Cup-like blasts in acute myeloid leukaemia with NPM1 and IDH2 mutations.

Abstract

An 86-year-old woman presented with fever and pneumonia. Her laboratory investigations showed leucocytosis (15 × 10⁹/L) with 92% blasts, anaemia (haemoglobin 5.5 g/dl), thrombocytopenia (platelet 31 × 10⁹/L), and elevation of fibrinogen degradation products (FDPs > 120 μg/ml). The patient refused bone marrow examination. Hypogranular blasts without Auer rods containing nuclear invagination, the so-called “cup-like” or “fish-mouth” appearance, accounted for approximately 17% of the blasts in peripheral blood. Blasts were strongly positive for myeloperoxidase and showed normal female karyotype (46,XX) [Figure 1]. The immunophenotypic features of the blast included expression of CD13(dim), CD33 and CD56 and absence of CD34 and HLA-DR expression, which mimicked those of acute promyelocytic leukaemia (APL) [Figure 2]. Targeted next-generation sequencing using the Oncomine Myeloid Research Assay (Thermo Fisher Scientific, MA, USA) revealed pathogenic variants with allele frequencies greater than 1% in nucleophosmin 1 (NPM1; p.Trp288CysfsTer12), isocitrate dehydrogenase 2 (IDH2; p.Arg140Gln) and Fms-like tyrosine kinase 3 (FLT3; p.Asn676Lys), of which the variant allele frequencies (VAF) were 47.94%, 51.3%, and 3.55%, respectively. The patient was eventually diagnosed with acute myeloid leukaemia (AML) with mutated NPM1. AML with cup-like blasts (CLB-AML) is defined as the presence of more than 10% of blasts with nuclear invaginations that span at least 25% of the nuclear diameter, which are commonly associated with AML M1/2 (myeloid) and M4/5 (myelomonocytic/monocytic) in the FAB classification. NPM-1 and FLT3-ITD mutations have been detected in more than 60% of CLB-AML cases with normal karyotype. NPM1-mutatd AML showing APL-like immunophenotype, negative for both CD34 and HLA-DR, often harbours co-mutations in IDH1/2 or TET2 [1]. Furthermore, high D-dimer/FDP levels, CLB, and APL-like immunophenotype are frequently observed in AML with mutated NPM1 harbouring FLT3 or IDH1/2 co-mutations [2]. Our case is consistent with these clinical, morphological, and molecular features. VAF of FLT3 mutation is less than 5% and much lower compared to that of NPM1 and IDH2, which means that FLT3 mutation may not affect the cup-like morphology and clinical presentation in our case. NPM1-mutated AML carrying concurrent FLT3-ITD mutation especially with high (≥0.5) allelic ratio is well known to be associated with poor prognosis. Molecular analysis is very important in CLB-AML with APL-like phenotype in terms of predicting prognosis and determining the optimal treatment strategy including allogeneic stem cell transplantation or molecular targeted therapies such as FLT3 or IDH1/2 inhibitors. We thank Dr. Makoto Ikejiri, Dr. Kaname Nakatani, and Dr. Keiki Nagaharu at Mie University Hospital for NGS analysis. We thank Gabrielle White Wolf, PhD, from Edanz Group (http://en-author-services.edanz.com/ac) for editing a draft of this manuscript. Y. Sugimoto has received honoraria from Novartis, funding from Takara Bio, and research support from Astellas, Kyowa Kirin, and Ono, and is an accepted researcher from Shojunkai Takeuchi Hospital. All other authors do not have any conflicts of interest to declare.