Table 1.
Genetic subgroups as indication criteria for small-molecule targeted agents and guide for patient stratification in pediatric acute leukemia.
| Genetic Subgroup | Possible Small-Molecule Targeted Agent or Risk Prediction | Refs |
|---|---|---|
| ALL | ||
| Ph+ (BCR-ABL1) | TKI, Aurora kinase (alisertib) | [100] |
| TCF3-PBX1 | PI3Ki (idelalisib), considerable response to chemotherapy | [101] |
| TCF3-HLF | therapy-resistant disease, BCL2i (venetoclax) | [102] |
| KMT2A rearrangement | FLT3i (quizartinib), DOT1L-i (pinometostat), proteasome inhibitor (bortezomib), HDACi ± DNMTi aHSCT when poor response to induction is detected |
[103] |
|
ETV6-RUNX1, ETV6-RUNX1-like, DUX4 rearrangement (often coincide with ERGdel) |
Excellent prognosis, reduced intensity treatment may be considered |
[57] |
| MEF2D rearrangement | HDACi (panabinostat), proteasome inhibitor (bortezomib) | [96] |
| ZNF384 rearrangement | FLT3i (sunitinib) | [104] |
| NT5C2 alteration | Anticipate thiopurine resistance, often associated with relapse | [105] |
| CREBBP alteration | Anticipate corticosteroid resistance | [106] |
| Hypodiploid | BCL2i (venetoclax), aHSCT | [107] |
| High hyperdiploid | Low-risk disease | [13] |
| iAMP21 | High-risk disease | [108] |
| NOTCH1 + | PSEN1i (γ-secretase complex inhibition), | [109] |
| IKZF1 plus | in the presence of IKZF1 alteration, FAKi potentiates other drugs’ antitumor effect High-risk disease (even with low MRD values) |
[110] |
| MYC rearrangement | Resistant disease course | [111] |
| NUP214-ABL1 | TKI | [112] |
| oncogene activation (eg. TAL1, LYL1, LMO1, TLX1, TLX3) by translocation with TCR genes | Varying, but substantial prognostic effect | [113] |
| CDKN2A/CDKN2B deletions | CDK4/CDK6i (palbociclib), | [114] |
| KMT2A-ENL | Despite KMT2A rearrangement, the prognosis is not poor in T-cell, ALL and aHSCT is generally avoidable | [115] |
| Ph-like precursor B-cell ALL | [116,117] | |
| ABL class (ABL1, ABL2, CSF1R, PDGFRA, PDGFRB) | Dasatinib | |
| CRLF2 class (IGH-CRLF2, P2RY8-CRLF2, CRLF2mut) | USP9Xi, HDACi (givinostat) | |
| JAK2/EPOR class (JAK2, EPOR, PAX5) | JAKi (ruxolitinib) | |
| Ras/MAPK class (NRAS, KRAS, PTPN11, NF1) | MEKi (trametinib) | |
| Rare kinase fusions (NTRK3, FGFR1, PTK2B, TYK2, DGKH, LYN) | NTRKi (larotrectinib, NTRK3), ALKi/ROS1i (crizotinib, NTRK3), ponatinib (FGFR1), FAKi (PTK2B), TYK2i (TYK2) | |
| IKZF1 alteration in Ph-like cases | Retinoid use potentiates TKIs’ effect | |
| AML | ||
| KMT2A rearrangement | DOT1Li (pinometostat) | [118] |
| NUP98 rearrangement | CDK6i (palbociclib), BCL2i (navitoclax) High-risk disease (need for aHSCT) |
[119,120] |
| CBF-AML (inv(16): CBFB-MYH11, t(8;21): RUNX1-RUNX1T1) | KITi (dasatinib) Low-risk disease |
[121] |
| FLT3 activating mutations | FLT3i (midostaurin, crenolanib, gilteritinib, lestaurtinib, quizartinib, sorafenib) |
[15] |
|
The coincidence anticipates a favorable prognosis, outcomes are better than in FLT3-ITDneg cases | |
|
Usually unsuccessful induction, dismal prognosis, need for aHSCT | |
| IDH1/IDH2 mutations (rare in children) | IDHi (enasidenib, ivosidenib) | [122] |
| HIF1A, BRE and CLEC7A expression levels | Drug resistance toward cytarabine, daunorubicin, and/or etoposide | [123] |
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; Ph, Philadelphia; TKI, tyrosine kinase inhibitor; aHSCT, allogeneic hematopoietic stem cell transplantation; MRD, minimal residual disease; ITD, internal tandem duplication.