Hematological malignancies

Acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by a clonal expansion of myeloid cells in the marrow frequently resulting in hematopoietic insufficiency (granulocytopenia, thrombocytopenia, or anemia). Recurrent chromosomal structural aberrations are encountered that greatly contribute to improvements in prognostication. However, approximately 50% of patients with AML are cytogenetically normal (CN) and lack those recurrent structural abnormalities. In the last decades the identification of numerous novel somatic mutations in AML patients, including this cytogenetic normal (CN) group, that serve as prognostic markers and/or potential therapeutic targets have led to an important progress to the treatment of AML. In the NGS panel we test for the presence of mutations in 31 genes. The recommendations of the ELN2022 guidelines are included in this panel.

Myelodysplastic syndromes

Myelodysplastic syndromes (MDS) represents a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis resulting in an expansion of poorly differentiated hematopoietic precursors with a propensity to transform into AML. MDS patients are risk-stratified according to the International Prognostic Scoring System (IPSS).

Analysis of genes that are frequently mutated in MDS is relevant for patients suspected for MDS as the absence of mutations make this diagnosis less likely, and these patients have significantly lower risk for disease progression. Moreover, the presence of certain mutations are related to prognosis, independently of other established risk factors (Steensma DP). Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, whereas mutations in SF3B1 are favorable (Bejar et al).
Furthermore, also in patients with cytopenia in the absence of dysplasia, the presence of specific combinations of mutations, such as a mutation in TET2, DNMT3A or ASXL1 together with co-mutations in RUNX1, EZH2, CBL, TP53, NRAS or IDH2 or a mutation in spliceosome genes (SF3B1, SRSF2, U2AF1, ZRSR2) is of prognostic significance, as 70-95% of these patients develop MDS/AML within 4 years. These patients have a comparable survival and disease progression as patients diagnosed with MDS without excess blasts (Malcovati et al). More recently it has been demonstrated that even in healthy subjects the presence of somatic mutations in IDH1, IDH2, TP53, DNMT3A, TET2 or spliceosome genes significantly increased the odds of developing AML, with very high risk in individuals with IDH1, IDH2 or TP53 mutations (Desai et al).

Thus, analysis of mutations in MDS patients has clear prognostic significance and can improve risk-stratification of MDS.

Myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) comprise a group of clonal hematopoietic stem cell disorders characterized by overproduction of one or more myeloid cell lineages. MPN patients have a tendency to transform to AML and a risk of vascular events (thrombosis). Almost all MPNs are associated with clonal abnormalities and account for two main groups: BCR-ABL1-positive chronic myeloid leukemia (CML) and the BCR-ABL1-negative MPN. The BCR-ABL1 negative MPN group encompasses polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic neutrophilic leukemia and MPN unclassifiable. JAK2 V617F mutations are commonly encountered in MPN (PV:95%, ET:60%, PMF:40-50%) (Kralovics et al). JAK2V617F-negative PV might show mutations in JAK2 exon12 (Scott et al), whereas JAK2V617F-negative ET and PMF may show activating mutations in the MPL gene (Boyd et al). Frameshift mutations in the CALR exon 9 are commonly encountered in JAK2/MPL wild-type ET and PMF (70-85%) (Klamfl et al). In the absence of JAK2, CALR or MPL mutations the presence of somatic mutations in other genes (e.g. ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1) can possibly unravel the clonal nature of the disease (Tefferi, Vainchenker).