The clinical impact of the molecular landscape of acute myeloid leukemia

Abstract

Research into the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. Despite the progress in unraveling the tumor genome, only a small number of recurrent mutations have been incorporated into risk-stratification schemes and have been proven to be clinically relevant, targetable lesions. The current World Health Organization Classification of myeloid neoplasms and leukemia includes eight AML categories defined by recurrent genetic abnormalities as well as three categories defined by gene mutations. We here discuss the utility of molecular markers in AML in prognostication and treatment decision-making. New therapies based on targetable markers include IDH inhibitors (ivosidenib, enasidenib), venetoclax-based therapy, FLT3 inhibitors (midostaurin, gilteritinib, and quizartinib), gemtuzumab ozogamicin, magrolimab and menin inhibitors.

Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition

“…29,31,32 Accumulation of epigenetic modifications together with occurrence of TET2, IDH1, and IDH2 gene mutations are proposed as the main driven genetic events favoring MDS transformation to AML. 7,29,33 Most frequent mutations involve SF3B1, TET2, ASXL1, SRSF2, DNMT3A, RUNX1, U2AF1, ZRSR2, STAG2, TP53, EZH2, CBL, JAK2, BCOR, IDH2, NRAS, and NF1 genes, and some of these alterations have prognostic impact, such as SF3B1 mutations associated with the presence of ring sideroblasts and altering spliceosome machinery activities. 6,29,31,34 Overall, MDS show a higher genomic instability, as cytogenetics abnormalities are found in about 50% of patients, while whole exome sequencing can detect recurrent somatic mutations in 80%-90% of cases, usually six per exome in low-risk MDS and nine in MDS with excess blasts.…”

“…In MDS, genetic landscape differs between low‐ and high‐risk MDS and between those myelodysplasias that rapidly progress to AML 29,31,32 . Accumulation of epigenetic modifications together with occurrence of TET2 , IDH1 , and IDH2 gene mutations are proposed as the main driven genetic events favoring MDS transformation to AML 7,29,33 . Most frequent mutations involve SF3B1 , TET2 , ASXL1 , SRSF2 , DNMT3A , RUNX1 , U2AF1 , ZRSR2 , STAG2 , TP53 , EZH2 , CBL , JAK2 , BCOR , IDH2 , NRAS , and NF1 genes, and some of these alterations have prognostic impact, such as SF3B1 mutations associated with the presence of ring sideroblasts and altering spliceosome machinery activities 6,29,31,34 .…”

Myeloid NGS Analyses of Paired Samples from Bone Marrow and Peripheral Blood Yield Concordant Results: A Prospective Cohort Analysis of the AGMT Study Group

“…The patients may also decline repeated bone marrow evaluations [ 35 ]. Thus, a real-world clinical need exists to be able to obtain information on the mutational status of a patient’s disease without the requirement for repetitive bone marrow evaluations, especially as frequent molecular monitoring is desirable for adequate risk stratification [ 31 , 57 ], prognostication [ 15 , 32 ], and for adequate clinical management [ 58 , 59 , 60 , 61 ].…”

Acute myeloid leukemia: introduction to a series highlighting progress and ongoing challenges

“…In the first paper 9 Sabine Kayser and Mark Levis summarize the current knowledge of the molecular landscape of AML, focusing particularly on the utility of molecular markers in prognostication and treatment decision-making in AML. The second paper 10 broadens the view on AML biology with an emphasis on therapy-resistant cells harboring stem cell properties.…”