Clinical Impact of NPM1 Mutation Subtypes in a Monocentric Cohort of Acute Myeloid Leukemia

Rapid Communication

Ann Hematol Oncol. 2020; 7(4): 1296.

Clinical Impact of NPM1 Mutation Subtypes in a Monocentric Cohort of Acute Myeloid Leukemia

Sciumè M1*, Fabris S1, Ciceri G1, Mattiello V1,2, De Roberto P1, Neri A1,2, Baldini L1,2 and Fracchiolla NS1

¹Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy

²Università Degli Studi di Milano, Italy

*Corresponding author: Sciumè M, Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Italy

Received: April 22, 2020; Accepted: May 20, 2020; Published: May 27, 2020

Abstract

Acute Myeloid Leukemia (AML) with mutated Nucleophosmin Member 1 (NPM1) was recently recognized as a distinct entity. The most common NPM1 mutation is type A, generally considered of favorable prognosis. We aimed to evaluate the relevance of A and non-A type NPM1 mutations on clinical profiles and outcomes in a monocentric cohort of adult patients with newly diagnosed NPM1-mutated AML. We identified 30 consecutive patients over a 4-year period. Type A mutations were found in 22 cases and non-A type in 8 cases. Thirteen patients received intensive chemotherapy (8 type A, 5 non-A type) with Complete Remission (CR) in 10 cases (5 type A, 5 non-A type), while 11 patients received a hypomethylating agent (9 type A, 2 non-A type) with CR in 2 type A cases. Median Overall Survival (OS) and disease free survivals were 6.5 and 9 months; OS showed a trend towards a statistical significance for non-A type cases. Despite the limited number of patients, our study suggests that NPM1 genotypes had no impact in terms of CR rates after intensive chemotherapy; the possible association of NPM1 mutation type with OS deserves further investigations on larger series.

Keywords: Acute myeloid leukemia; NPM1 mutation; Prognosis

Abbreviations

NPM1: Nucleophosmin Member 1; AML: Acute Myeloid Leukemia; ITD: Internal Tandem Duplication; FLT3: Fms-Related Tyrosine 3 Gene; NES: Nuclear Export Signal; MRD: Minimal Residual Disease; OS: Overall Survival; DFS: Disease Free Survival; WBC: White Blood Cell Count; CR: Complete Remission

Introduction

The nucleophosmin Member 1 (NPM1) is a nucleolar protein with pleiotropic functions in ribosome biogenesis, messenger ribonucleic acid processing, chromatin remodeling, apoptosis and genome stability [1-3]. Acute Myeloid Leukemia (AML) with mutated NPM1 was recognized as a distinct entity by the 2016 revision to the World Health Organization classification of acute leukemia [4]. It accounts for 50-60% of de novo normal-karyotype AML and it is generally associated to a favorable prognostic impact when additional Internal Tandem Duplication (ITD) in the Fms-Related Tyrosine 3 gene (FLT3) gene is absent [4-6]. Almost all NPM1 mutations occur within exon 12 and involve frameshift insertions; these mutations cause a change in the NPM1 protein sequence and an early truncation in the Nuclear Export Signal (NES) motif, resulting in a cytoplasmic localization of the protein [1-3,5]. Approximately 80% of NPM1 mutations are type A (frameshift mutation due to tandem duplication of a TCTG tetranucleotide sequence), followed by 10% of type B (CATG) or type D (CGTG). Other rare mutations can be found in the remaining 10% [1-3,5]. So far only few studies investigated the prognostic role of different subtype of NPM1 mutations, with controversial results [7-9].

Materials and Methods

The aim of the present study was to assess the association of A type versus non-A type NPM1 mutations with specific clinical features and their relevance on outcomes in a monocentric cohort of AML consecutive patients. NPM1 mutations were detected by Sanger sequencing and molecular Minimal Residual Disease (MRD) was determined by real-time quantitative polymerase chain reaction analysis (sensitivity 10-5). The 2017 European Leukemia Net guidelines was used to assess the genetic risk classification and response to treatment [10]. Relationships between categorical variables were assessed by chi-squared test; p values <0.05 were considered significant. Overall Survival (OS) and Disease Free Survival (DFS) curves were estimated using the Kaplan–Meier method. the study was approved by ethic committees of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano (711_2018). The research was conducted in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 2013.

Results and Discussion

Thirty NPM1-mutated AML patients consecutively diagnosed at our Hematology Department between July 2014 and April 2019 were identified in the institutional database. Clinical data, diagnostic workup and treatment modalities are shown in (Table 1).

Citation: Sciumè M, Fabris S, Ciceri G, Mattiello V, De Roberto P, Neri A, et al. Clinical Impact of NPM1 Mutation Subtypes in a Monocentric Cohort of Acute Myeloid Leukemia. Ann Hematol Oncol. 2020; 7(4): 1296.