Page 82 - Haematologica-April 2018

Correspondence:
olga.weinberg@childrens.harvard.edu
Received: September 29, 2017. Accepted: January 4, 2018. Pre-published: January 11, 2018.
doi:10.3324/haematol.2017.181842
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Acute Myeloid Leukemia
Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities
Olga K. Weinberg,1 Christopher J. Gibson,2 Traci M. Blonquist,3
Donna Neuberg,3 Olga Pozdnyakova,4 Frank Kuo,4 Benjamin L. Ebert5 and Robert P. Hasserjian5
1Department of Pathology, Boston Children’s Hospital; 2Division of Hematology, Brigham and Women’s Hospital, Dana Farber Cancer Institute; 3Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute; 4Department of Pathology, Brigham and Women’s Hospital and 5Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
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 megakary- ocytic 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 sep- arated 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.
Introduction
Acute myeloid leukemia (AML) is a complex and dynamic disease, characterized by multiple somatically acquired driver mutations, co-existing competing clones, anddiseaseevolutionovertime.1-3 Amajorchallengeintheapplicationofmutation information to clinical management of AML patients is how to integrate it into existing AML risk stratification and classification schemes. The 2016 WHO Classification incorporates cytogenetics, clinical ontogeny, dysplastic morphology in background hematopoietic cells, and the status of certain mutations (NPM1, RUNX1, and CEBPA).4 One main distinction between the WHO Classification and other AML risk stratification schemes, such as the European LeukemiaNet5 and National Comprehensive Cancer Network (NCCN),6 is its use of dysplastic mor- phology to categorize cases in an adverse risk group, AML with myelodysplasia- related changes (AML-MRC). Although there is general agreement as to the adverse effect of MDS-related cytogenetics on the outcome of de novo AML, the clinical and biological significance of morphological dysplasia in this setting is controversial.7
Haematologica 2018 Volume 103(4):626-633
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