The mutation is more common than expected and associated with poor outcomes, according to researchers from St. Jude Children’s Research Hospital.
In children with relapsed pediatric acute myeloid leukemia (AML), UBTF tandem duplications (UBTF-TD) were common and associated with poor outcomes, according to research from scientists at St. Jude Children’s Research Hospital. The findings were published in Blood Cancer Discovery.
The researchers used tumor samples from 136 patients with relapsed AML from the St. Jude Children’s Research Hospital tissue resource core facility. They performed genetic and transcriptional profiling to define the spectrum of alterations. In addition to demonstrating overrepresentation of WT1, KMT2A, and NUP98 alterations in relapsed AML, they identified tandem duplications in exon 13 of UBTF.
In addition, 417 patients from previous studies were included in an extension cohort.
“We have a number of clinical trials at St. Jude for relapsed AML, so that gave us access to a large cohort of samples, and that is where the collaboration with our colleagues in Computational Biology became really beneficial to help us analyze the genetics,” coauthor Jeffery Klco, MD, PhD, St. Jude Department of Pathology, said in a statement. “It became clear early on that there was a group of cases who had curious alterations in this gene UBTF, which had really only been superficially considered in the past.”
The UBTF-TD occurred in nearly 9% of pediatric patients with relapsed AML. The data also showed that many cases of FLT3 or WT1–positive pediatric patients with AML that seemed to lack an initiating event actually harbored UBTF-TD.
According to the researchers, the frequency of UBTF mutations in patients with relapsed AML was surprising because “UBTF mutations have rarely been observed in myeloid malignancies.”
In the main cohort there were 12 cases of relapsed AML with UBTF-TD. In the extension cohort, there were an additional 15 cases. Most of these cases occurred in early adolescence with a median age of 12.6 years. The median time from diagnosis to relapse was 1.1 years. The most common mutations that UBTF-TD occurred with were FLT3 internal tandem duplication (44.4%) or WT1 (40.7%).
The researchers also investigated the prevalence of UBTF-TDs in new cases of AML in pediatric and adult populations. The mutation occurred in 4.3% of new cases in the pediatric AAML1031 trial (n = 1035). The mutations were less common in the adult AML cohorts (TCGA, n = 151; BeatAML, n = 220). Only 0.9% of new cases in the adult cohorts had UBTF alterations.
In the AAML1031 trial, the patients with UBTF-TD had a 5-year overall survival of 44%. In comparison, patients without the mutation had a 64% survival (P = .018). The 5-year event-free survival was also lower for patients with the mutation (30% vs 45%, P =.078).
At the end of first induction, UBTF-TD was also strongly associated with positive minimal residual disease, which contributes to the recurrence of cancer.
“This is an extremely difficult mutation to detect, so a lot of work went into developing the right algorithms. We had to develop our method from scratch,” said co-corresponding author Xiaotu Ma, PhD, St. Jude Department of Computational Biology. “Most of the existing methodologies assume there is only one event creating these kinds of mutations but, as with UBTF-TD, that isn’t always the case."
“Now that we know what we’re looking for and how to find it, we can readily incorporate it into clinical genomics,” Ma said.
Umeda M, Ma J, Huang BJ, et al. Integrated genomic analysis identifies UBTF tandem duplications as a recurrent lesion in pediatric acute myeloid leukemia. Blood Cancer Discov. Published online February 16, 2022. doi:10.1158/2643-3230.BCD-21-0160