Submitting Author: Calvo, Xavier, MD
Institution: Hospital Clínic, Barcelona
Additional authors:Maria Rozman, Neus Villamor, Dolors Costa, Marta Aymerich, Jordi Esteve, Dolors Colomer, Xavier Andrade.
Session: AML with recurrent genetic mutations Part II

A 56 year old male consulted due to fever, gingivitis and skin lesions for the last two weeks. She had no previous relevant medical history. The main findings on examination were: cervical and submandibular lymph nodes, gingival hypertrophy, hepatomegaly and splenomegaly, papular and nodular skin lesions in trunk and extremities and dorsal distal hypoesthesia of right foot. The laboratory tests showed severe leukocytosis, mild anemia and thrombocytopenia: Hb 106 g/L, MCV 86 fL, WBC 121.1x10^9/L (blasts 88%), Platelets 58 x10^9/L.

The patient was diagnosed of AML. He obtained a CR after induction therapy but relapsed two months later. He was refractory to the second line treatment and died waiting a cord blood HSCT.

Peripheral blood & bone marrow aspirate smears stained with May-Grunwald Giemsa, and cytochemistry: myeloperoxidase (MPO), naphtol-AS-D-acetate esterase (NASDA) and alfa-naphtil-butirate esterase (ANBE).

The bone marrow aspirate was hypercellular, with 2% erythroid precursors, 7% granulocytic precursors, 87% blasts and 4% other cells (lymphocytes, plasma cells, macrophages). Megakaryocytes were present but much diminished.

Blasts had a medium-large size, a round nucleus with finely dispersed chromatin, prominent nucleoli, wide basophilic cytoplasm with blebs and mild granulation. Few elements showed Auer rods. The MPO was weakly positive in 25% of blasts, NASDA was negative and ANBE was intensely positive in 10% of blasts.

Flow cytometry:

Almost all the sample was constituted by immature cells (intermediate FSC/SSC, CD45+ weak, CD34+ partial (30% of blasts), HLA-DR+) of myeloid origin (MPO+ weak, CD117+, CD33+, CD13+) with monocytic differentiation (CD64+, CD36+, CD4+, CD11c+) and co-expression of CD7 and CD5.

46, XY [20]

- Exon 12 mutation of nucleophosmin (NPM1) was positive

- FLT3 internal tandem duplication (FLT3-ITD) was positive (ratio M/WT: 0.45; size of mutated band: 90 bp)

- Retrospectively.... DNMT3A mutation (R882H)

Patient evolution was very bad although his mutational status (NPM1m and ratio of FLT3-ITD < 0.5) was of “good “ prognosis (Schnittger S et al, Leukemia 2011). We retrospectively performed the exon sequencing of DNMT3A and we found the R882H mutation. Probably it would have been a very useful information at time of diagnosis.

The prognostic significance of the mutational status of NPM1, the mutated/wild type ratio of FLT3-ITD and DNMT3A in the intermediate-risk acute myeloid leukemia is a subject of ongoing debate in recent years and this case illustrates very well their prognostic significance.

Acute myeloid leukemia M5 subtype (FAB classification) with normal karyotype, NPM1 mutated, DNMT3A mutated and FLT3-ITD

Acute myeloid leukemia with NPM1 mutation, DNMT3A mutation, and FLT3 ITD mutation

Case 91