Prevalence, clinical implications and impact of stem cell transplantation in UBTF-TD positive AML

Abstract Background: Recurrent tandem duplications (TDs) of upstream binding transcription factor (UBTF) have recently been described in adult and pediatric AML, with prevalence ranging from 1.5% to 4%. Comprehensive studies on the true age-associated prevalence, concomitant genomic alterations and associated response and potential therapies is yet to be defined. In a collaborative effort, we investigated the prevalence and prognostic impact of this alteration in a large and well characterized cohort of AML patients across all age ranges and provide the genomic make up and clinical outcome for children and young adults with UBTF-TD positive AML. Methods: Available diagnostic specimens from 2148 patients with newly diagnosed AML (0-30 years), registered in 4 consecutive COG prospective trials, were screened for the presence of UBTF-TDs. RNA-seq files were analyzed for TDs on exon 13 of UBTF using CICERO and confirmed by fragment length analysis. Overall and event-free survival (OS and EFS) were estimated using the Kaplan-Meier method. The study was conducted in concordance with the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act. To help determine the prevalence of UBTF-TD across all age ranges we combined our data with a previously published UBTF-TD study of 4247 adult AML patients (PMID: 39564724). Results: Diagnostic DNA from 2148 children and young adults with AML were screened and 95 UBTF-TDs were identified (4.4%). In this cohort, median age for those with and without UBTF-TD was 13 years (range, 3.0-27.3) vs 9.8 years (range, 0-29.8) (p<0.001). In the combined adult and pediatric data totaling 6395 patients (age range 0->80 years), overall prevalence was 2.3% with a clear age-associated prevalence. UBTF-TD was absent in those <3 years of age and extremely rare (<0.5%) in patients >50 years. Prevalence of UBTF-TD was highest in those aged 5-21 years (6.4%) with the prevalence of 2-3% in all other ages with the above-mentioned exceptions. Fusion transcripts, including KMT2A rearrangement, t(8;21), inv(16), CEBPA mutations were not detected. However, there was a high enrichment of concomitant genomic alterations in those with UBTF-TD, including enrichment of FLT3-ITD (79%, p<0.001), WT1 mutations (45%, p<0.001), and trisomy 8 (39%, p<0.001). Transcriptional profiling studies demonstrated that those with UBTF-TD have significantly upregulated PRDM16 and multiple HOXB genes, resulting in an enrichment in embryonic skeletal development networks. A distinct epigenome profile was observed with UBTF-TD patients clustering within FLT3-ITD and WT1 co-occurring blocks. Response and outcome data were available for 86 patients. Those with and without UBTF-TD had a complete remission (CR) rate of 55% and 78% (p<0.001), and post induction MRD-positive rates of 75% and 27%, respectively (p<0.001). The 5-year EFS was 30% and 46% for those with and without UBTF-TD (p=0.007), with an associated OS of 48% and 62% (p = 0.011). Presence or absence of FLT3-ITD, trisomy 8 or WT1 mutation did not affect the outcome of UBTF-TD patients. The single most significant determinant of outcome was consolidation with allogeneic stem cell transplantation (SCT) in first CR. Of the 86 patients with UBTF-TD, 40 achieved and remained in CR at the end of intensification, where 27 underwent SCT and the remaining 13 continued systemic chemotherapy. The DFS from end of intensification was 68% for SCT recipients vs 8% for those who received chemotherapy (p<0.001). The corresponding OS from SCT was 73% and 23% (p=0.003) for those with and without UBTF-TD. Presence or absence of co-occurring FLT3-ITD did not affect the favorable impact of SCT. Conclusion: We present age-associated prevalence of UBTF-TD with significant prevalence in adolescents and young adults and confirm a strong co-occurrence of UBTF-TD with trisomy 8, FLT3-ITD and WT1 mutations. We further confirm high induction failure and dismal outcomes with conventional chemotherapy. However, we demonstrate that AML with this variant is highly allo-responsive with more favorable outcomes in those consolidated with allogeneic SCT in first CR. Given lack of response to chemotherapy and high responsiveness to SCT, incorporation of diagnostic tools to ensure identification of patients with this alteration and delivering optimal therapy to ensure that they can receive SCT in first CR is critical to improve the chance of cure.