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Page 389 Santiago et al. J Transl Genet Genom 2021;5:380-95 https://dx.doi.org/10.20517/jtgg.2021.16

Table 1. Precision medicine opportunities in pediatric acute lymphoblastic leukemia
Preclinical - single patient
ALL subtypes Therapies Clinical trials Phase
experience
+
Ph ALL Imatinib AALL0031 (NCT00022737) 3
EsPhALL2010 (NCT00287105) 2
CCCG-ALL-2015 3
EsPhALL 2017/COG AALL1631 3
(NCT03007147)
Dasatinib AALL0622 (NCT00720109) 2
AALL1122 (NCT01460160) 2
CCCG-ALL-2015 3
Ponatinib NCT04501614 1/2
[92]
Rexinoids
FAK inhibitors [93]
Ph-like ALL Dasatinib AALL1131 (NCT02883049) 3
- With ABL-class fusions Total Therapy XVII (NCT03117751) 3
DFCI ALL 16-001 (NCT03020030) 3
- With JAK-STAT pathway lesions Ruxolitinib AALL1521 (NCT02723994) 2
Total Therapy XVII (NCT03117751) 3
- With NTRK fusions Larotrectinib ADVL1823 (NCT03834961) 2
[85]
PI3K/AKT/mTOR inhibitors
KMT2A-R ALL Lestaurtinib AALL0631 (NCT00557193) 3
Azacitidine AALL15P1 (NCT02828358) 2
Vorinostat/ TINI (NCT02553460) 1/2
Bortezomib
Menin NCT04811560 (adults only) 1
inhibitors
DOT1L NCT02141828 1
inhibitors
Venetoclax NCT03826992 1
[94]
Hypodiploid ALL Venetoclax
[95]
ZNF384-R ALL FLT3 inhibitors
[33]
MEF2D-R ALL HDAC inhibitors
T-ALL Venetoclax NCT00501826 2
- NOTCH pathway mutations Y-secretase inhibitors
Soluble notch proteins
[96]
Mastermind inhibiting peptides
- JAK-STAT mutations Ruxolitinib Total Therapy XVII (NCT03117751) 3
- ETP ALL
- PI3K/AKT/mTOR pathway Everolimus PI3K/AKT/mTOR inhibitors [97] DFCI 11-237 (NCT01523977) 1
mutations [98]
Farnesyltransferase inhibitors
- Ubiquination Bortezomib AALL1231 (NCT02112916) 3
Carfilzomib Total Therapy XVII (NCT03117751) 3
CFZ008 (NCT02303821) 1
B and T-ALL Palbociclib AINV18P1 (NCT03792256) 1
- Cell cycle control Ribociclib NCT03740334 1
- Ras pathway mutations Selumetinib NCT03705507 1/2

ALL: Acute lymphoblastic leukemia; ETP: early T-cell precursor; HDACi: HDAC inhibitor; KMT2A-R: KMT2A rearranged; MEF2D-R: MEF2D
+
rearranged; Ph : Philadelphia positive; T-ALL: T-cell acute lymphoblastic leukemia; ZNF384-R: ZNF384 rearranged.

Proapoptotic targeted therapy
Proapoptotic agents, acting as cell death inducers by overcoming chemoresistance, represent another
promising therapeutic opportunity for ALL . KMT2A rearrangements, frequently observed in infant ALL,
[99]
are known to confer resistance to apoptosis, emphasizing the interest of apoptotic inducer for this
subgroup [100,101] . A study on xenografts confirmed the activity of the selective BCL-2 inhibitor, venetoclax, for
KMT2Ar ALL models, while other ALL subtypes escaped venetoclax inhibition by activating the bcl-x