Children With Down Syndrome

Approximately 2% to 3% of childhood ALL cases occur in children with Down syndrome.[69-72] ALL in pediatric patients with Down syndrome is characterized by a lower incidence of both favorable (e.g., ETV6::RUNX1 and high hyperdiploidy with favorable trisomies) and unfavorable (e.g., BCR::ABL1, KMT2A rearrangements, low hypodiploidy, t(9;22)(q34;q11.2) or t(4;11)(q21;q23)) biology and a near absence of T-cell phenotype.[69-71,73,74]

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.[75-79] 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.[74,79,80]

Patients with Down syndrome have an increased risk of developing toxicities from treatment, including infections, mucositis, and seizures. In some studies, outcomes of children with Down syndrome and ALL have been reported to be inferior,[69,70,81-83] although in other studies, patients with Down syndrome appeared to fare as well as those without Down syndrome.[84,85] Inferior outcomes for patients with Down syndrome, when observed, are related to both an increased risk of relapse, as well as increased frequency of treatment-related mortality.[69-71,74,81,82]

Because of the well-established increase in toxicity experienced by patients with Down syndrome, some ALL protocols (such as those of the COG) have de-intensified risk-based treatment for patients with Down syndrome and ALL to minimize exposure to the morbid components of therapy. While this treatment reduction strategy reduces the frequency and severity of toxicities, its impact on antileukemic outcomes is not yet known.