or Modulation?

Abstract

Acute myeloid leukemia (AML) is a clonal disease caused by genetic abberations occurring predominantly in the elderly. Next generation sequencing (NGS) analysis has led to a deeper genetic understanding of the pathogenesis and the role of recently discovered genetic precursor lesions (clonal hematopoiesis of indeterminate/oncogenic potential (CHIP/CHOP)) in the evolution of AML. These advances are reflected by the inclusion of certain mutations in the updated World Health Organization (WHO) 2016 classification and current treatment guidelines by the European Leukemia Net (ELN) and National Comprehensive Cancer Network (NCCN) and results of mutational testing are already influencing the choice and timing of (targeted) treatment. Genetic profiling and stratification of patients into molecularly defined subgroups are expected to gain ever more weight in daily clinical practice. Our aim is to provide a concise summary of current evidence regarding the relevance of NGS for the diagnosis, risk stratification, treatment planning and response assessment in AML, including minimal residual disease (MRD) guided approaches. We also summarize recently approved drugs targeting genetically defined patient populations with risk adapted- and individualized treatment strategies.

Keywords: AML; NGS; acute myeloid leukemia; minimal residual disease; next generation sequencing; targeted therapy.

Figure 1

Pathogenesis of AML. (A) Premalignant stages preceeding to evolution of AML: early mutations in hematopoietic stem cells lead to clonal hematopoiesis (CHIP/CHOP) with genetically different premalignant stem cell subclones. (B) Subclonal genetic heterogeneity alongside AML development and progression is schematically depicted. NGS-based characterization of clonal and subclonal mutations is important for prognosis, treatment and response assessment (see text for explanations). HSC: Hematopoietic stem cell, VAF: Variant allelic frequency, CHIP: Clonal hematopoiesis of indeterminate potential, CHOP: Clonal hematopoiesis with substantial oncogenic potential, MRD: Minimal residual disease; NGS: Next generation sequencing, NCCN: National Comprehensive Cancer Network, ELN: European Leukemia Network.

Figure 2

Cellular localization and mechanism of action of drugs targeting specific mutations. I. Targeting mutant FLT3 with TKI-inhibitors including midostaurin, quizartinib, crenolanib, gilteritinib and lestaurtinib. Mutations in FLT3 are present in approx. 30% of AML patients. II. Targting mutant IDH1 and IDH2 with IDH1 and IDH2 inhibitors including enasidenib and ivosidenib. Mutations in IDH are present in approx. in 30% of elderly AML patients. Both TET2 loss-of-function and IDH1/2 gain-of-function mutations result in reduced 5-hmC levels and in global promoter (and histone) hypermethylation. III. Targeting Bcl-2: Venetoclax binds to Bcl-2 thereby causing translocation of proapoptotic proteins (BIM, BAX) to the mitochondria. FLT3-ITD: fms like tyrosine kinase 3-internal tandem duplication; FLT3-TKD: fms like tyrosine kinase 3-tyrosine kinase domaine; STAT5: Signal transducer and activator of transcription 5; PI3K: Phosphoinositide 3-kinase; AKT: proteine kinase B; Ras/Raf: Rat sarcoma/rapidly accelerated fibrosarcoma; MEK: Mitogen-activated protein kinase kinase; ERK: extracellular signal–regulated kinases; bcl-2: B-cell lymphoma 2; BIM: Bcl-2-like protein 11; BAX: Bcl-2-associated X protein; IDH: isocitrate dehydrogenase; α-KG: alpha ketoglutarate; Fe(II): iron; 5-mC: 5-methylcytosine; 5-hmC: 5-hydroxymethylcytosine; TET2: Tet methylcytosine dioxygenase 2; 5-fC: 5-fluorcytosine, JMJC: Jumonji C -domain-containing proteins.