Page 61 - Haematologica Vol. 107 - September 2022

ARTICLE - Genetic abnormalities in older ALL patients
T. Creasey et al.
Online Supplementary Table S8). Even though the outcome of these older patients was poor there was evidence that tumor genetics remained a strong risk factor (Figure 5), as we have previously demonstrated for younger adults.23 Pa- tients with standard-risk genetics had the best outcome with 84% entering remission and 5-year event-free and overall survival rates of 28% and 41%, respectively. In com- parison, over a third of patients with very high-risk gen- etics did not go into remission and all 28 patients with genetic high-risk or very high-risk disease died within 5 years of diagnosis.
Regarding patients with B-other ALL with gene rearrange- ments identified, all three patients with ZNF384-re- arranged ALL survived more than 2 years from diagnosis whereas six out of eight of those with CRLF2 rearrange- ments and four out of six with IGH translocations (exclud- ing CRLF2 partners) died within 2 years (Table 1).
Of the 40 patients with IKZF1 deletions, no significant dif- ference in outcome was identified between those with focal deletions of exons 4-7 (generating the dominant negative IK6 isoform)33 compared with patients with other IKZF1 deletions (Online Supplementary Table S9).
Discussion
To our knowledge, our study provides the largest genetic and genomic characterization to date of older adults with ALL.
The landscape of primary chromosomal abnormalities and CNA is distinct from that observed in children and younger adults. T-ALL was only seen in 5% of cases, which is less than half the rate seen in younger adults.34
Overall, a quarter of patients had BCR-ABL1-positive ALL, although the frequency of this did not increase further over the age of 60 years. This corroborates the findings from a large analysis of three German Multicenter study group for adult ALL (GMALL) trials in which the proportion of BCR-ABL1-positive cases reached a plateau after 45 years of age.35 In comparison, our study highlights that HoTr becomes more common with advancing age, such that it is encountered in <2% of childhood patients,36 4- 9% of adults aged 25-60,23 rising to around 15% of adults aged 60 years and over in our cohort. Other high-risk cytogenetic subgroups, specifically KMT2A fusions and complex karyotypes were present in 6% and 3% of pa- tients, respectively, which are similar rates to those seen in younger adults.5,23 We found a lower frequency of CRLF2 rearrangements than found in two USA studies that in- cluded older adults.12,37 This could be related to the higher prevalence of Hispanic ancestry in the USA, and the as- sociated inheritance of GATA3 risk alleles, which confer an elevated risk of CRLF2-rearranged ALL.38 In comparison to younger patients, ABL-class fusions were notably ab-
sent in our cohort. Other studies have similarly identified very low frequencies of ABL-class fusions in older indi- viduals. Indeed, only two cases were identified in 103 adults aged 60 years or over in a recent large USA study.6 Data from the GMALL group similarly demonstrated a rapid decrease in the frequency of Ph-like ALL in older age groups.39
Although we limited our survival analysis to UKALL14 pa- tients, we highlight that prognosis remains very poor in older adults with ALL (Figure 5). However, consistent with recent studies, patients with ZNF384 rearrangements seemed to have a favorable outcome.23
CNA in key genes recurrently disrupted in ALL were dis- covered in the majority of patients. IKZF1 loss was present in over half of all cases tested by SNP array, occurring in 68% of BCR-ABL1-positive and 40% of BCR-ABL1-negative ALL. The high rate of IKZF1 loss in BCR-ABL1-positive ALL is consistent with much of the published literature.24,40 However, the frequency of IKZF1 deletion in the older pa- tients with BCR-ABL1-negative ALL was double that re- ported in younger adults (40% vs. 19%).41 This discrepancy is at least in part driven by the increased frequency of low hypodiploid cases, as these usually only retain one copy of chromosome 7. However, IKZF1 deletions were still en- countered in 36% (10/28) of B-other cases. Deletions in other key driver genes in BCP-ALL (CDKN2A/B, PAX5, RB1, ETV6 and EBF1) were also encountered more frequently than in younger patients.23
The high-risk IKZF1plus copy number profile was identified in over a third of patients, although its prognostic impact in older adults still needs to be elucidated. Interestingly, no focal ERG deletions, which are associated with a favor- able outcome, were detected.42 Overall, these data con- firm that all genetic biomarkers typically associated with a good prognosis, namely ETV6-RUNX1 fusion, high hyper- diploidy and ERG deletions are exceedingly rare in older adults with ALL, contributing to the adverse outcomes of this population of patients. By virtue of the techniques used, we recognize that we were not able to identify cer- tain novel subgroups, such as the recently described PAX5-driven subtypes6 or DUX4 rearrangements, although the latter are associated with ERG deletions in the major- ity of cases.43
Importantly, our study highlighted therapeutically action- able targets that would merit further investigation in older adults. We identified KDM6A deletions and mutations in 5% (4/78) and 9% (2/23) of screened patients, respectively. KDM6A (also known as UTX) on Xp11.3 is an H3K27me3 de- methylase, involved in epigenetic regulation through re- pression of PRC2/EZH2 activity. Recurrent KDM6A mutations have been identified in T-ALL, and have been shown to have gender-specific tumor suppressor effects.44 KDM6A escapes X-inactivation in females and therefore retains biallelic expression. Hence, loss of tumor sup-
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