Abstract 3479: UBTF tandem duplications (UBTF-TD) in childhood AML: Enrichment in FLT3-ITD and association with clinical outcome
Authors: Robinson Leila , Leonti Amanda , Alonzo Todd A. , Wang Yi-Cheng , Redell Michele S. , Ries Rhonda E. , Smith Jenny L. , Hylkema Tiffany A. , Le Quy , Kolb E Anders , Aplenc Richard , Ma Xiaotu , Klco Jeffrey , Tarlock Katherine , Meshinchi Soheil 
Published: June 2022

Abstract
Childhood AML is an aggressive disease with high rates of failures and poor survival. We have demonstrated that the molecular landscape of AML in children is distinct, and co-occurrence of variants modulate outcomes. Recent discovery of tandem duplication (TD) of the UBTF gene in AML, with enrichment in FLT3-ITD has implicated yet another mutation whose cooperation with FLT3-ITD may modify outcome. Here, we provide a comprehensive evaluation of UBTF-TD in de novo AML and define its clinical implications within FLT3-ITD patients. Initial interrogation of transcriptome data from 1,158 children enrolled on COG AAML1031 identified 50 cases of UBTF-TD (4.3%). Overwhelming majority of UBTF-TD cases were observed in FLT3-ITD cases (77%), vs. that of 1.2% in those without FLT3-ITD (p&lt;0.001). Given extreme enrichment of UBTF-TD in FLT3-ITD, we inquired whether cooperation of UBTF-TD and FLT3-ITD creates a distinct clinical entity. To this end we screened diagnostic DNA from 400 FLT3-ITD patients treated on three consecutive CCG/COG trials (COG AAML1031, COG AAML0531, and CCG-2961) by PCR and fragment analysis. UBTF-TD was identified in 61 FLT3-ITD cases (15.3%).
The data presented here forth focuses on evaluation of implications of UBTF-TD in FLT3-ITD positive patients only. Within the FLT3-ITD patients, initial correlation of UBTF-TD with demographics, disease characteristics, and associated genomic variants was conducted. Patients with and without UBTF-TD had a similar median age at diagnosis (p=0.322), lower diagnostic WBC (p=0.010) and higher marrow blast % (p&lt;0.001). There was a stark paucity of cooperating variants that commonly co-occur with FLT3-ITD, with a single NPM1 mutation (1.6% vs. 29%, p&lt;0.001) and no NUP98 fusions (0% vs. 23%, p&lt;0.001). There was a significant enrichment of WT1 mutations, with 45% UBTF-TD patients with a WT1 mutation (FLT3-ITD/UBTF-TD/WT1), vs. 11% in UBTF-WT (p&lt;0.001). Trisomy 8 (Tri8) was seen in 15% of UBTF-TD. Patients with UBTF-TD had a lower CR rate (44% vs. 60%, p = 0.018), and Higher MRD rate (38% vs. 21%, p&lt;0.001). Patients with and without UBTF-TD had an EFS of 28% vs. 42% (p=0.047) with a corresponding OS of 40% and 57% (p=0.019). Given enrichment of WT1 mutations and Tri8 in patients with UBTF-TD, we studied the outcome UBTF-TD patients in the context of these two variants. FLT3-ITD/UBTF-TD/WT1 patients had a 5-year EFS of 17% vs. 38% for similar patients without WT1 mutations (p=0.0062). Patients with UBTF-TD with additional Tri8 had a similarly poor outcome with an EFS of 23% with a corresponding OS of 33%, providing a distinct high risk UBTF-TD cohort (+WT1 or Tri8), whereas the remaining UBTF-TD patients had a more favorable outcome with EFS and OS of 64% and 86%, respectively (p&lt;0.0001, and p&lt;0.0001). UBTF-TD is a novel genomic entity with high enrichment in patients with FLT3-ITD and a distinct clinical outcome driven by cooperating WT1 mutation and Tri8.
Citation Format: Leila Robinson, Amanda Leonti, Todd A. Alonzo, Yi-Cheng Wang, Michele S. Redell, Rhonda E. Ries, Jenny L. Smith, Tiffany A. Hylkema, Quy Le, E Anders Kolb, Richard Aplenc, Xiaotu Ma, Jeffrey Klco, Katherine Tarlock, Soheil Meshinchi. UBTF tandem duplications (UBTF-TD) in childhood AML: Enrichment in FLT3-ITD and association with clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3479.