Diagnostic and therapeutic implications of genetic heterogeneity in myeloid neoplasms uncovered by comprehensive mutational analysis

Abstract

While growing use of comprehensive mutational analysis has led to the discovery of innumerable genetic alterations associated with various myeloid neoplasms, the under-recognized phenomenon of genetic heterogeneity within such neoplasms creates a potential for diagnostic confusion. Here, we describe two cases where expanded mutational testing led to amendment of an initial diagnosis of chronic myelogenous leukemia with subsequent altered treatment of each patient. We demonstrate the power of comprehensive testing in ensuring appropriate classification of genetically heterogeneous neoplasms, and emphasize thoughtful analysis of molecular and genetic data as an essential component of diagnosis and management.

Keywords: BCR-ABL1; CML; JAK2; Myeloproliferative neoplasm.

Fig. 1

Patient 1: (A): Bone marrow biopsy from 2013 shows granulocytic hyperplasia. Megakaryocytes are increased in numbers with frequent clusters, including occasional hyperchromatic forms. (B): Reticulin stain on 2013 bone marrow biopsy shows marked fibrosis. (C): Bone marrow biopsy from 2015 shows sheets of myeloid blasts, consistent with acute myeloid leukemia. (D): Molecular analysis shows CALR mutant allele frequency increased over time, with appearance of IDH2 mutation and transient BCR-ABL1 positivity.

Fig. 2

Patient 2: (A): Rare dysplastic neutrophils are noted in the peripheral blood smear. (B): Bone marrow aspirate smear shows occasional dysplastic megakaryocytes with nuclear separation.