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EHA 2021 | Redefining low risk high hyperdiploidy in pediatric ALL

Anthony Moorman, PhD, Newcastle University, Newcastle, UK, discusses the findings of a study investigating risk factors which can be used to define a low-risk subgroup of patients with pediatric acute lymphoblastic leukemia (ALL) and high hyperdiploidy. High hyperdiploidy occurs in around 30-35% of cases of B-cell precursor ALL and is strongly associated with good outcomes, however relapses do occur. Prof. Moorman summarizes the key findings of the study and talks on how defining a low-risk subgroup could be used to identify patients eligible for dose escalation. This interview took place at the virtual European Hematology Association (EHA) Congress 2021.

Transcript (edited for clarity)

High hyperdiploidy is one of the most common chromosomal abnormalities that you see in pediatric acute lymphoblastic leukemia, and it accounts for about 30 to 35% of B-cell precursor acute lymphoblastic leukemia. Although it’s been associated with a good outcome in multiple clinical trials, the relapse rate is still reasonably high, and given its prevalence high hyperdiploidy still accounts for a large number of relapses in ALL...

High hyperdiploidy is one of the most common chromosomal abnormalities that you see in pediatric acute lymphoblastic leukemia, and it accounts for about 30 to 35% of B-cell precursor acute lymphoblastic leukemia. Although it’s been associated with a good outcome in multiple clinical trials, the relapse rate is still reasonably high, and given its prevalence high hyperdiploidy still accounts for a large number of relapses in ALL. Therefore, defining the precise metrics of high hyperdiploidy is very important.

Now, historically, high hyperdiploidy has been defined simply by the number of chromosomes in the leukemia karyotype, with a modal number of 51 to 65 or 67 chromosomes indicating high hyperdiploidy. Over the past 20 years, many study groups have looked to see whether the modal chromosome number or specific trisomies are associated with either a good or a poor outcome within this subgroup. Although many papers have identified significant associations, very few of them have been validated in independent study groups.

Also, very few studies have taken a kind of comprehensive global look at all the risk factors within high hyperdiploidy. This is what we did in this study. We used two large contemporary serial clinical trials based in the UK and analyzed all existing and potential risk factors within high hyperdiploidy. What we found is we found that you needed to know the trisomic status of four chromosomes to get the maximum amount of prediction power within these cohorts.

Furthermore, we’ve identified a pattern of chromosomal gain based on the gain of chromosome 17, 18, 5, and also 20, and, if you had a particular profile of those gains, we identified a group of patients had a very low risk of relapse of up to 10 years, which was less than 5%. In the remaining patients that didn’t have this good-risk profile, their relapse rate was around 15%, which is much more like the relapse rates you expect to see with intermediate cytogenetics.

So, then we looked at the validation cohort, this is based on a trial called UKALL2003, we found that 80% of patients had this good-risk copy number profile, i.e., this good risk pattern of trisomies, and the remaining 20% had the poor-risk one. So, by far the vast majority of high hyperdiploidy patients have this good-risk pattern of chromosome gain.

We compared this pattern of chromosome gain, this profile, with existing risk factors in high hyperdiploidy including the triple trisomy of chromosomes 4, 10, and 17, which is used by the Children’s Oncology Group in America. We found that our definition was as good as the triple trisomy used by the Children’s Oncology Group, but it accounted for a much larger proportion of patients with the traditional definition of high hyperdiploidy or 51 to 65 chromosomes.

So, going forward, we feel that our new definition of high hyperdiploidy based around the gain and trisomic status of these four chromosomes is a much more powerful way of identifying a large group of pediatric ALL patients that could be considered for treatment de-escalation. In contrast, the patients with a poor-risk profile are definitely a group of patients, admittedly only 20% of the traditional high hyperdiploidy group, that should not be considered for treatment de-escalation because of that relapse risk. All the other results that we found were independent of MRD at the end of induction as based on the data that we had in UKALL2003.

Going forward, we feel that the definition of high hyperdiploidy should now shift away from just simply counting chromosomes, to looking at the pattern of chromosome gain in the carrier type and in order to define a better and larger low-risk group of pediatric acute lymphoblastic leukemia. Obviously, this means that we would have to identify the trisomy status of all the chromosomes. However, many genetic laboratories around the world are now using SNP arrays in order to enhance the genetic testing of patients at initial diagnosis, and of course, if you do a SNP array, you will automatically identify the trisomic status of all chromosomes with a high degree of accuracy. So, we feel that our profile will be easily identifiable going forward and also offer a better definition for risk stratification.

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