Impact of Age and Treatment Group in Childhood High Hyperdiploid Low Risk B-Cell Acute Lymphoblastic Leukemia (ALL): Results of the CLG-EORTC 58951 Study
Authors: Clement Laura , Suciu Stefan , Luquet Isabelle , Ferster Alina , Yakouben Karima , Uytterbroeck Anne , Paillard Catherine , Sirvent Nicolas , Costa Vitor , De Moerloose Barbara , Mazingue Francoise , Plouvier Emmanuel , Munzer Martine , Poirée Maryline , Minckes Odile , Millot Frédéric , Plantaz Dominique , Piette Caroline , Speleman Frank , Cavé Hélène , VanderWerff-tenBossch Jutte , Rohrlich Pierre Simon , Bertrand Yves , Benoit Yves , Plat Geneviève 
Published: October 2019

Abstract
Background:
Since the last decades, pediatric ALL classification has integrated new cytogenetic and genomic data, and several genetic risk factors are identified for treatment stratification.
Hyperdiploidy, which is the most common cytogenetic abnormality pattern of pediatric B-lineage ALL, is known since the early 80s and is found in 25-30% of cases. It has been recognized as an isolated good prognostic factor, especially High Hyperdiploidy (HeH), defined by a modal chromosome number higher than 50.
In addition, treatment descalations were performed based on NCI criteria for low risk ALL (low leucocytosis < 10 x 109/L and/or age from 1 to ²10 years old) and/or lack of high risk features.
Aim:
The aim of this study was to assess whether age, under or over 10 years old, has a prognostic impact on the outcome in children presenting B-cell ALL with low risk criteria, and whether therapeutic intensification might improve the outcome within each age group.
Methods:
Among 2039 patients treated in EORTC 58951 (BFM backbone) from 1998 to 2008, 370 children with B-cell ALL and low risk criteria such as HeH (with classical profile of chromosome gains), low leucocytosis (< 10x109/L), a lack of CNS or gonadal involvement and a lack of very high features (poor response to prephase) were included in this study. Hyperdiploidy was determined either by cytogenetics or flow cytometry.
Patients were stratified into 2 risk groups: very low risk (VLR) group or standard risk (AR1) group. VLR group was defined by the criteria indicated above. It led to a less intensive treatment, particularly lower number of injections of anthracyclines and alkylating agents. AR1 group included children with surreptitious or hemorrhagic CNS involvement, and/or HeH with mismatch between modal chromosome number and DNA index.
The upper limit of age in the EORTC 58951 was less than 18 years.
Main endpoints were Event-Free Survival (EFS) and Overall Survival (OS).
Results:
Overall patients with low risk hyperdiploid B-cell ALL features treated according to a VLR or AR1 protocol had 6-year EFS and OS rates of 90.3% and 96.2% respectively. These results were comparable to previous published studies on hyperdiploidy in childhood B-lineage ALL.
All patients but one reached complete remission after the induction phase.
There were 315 children aged less than 10 years old and 55 patients aged 10 to 17 years old.
Among children aged 10 years and older treated in VLR or AR1 groups, 6-year EFS and OS rates were respectively 86.7% and 96.4%. In comparison, among less than 10 year old childrentreated in VLR or AR1 groups, 6-year EFS and OS rates were respectively 89.8% (p=0.42) and 95.9% (p=0.93). Age did not appear as a significant prognostic factor in the outcome.
Furthermore, among children aged 10 years and older, those treated in the standard risk group (AR1) had 6-year EFS and OS rates of 90% and 100% respectively. This seemed better than for children treated in the very low risk group, with respectively 84% and 92% rates. However, no significant gain was found for children who received standard risk treatment (for EFS and OS rates: p=0.47 and p=0.12 respectively). Relapse and treatment toxicity rates were comparable in both groups.
Concerning long-term cardiac toxicity, despite the fact that no significant difference was found between the two risk groups of treatment, standard treatment leads to higher dose of anthracyclines and an increased theoretical risk of cardiac toxicity.
Conclusion:
In conclusion, age did not appear as a significant prognostic factor in outcome of children treated for a low risk B-cell ALL. Moreover, among children aged 10 years and older, therapeutic intensification in standard risk group did not lead to a significant gain in outcome. However, results are not significant, partly due to a low number of patients, and larger studies should be performed to evaluate whether these children could benefit from a less intensive treatment.

Disclosures
No relevant conflicts of interest to declare.