Low Prevalence of IDH1 gene Mutation In Childhood AML In Italy.
Authors: Pigazzi Martina , Ferrari Giulia , Masetti Riccardo , Falini Brunangelo , Martinolli Francesco , Basso Giuseppe , Biondi Andrea , Pession Andrea , Cazzaniga Giovanni 
Published: October 2019

Abstract
Abstract 1678

Introduction:
The IDH1 gene encodes for NADP+-dependent isocitrate dehydrogenase 1 enzyme, which catalyzes the oxydative decarboxylation of isocitrate to α-ketoglutarate. Acquired somatic mutations of the R132 residue of IDH1 have been detected in adults with de novo AML, while so far no IDH1 mutations were detected in a series of 257 children in USA. The role of IDH1 mutations in the pathogenesis of AML is still unclear.

Material and Methods:
From 01/12/2002 to 31/12/2007, 205 childhood AML patients were enrolled into the multicentric AIEOP-LAM 2001/02 protocol. Among them, we analyzed the prevalence of IDH1 mutations in 165 patients for whom material was available. IDH1 gene mutations have been analyzed by PCR amplification and sequencing of the exon 4. The clinical and biological features of the analyzed and not analyzed population were not statistically different.

Results:
In this series of childhood AML cases, 4 out of 165 cases (2.4%) were positive for IDH1 mutations. All patients were male, the age at diagnosis ranged from 3 to 14 years, while the WBC count at diagnosis ranged from 8750 to 233970 WBC/ml. Three of them had FAB M1 and one M2; none of them had localization in the central nervous system, while one had lymph nodes involvement. Two of the 4 children with the IDH1 mutation had a normal karyotype while two carried different clonal translocation. One patient carried the FLT3-ITD mutation at diagnosis, whereas no other known associated mutations were found. Based on cytogenetics, all of them were classified within the high risk group. Complete remission was achieved in all cases, and all but one received BMT. Two patients had a medullary relapse and all are alive, after 20, 26, 33 and 33 months from BMT. All patients carried the R132H IDH1 mutation. The mutation was specific of the leukemia cells, being absent in the remission phase of all patients. Interestingly, the R132H mutation was detected at the relapse stage of one patient, but not at the relapse of the second patient, suggesting that IDH1 mutations could represent a secondary lesion in the pathogenesis of leukemia. Because 2/4 IDH1 mutated cases in the sequential screening had a normal karyotype, we extended the mutational screening to all Italian childhood cases diagnosed as AML with normal karyotype from 13/10/2000 to 15/04/2010. Out of the additional 97 cases with normal karyotype, only 1 carried a IDH1 mutation (R132H).

Conclusions:
In summary, we showed that IDH1 gene mutation can be detected also in pediatric AML, with an estimate prevalence of 2.4% (4/165) in the Italian series. The low prevalence does not allow any prediction on the outcome, although all patients are alive at different time after BMT, even in the presence of FLT3-ITD mutation (one patient). The clinical and biological characteristics of the mutated patients seemed not to be different from the overall childhood AML population, and similar to the adult IDH1 mutated cases. The R132 mutation is the only pediatric mutation detected so far. The extended series to a total number of 186 childhood AML with normal karyotype identified 3/186 mutations (1.6%) in this specific subgroup. Therefore, it does not seem that IDH1 mutation is more prevalent in normal karyotype. In addition, even considering that the IDH1 mutation could not be present at the relapse (like it happens for FLT3 mutations), it is questionable the role of these abnormalities, and whether those mutations in ‘normal cytogenetic’ subgroup could be sufficient for the clinical disease emergence, or further events must be discovered in the complex and multistep pathogenesis of leukemia.

Disclosures:
No relevant conflicts of interest to declare.