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Santiago et al. J Transl Genet Genom 2021;5:380-95 https://dx.doi.org/10.20517/jtgg.2021.16 Page 390

[99]
pathway . More recently, venetoclax appeared to provide in vitro and in vivo efficacy for controlling the
leukemic burden in hypodiploid ALL, in TCF3-HLF ALL and in ETP ALL [94,102,103] . The potential activity in
T-ALL has been reinforced by case reports of venetoclax activity, in association with decitabine or
bortezomib [104,105] . A pediatric phase 1 clinical trial of venetoclax with chemotherapy combination showed
good tolerance to the regimen and encouraging clinical activity in ALL patients . The addition of the
[106]
BCL-2/BCL-X /BCL-W, navitoclax, to venetoclax and chemotherapy seems to enhance the clinical activity
L
of venetoclax by overcoming escape pathways. A phase 1 study with this combination reported a promising
activity of 86% of response in pediatric relapsed/refractory ALL patients, among whom 56% achieved
negative MRD . Targeting proapoptotic pathway offers an optimistic outlook in the landscape of R/R ALL
[107]
treatment, but the best combination and ideal target population have yet to be determined.

Therapeutic opportunities for rare molecular subgroups
The modern genomic taxonomy of ALL identified some therapeutic susceptibility in rare molecular subsets,
but clinical validation is required. The extensive genomic characterization by whole genome and
transcriptome analysis of a ZNF384-rearranged ALL patient revealed a highly aberrant FLT3
overexpression. This patient, presenting with refractory disease, happened to be highly sensitive to the FLT3
inhibitor, sunitinib, leading to deep MRD-negative response and long-term survival . This case illustrates
[95]
how the combination of genome and transcriptome analysis can lead to the identification of unsuspected
therapeutic vulnerabilities. Another example is the constant overexpression of the histone deacetylase
HDAC9, a transcriptional target of MEF2D, observed in MEF2D-rearranged ALL. Xenograft models were
used to test the therapeutic vulnerability of MEF2Dr ALL to the HDAC inhibitor, panabinostat, and showed
exquisite in vivo sensitivity . No clinical experience has been reported yet. Finally, IKZF1 inactivating
[33]
mutations induce in vitro stem cell and adhesive properties and alter the response to dasatinib in BCR-ABL1
mouse models. Retinoids and focal adhesion kinase (FAK) inhibitors have the ability to reverse these
mechanisms, thus restoring dasatinib sensitivity [92,93] . Retinoids and FAK inhibitors constitute potential
therapeutic avenues that can be explored for IKZF1-mutated Ph ALL and Ph-like ALL, and for the IKZF1
+
N159Y subgroup.

A major challenge for the translation and implementation of the modern ALL taxonomy into pragmatic
clinical algorithms is the limited access to comprehensive NGS platforms and their relatively long
turnaround time, making it challenging for real time patient’s care. Nevertheless, a number of clinically-
validated NGS assays are increasingly available and being incorporated into frontline ALL trials. For
example, the Rapid Heme Panel, a DNA-based NGS diagnostic assay currently used in the DFCI ALL 16-
001 study for the detection of sequence mutations and CNAs, is able to deliver results within 10 days for
[108]
risk stratification . Gene expression profiling for the identification of Ph-like ALL has now been largely
replaced by the TaqMan low-density array (LDA) microfluidic card measuring the expression of 8- or 15-
gene panels to determine the Ph-like ALL signature. This LDA-based approach has provided a rapid and
cost-effective screening modality to identify patients with probable Ph-like ALL (LDA-positive) who require
further detailed genomic characterization. To identify targetable kinase-activating alterations, the ArcherDx
FusionPlex Heme panel uses anchored multiplex PCR-based enrichment with the ability to detect novel
fusions involving 87 genes associated with hematologic malignancies . The AIEOP-BFM consortium is
[109]
now incorporating array comparative genomic hybridization to identify the IKZF1 profile and panel-
plus
based RNA sequencing to detect targetable gene fusions for upfront risk stratification in their frontline ALL
trial . At the level of a single center, the St. Jude Children’s Research Hospital attests that a full DNA- and
[110]
RNA-based sequencing approach is feasible within 4 weeks and suitable for integration into patient’s real-
time management . The modernization of sequencing technologies and the development of standardized
[111]
bioinformatic pipelines for timely data analysis should facilitate routine clinical implementation of genomic
profiling for pediatric ALL.