High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in 20% to 25% of cases of precursor B-cell ALL, but very rarely in cases of T-cell ALL. Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase FISH may detect hidden hyperdiploidy. High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low WBC count) and is itself an independent favorable prognostic factor.[112,113] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites, which may explain the favorable outcome commonly observed in these cases.
While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.
Patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have been shown to have a particularly favorable outcome as demonstrated by both Pediatric Oncology Group (POG) and Children's Cancer Group (CCG) analyses of NCI standard-risk ALL. POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.
Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified based on the prognostic significance of the translocation. For instance, in one study, 8% of patients with the Philadelphia chromosome (t(9;22)) also had high hyperdiploidy, and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Philadelphia chromosome–positive (Ph+) high hyperdiploid patients.
Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy). These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome, similar to those with hypodiploidy.
Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy. Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[120,121,122] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[120,122]Hypodiploidy (<44 chromosomes)
Precursor B-cell ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying based on modal chromosome number into the following four groups:
- Near-haploid: 24 to 29 chromosomes (n = 46).
- Low-hypodiploid: 33 to 39 chromosomes (n = 26).
- High-hypodiploid: 40 to 43 chromosomes (n = 13).
- Near-diploid: 44 chromosomes (n = 54).
Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases.[119,123] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.
The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL. In near-haploid ALL, alterations targeting receptor tyrosine kinase signaling, Ras signaling, and IKZF3 are common. In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these mutations are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.