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Page 387 Santiago et al. J Transl Genet Genom 2021;5:380-95 https://dx.doi.org/10.20517/jtgg.2021.16

deficiency [56-58] . The children with DS have a 10- to 20-fold increased risk of developing ALL compared to
the general population [57,59] . DS-ALL, unlike DS-related acute myeloid leukemia, occurs rarely in the first
year of life and is associated with an inferior outcome in comparison to non-DS ALL. The lower survival
can be attributed to a higher relapse rate and a susceptibility to chemotherapy in DS patients who display a
heightened treatment-related toxicity. Nevertheless, the survival difference is not observed across different
clinical trials and might be explained by the specific genomic landscape of DS-ALL [57,60] . ALL from DS
patients is less likely to carry favorable cytogenetic alterations, such as ETV6-RUNX1 or hyperdiploidy, and
is enriched in CRLF2 rearrangements, in 50% to 60% of DS-ALL cases, with frequent JAK2 mutations, a
similar profile to what is encountered in Ph-like ALL [59-61] . However, in contrast to HR B-ALL without DS,
the presence of CRLF2 alterations in DS-ALL does not correlate with a worse prognosis, as reported by a
large retrospective cohort comprising 317 DS-ALL patients treated on COG clinical trials between 2003 and
[62]
2016 .
New germline alterations have been recently discovered since the NGS advent. The germline variants
conferring ALL susceptibility can be subdivided into two categories: (1) rare pathogenic germline variants
with high penetrance (TP53 and transcription factor genes ETV6, PAX5 and IKZF1) found in families with
high ALL incidence; (2) a growing number of common inherited variants with low penetrance detected via
genome wide association studies (GWAS) (ARID5B, CEBPE, CDKN2A/B, GATA3, PIP4K2A, TP63) [56,63-65] .
Similar to somatic alterations in IKZF1, germline mutation alters IKAROS function and affects treatment
sensitivity both in vivo and in vitro by reducing dexamethasone and dasatinib tyrosine kinase activity in
[66]
leukemic cells . Some of these inherited variants predispose to specific ALL molecular subgroups.
Inherited TP53 mutations, causing Li-Fraumeni syndrome, occur in about 50% of low-hypodiploid ALL .
[64]
Variants in GATA3 are strongly associated with Ph-like ALL, while TP63 variants preferably relate to the
ETV6-RUNX1 subgroup and PIP4K2A to the hyperdiploid ALL [65,67-69] . Finally, GWAS has uncovered the
association of inherited gene polymorphisms and drug sensitivity or toxicity and laid the foundation for
clinical pharmacogenomics. The most significant are TPMT and NUDT15 variants responsible for
[65]
thiopurine-induced myelosuppression . The prevalence of these variants follows ethnic variations; the
former being more frequent in African descendent and the latter in people from East Asian or Hispanic
origins. Heterozygous patients for these variants tolerate lower dose of thiopurine, approximately 60% to
70% of the usual dosing, while homozygous patients exhibit extreme mercaptopurine sensitivity and
necessitate drastic dose reduction to 10% of the intended dose. Pre-emptive screening for these variants is
[70]
now recommended for pharmacogenomics-based therapy adjustment .

TARGETED PRECISION MEDICINE OPPORTUNITIES
The most spectacular survival improvement for relapsed and refractory (R/R) ALL has been achieved with
the recent advent of immunotherapy. Bispecific T-cell engager antibody (e.g., blinatumomab), antibody-
drug conjugates (e.g., inotuzumab ozogamicin), or cellular therapy (e.g., chimeric antigen receptor T-cells),
have shown impressive response in heavily pretreated R/R ALL [71-73] . Immunotherapy-based treatment
strategies, targeting common ALL surface antigens, have the advantage of being agnostic to sentinel genetic
alterations, and therefore, can be applied to a broader patient population . Thus, there is still room for
[10]
improvement since a non-negligible proportion of patients fail to respond or relapse after immunotherapy.
We hereby review emergent molecularly targeted therapies and precision medicine opportunities in
pediatric ALL with the potential for further survival improvement.

+
Ph ALL
The success of tyrosine kinase inhibitor (TKI)-based treatment in Ph ALL is certainly one of the most
+
eloquent examples of precision oncology. Until the early 21st century, Ph ALL, which concerns 3% to 5% of
+