Prognostic Role of Minimal Disseminated Disease and NOTCH1/FBXW7 Mutational Status in Children with Lymphoblastic Lymphoma: The AIEOP Experience.

Federica Lovisa,Daniela Onofrillo,Ilaria Gallingani,Lara Mussolin,Marco Pizzi,Veronica Maria Folsi,Alessandra Biffi,Marta Pillon,Luciana Vinti,Elena Varotto,Elisa Carraro,Matilde Piglione,Barbara Michielotto,Barbara Buldini,Cristiano Pasin,Salvatore Buffardi,Paola Muggeo,Anna Garbin,Carlotta Caterina Damanti ,Emanuele S G D'amore

doi:10.3390/diagnostics11091594

Abstract

NOTCH1/FBXW7 (N/F) mutational status at diagnosis is employed for T-cell lymphoblastic lymphoma (T-LBL) patients’ stratification in the international protocol LBL 2018. Our aim was to validate the prognostic role of Minimal Disseminated Disease (MDD) alone and in combination with N/F mutational status in a large retrospective series of LBL pediatric patients. MDD was analyzed in 132 bone marrow and/or peripheral blood samples by flow cytometry. Mutations in N/F genes were analyzed on 58 T-LBL tumor biopsies. Using the previously established cut-off of 3%, the four-year progression-free survival (PFS) was 57% for stage I–III patients with MDD ≥ 3% versus 80% for patients with MDD inferior to cut-off (p = 0.068). We found a significant worsening in the four-year PFS for nonmutated (51 ± 12%) compared to mutated patients (100%, p = 0.0013). Combining MDD and N/F mutational status in a subgroup of available cases, we found a statistically significant difference in the four-year PFS for different risk groups (p = 0.0012). Overall, our results demonstrate that N/F mutational status has a more relevant prognostic value than MDD at diagnosis. However, the combination of N/F mutations with MDD analysis could identify patients with very aggressive disease, which might benefit from a more intensive treatment.

Highlights

Pediatric lymphoblastic lymphoma (LBL) represents the second most frequent nonHodgkin lymphoma (NHL) subtype and accounts for approximately 25–35% of all NHL diagnosed in childhood and adolescence [1]
We confirmed the high frequency of disease dissemination at diagnosis in a large cohort of LBL pediatric patients treated in AIEOP centers
Results were considered, no statistically significant difference was observed in the fouryear progression-free survival (PFS) of patients with Minimal Disseminated Disease (MDD) values above or below the chosen cut-off

Summary

Introduction

Pediatric lymphoblastic lymphoma (LBL) represents the second most frequent nonHodgkin lymphoma (NHL) subtype and accounts for approximately 25–35% of all NHL diagnosed in childhood and adolescence [1]. During the last few years, great progress has been made by the scientific community in the study of pediatric LBL, and this allowed to improve our knowledge about the disease biology and to design clinical and diagnostic strategies leading to eventfree survival (EFS) and overall survival (OS) probabilities exceeding 80% [4,5]. The study of minimal disseminated disease (MDD) and the genetic analysis of the mutational status of NOTCH1/FBXW7 (N/F) genes proved to be promising candidates for the prognostic evaluation of LBL patients [7,8,9,10]

Objectives

Methods

Conclusion