Down syndrome (trisomy 21)

In a large retrospective study that included 653 patients with Down syndrome and ALL, patients with Down syndrome had a lower complete remission (CR) rate (97% vs. 99%, P < .001), higher cumulative incidence of relapse (26% vs. 15%, P < .001) and higher treatment-related mortality (7% vs. < 1%, P < .001) compared with patients without Down syndrome.[71] Among the patients with Down syndrome, age younger than 6 years, WBC count of less than 10,000/µL, and the presence of the ETV6::RUNX1 fusion (observed in 8% of patients) were independent predictors of favorable EFS.

In a report from the COG, among patients with B-ALL who lacked KMT2A rearrangements, BCR::ABL1, ETV6::RUNX1, and hyperdiploidy with trisomies of chromosomes 4 and 10, the EFS and OS rates were similar in children with and without Down syndrome.[70]

Certain genomic abnormalities, such as IKZF1 deletions, CRLF2 aberrations, and JAK variants, are seen more frequently in ALL arising in children with Down syndrome than in those without Down syndrome.[73-77] Studies of children with Down syndrome and ALL suggest that the presence of IKZF1 deletions (but not CRLF2 aberrations or JAK variants) is associated with an inferior prognosis.[71,77,78]

A retrospective analysis included 130 patients with CRLF2-rearranged ALL and Down syndrome. Patients with the BCR::ABL1-like signature (25% of the CRLF2-rearranged cases) had an inferior outcome compared with those who lacked the BCR::ABL1-like signature (EFS rates, 39.5% ± 8.1% vs. 82.0% ± 4.4%; hazard ratio [HR], 5.27).[72]

The IGH::IGF2BP1 gene fusion occurs in approximately 3% of patients with Down syndrome. This fusion is rare in patients with ALL who do not have Down syndrome. In one retrospective analysis, the fusion was associated with a relatively favorable outcome (EFS rate, 87.5% ± 1.7%).[72]