Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities

Abstract

Despite improvements in our understanding of the molecular basis of acute myeloid leukemia (AML), the association between genetic mutations with morphological dysplasia remains unclear. In this study, we evaluated and scored dysplasia in bone marrow (BM) specimens from 168 patients with de novo AML; none of these patients had cytogenetic abnormalities according to the 2016 World Health Organization Classification. We then performed targeted sequencing of diagnostic BM aspirates for recurrent mutations associated with myeloid malignancies. We found that cohesin pathway mutations [q (FDR-adjusted P)=0.046] were associated with a higher degree of megakaryocytic dysplasia and STAG2 mutations were marginally associated with greater myeloid lineage dysplasia (q=0.052). Frequent megakaryocytes with separated nuclear lobes were more commonly seen among cases with cohesin pathway mutations (q=0.010) and specifically in those with STAG2 mutations (q=0.010), as well as NPM1 mutations (q=0.022 when considering the presence of any vs. no megakaryocytes with separated nuclear lobes). RAS pathway mutations (q=0.006) and FLT3-ITD (q=0.006) were significantly more frequent in cases without evaluable erythroid cells. In univariate analysis of the 153 patients treated with induction chemotherapy, NPM1 mutations were associated with longer event-free survival (EFS) (P=0.042), while RUNX1 (P=0.042), NF1 (P=0.040), frequent micromegakaryocytes (P=0.018) and presence of a subclone (P=0.002) were associated with shorter EFS. In multivariable modeling, NPM1 was associated with longer EFS, while presence of a subclone and frequent micromegakaryocytes remained significantly associated with shorter EFS.

Machine learning integrates genomic signatures for subclassification beyond primary and secondary acute myeloid leukemia

“…11,12 These AML subtypes are themselves nonspecific because of variation in the understanding of their pathogenetic links, especially in cases without overt dysplasia. 13,14 Without dysplasia, reliance is mainly on anamnestic clinical information that might be unavailable or cannot be correctly assigned because of a short prodromal history of antecedent myeloid neoplasm. Additionally, supervised analytic strategies to reproduce current pathomorphologic entities as gold standard using molecular features have been modest.…”

Effect of DNMT3A variant allele frequency and double mutation on clinicopathologic features of patients with de novo AML

“…BM aspirate smears were evaluated for blast count as well as dysplasia in the erythroid, granulocytic, and megakaryocytic lineages as previously reported. 22 Dysplasia was scored in a blinded fashion by 3 board-certified, expert hematopathologists (O.P., R.P.H., and O.K.W.). Each lineage was assessed for individual dysplastic features (erythroid precursors: megaloblastic change, multinucleation, and nuclear irregularities; granulocytic precursors: abnormal nuclear shape and hypogranulation; megakaryocytes: micromegakaryocytes, widely separated nuclear lobes, and hypolobated nuclei).…”

“…The severity of dysplasia in each lineage was scored on a scale of 0 to 4 (0, no dysplasia; 1, mild dysplasia; 2, moderate dysplasia; 3, significant dysplasia; 4, severe dysplasia), and the percentage of dysplastic cells in each lineage was quantified, as previously described. 22…”

Upfront allogeneic hematopoietic cell transplantation (HCT) versus remission induction chemotherapy followed by allogeneic HCT for acute myeloid leukemia with multilineage dysplasia: A propensity score matched analysis

“…Previous studies showed that mutations in CEBPA, NPM1, FLT3-ITD, NRAS, ASXL1, EZH2, BCOR, or STAG2 were altered in AML-MRC, particularly with the presence of dysplasia and a history of MDS and/or MDS-related cytogenetic abnormalities. 3,7,[34][35][36] These mutations might also affect the relapse incidences after HCT. Second, the types of induction chemotherapy and consolidation or salvage chemotherapy following induction chemotherapy could not be evaluated due to insufficient data.…”