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Researchers Report on Novel Pediatric AML Subtype Associated With Poor Outcomes at ASH Meeting

NEW YORK – At the American Society of Hematology's annual meeting on Tuesday, researchers reported on a newly identified subtype of relapsed pediatric acute myeloid leukemia characterized by somatic mutations in UBTF.

To identify the UBTF subtype, researchers from St. Jude Children's Research Hospital and elsewhere analyzed RNA sequencing, whole-genome sequencing, and target-capture sequencing data from 136 patients with relapsed pediatric AML. In this cohort, UBTF tandem duplications, or UBTF-TDs, occurred in 8.8 percent of patients.

Recognizing that UBTF-TDs are hard to find, the researchers developed a screening strategy to detect them more efficiently in RNA-seq data, which involved detecting the tandem duplication by a fusion caller, detecting indels on exon 13 using a bioinformatics approach described last year by Kohei Hagiwara et al., and counting reads with unmapped parts. They used that method to analyze data from 417 additional pediatric AML patients at diagnosis from other studies and found 15 other AML cases with the UBTF subtype.

Their analysis also helped refine understanding of other co-occurring mutations that patients with the UBTF subtype may have. For example, the researchers reported that UBTF-TDs are mutually exclusive with AML driver mutations seen in more common subtypes characterized by KMT2A rearrangements, which occur in about a quarter of pediatric AMLs, and NUP98 rearrangements, which are found in about 13 percent of patients. However, the UBTF-TDs did frequently occur with mutations in FLT3 or WT1.

To explore the prevalence of the subtype in larger cohorts, researchers then applied their UBTF-TD screening method to pediatric and adult AML cohorts from The Cancer Genome Atlas Program, or TCGA, the National Cancer Institute's BeatAML dataset, and the Children's Oncology Group study AAML1031.

In the AAML1031 study, which included 1,035 pediatric AML patients, the researchers identified UBTF-TDs in 4.3 percent of the cohort. However, in the two other cohorts, TCGA and BeatAML, which included adult patients, they found this alteration was less common, occurring in less than 1 percent of adult AML patients.

The research, presented at the meeting by Masayuki Umeda, a postdoctoral research associate at St. Jude Children's Research Hospital, also suggested patients with UBTF-TDs had poorer outcomes than those without. In the AAML1031 data in particular, Umeda pointed out that patients with the UBTF subtype appeared to have poorer outcomes when treated with cytotoxic chemotherapy and hematopoietic stem cell transplantation.

The five-year overall survival rate among patients with UBTF-TDs in the AAML1031 study was 43 percent, significantly lower than patients without these alterations. Three-quarters of these patients were also positive for minimal residual disease after their first induction therapy.

"Notably, despite the high frequency of FLT3-internal tandem duplications and WT1 mutations [with UBTF-TDs], the impact of UBTF-TDs on MRD is independent of co-occurring mutations in FLT3 and WT1, showing that UBTF-TD itself is a prognostic factor," Umeda said.

Umeda noted that his team is exploring drug candidates targeting UBTF-TDs in preclinical studies and that a "molecularly targeted therapy may be one option in the future."

"We just started exploring potentially targetable pathways in these subtypes using the human CD34 in vitro model," Umeda said in an email, estimating that "it will take at least two to three years to confirm the candidate drugs in in vivo mouse models" and publish the findings.