Molecularly Targeted Small Molecule Inhibitor Therapy for Pediatric Acute Lymphoblastic Leukemia: A Comprehensive Review of Clinical Trials
Simple Summary
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. BCR::ABL1-Directed Tyrosine Kinase Inhibitors
3.1.1. Imatinib
3.1.2. Dasatinib
3.1.3. Ponatinib
3.1.4. Nilotinib
3.1.5. Olverembatinib
3.2. Janus Kinase Inhibitors
Ruxolitinib
3.3. Proteasome Inhibitors
3.3.1. Bortezomib
3.3.2. Carfilzomib
3.3.3. Ixazomib
3.4. BH3 Mimetics
3.5. MEK Inhibitors
3.5.1. Selumetinib
3.5.2. Trametinib
3.6. Cyclin-Dependent Kinase Inhibitors
3.6.1. Palbociclib
3.6.2. Ribociclib
3.7. mTOR Inhibitors
3.7.1. Sirolimus
3.7.2. Everolimus
3.7.3. Temsirolimus
3.8. Epigenetic Modifying Agents
3.9. Histone Deacetylase Inhibitors (HDACi)
Vorinostat
3.10. Hypomethylating Agents (HMAs)
3.10.1. Azacitidine
3.10.2. Decitabine
3.11. Molecularly Targeted Treatment in Pediatric KMT2A-r ALL
3.12. FLT3 Inhibitors
3.12.1. Midostaurin
3.12.2. Lestaurtinib
3.13. Menin Inhibitors
3.13.1. Revumenib
3.13.2. Ziftomenib
4. Conclusions and Future Directions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AYAs | Adolescents and young adults |
ALL | Acute lymphoblastic leukemia |
AML | Acute myeloid leukemia |
B-ALL | B-cell precursor acute lymphoblastic leukemia |
BFM | Berlin–Frankfurt–Münster |
CAR-T | Chimeric antigen receptor T-cell therapy |
CCCG | Chinese Children’s Cancer Group |
CDK | Cyclin-dependent kinases |
CML | Chronic myeloid leukemia |
CML-CP | CML chronic phase |
CML-AP | CML accelerated phase |
CML-BP | CML blast phase |
CNS | Central nervous system |
COG | Children’s Oncology Group |
CR | Complete remission |
DFCI | Dana–Farber Cancer Institute |
DNMTi | DNA methyltransferase inhibitor |
EFS | Event-free survival |
EsPhALL | European intergroup study Philadelphia chromosome-positive ALL |
EMA | European Medicines Agency |
EOI | End of induction |
EOC | End of consolidation |
ETP | Early T-cell precursor |
FDA | Food and Drug Administration |
HDACi | Histone deacetylase inhibitor |
HEM-iSMART | International proof of concept therapeutic Stratification trial of Molecular Anomalies in Relapsed or Refractory HEMatological malignancies in children |
HMAs | Hypomethylating agents |
HR | High-risk |
HSCT | Hematopoietic stem cell transplantation |
IntReALL | I-BFM-SG international study for children and adolescents with relapsed ALL |
LLy | Lymphoblastic lymphoma |
MDACC | MD Anderson Cancer Center |
MEK | Mitogen-activated extracellular protein kinase |
MTD | Maximum tolerated dose |
NGS | Next-generation sequencing |
ORR | Overall response rate |
OS | Overall survival |
Ph+ | Philadelphia chromosome-positive |
Ph-like | Philadelphia chromosome-like |
PK | Pharmacokinetics |
PMC | Princess Máxima Center for Pediatric Oncology |
RP2D | Recommended phase II dose |
R/R R/I | Refractory/relapsed Refractory/intolerant |
SJCRH | St. Jude Children’s Research Hospital |
STAMP | Specifically targeting ABL myristoyl pocket |
TACL | Therapeutic Advances in Childhood Leukemia and Lymphoma |
T-ALL | T-cell acute lymphoblastic leukemia |
TKI | Tyrosine kinase inhibitor |
VXLD | Vincristine, dexamethasone, asparaginase, and daunorubicin regimen |
VPLD | Vincristine, dexamethasone, asparaginase, and doxorubicin regimen |
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Trial ID | Study Name | Status | Phase | Disease | Enrollment Period | N. Patients */ Age Eligibility (Years) | Key Results | Reference |
---|---|---|---|---|---|---|---|---|
BCR::ABL1-directed TKIs | ||||||||
Imatinib | ||||||||
NCT00004932 | - | Completed | 1 | CML, Ph+ ALL | 2000–2001 | 31/up to 21 | Good tolerance at doses ranging from 260 to 570 mg/m2 | Champagne et al. [23] |
NCT00022737 | COG AALL0031 | Completed | 3 | Ph+ ALL | 2002–2006 | 91/1–21 | 5-year EFS 71% (Cohort 5) | Schultz et al. [24] |
NCT00287105 | EsPhALL 2004 | Completed | 2 | Ph+ ALL | 2004–2009 | 160/1–17 | 4-year EFS 72.9% (Imatinib) vs. 61.7% (no imatinib) (p 0.24) in good-risk patients | Biondi et al. [25] |
NCT00287105 | EsPhALL 2010 | Completed | 2 | Ph+ ALL | 2010–2014 | 155/1–17 | 5-year EFS 62.7% in good-risk patients and 46.3% in poor-risk patients | Biondi et al. [26] |
NCT00137111 | Total Therapy XV | Completed | 3 | Ph+ ALL | 2004–2007 | 5/1–18 | 5-year EFS 68.6% (Imatinib + Dasatinib patients) | Jeha et al. [27] |
NCT03007147 | EsPhALL 2017/ COG AALL1731 | Active, not recruiting | 3 | Ph+ ALL, ABL-class ALL | 2017–2024 | 475/1–17 | - | - |
NCT04307576 | ALLTogether1 | Recruiting | 3 | ABL-class ALL | 2019-present | 6430/0–45 | - | - |
Dasatinib | ||||||||
NCT00316953 | CA180-038/ COG-ADVL0516 | Completed | 1 | CML, Ph+ ALL, solid tumor | 2006–2009 | 39/1–21 | MTD 85 mg/m2 (twice daily) | Aplenc et al. [28] |
NCT00306202 | CA180-018/ ITCC-005 | Completed | 1 | R/I CML, R/R Ph+ ALL | 2006–2009 | 58/1–21 | RP2D 80 mg/m2 (once daily) | Zwaan et al. [29] |
NCT00720109 | COG AALL0062 | Completed | 2/3 | Ph+ ALL | 2008–2012 | 60/1–30 | 5-year EFS 60% in good-risk patients and 67% in high-risk patients | Slayton et al. [30] |
NCT00549848 | Total therapy XVI | Completed | 3 | Ph+ ALL | 2007–2012 | 6/1–18 | 5-year EFS 68.6% | Jeha et al. [27] |
NCT01460160 | CA180-372/ COG AALL1122 | Completed | 2 | Ph+ ALL | 2012–2014 | 106/1–17 | 3-year EFS 65.5% | Hunger et al. [31] |
ChiCTR-IPR-14005706 | - | Completed | 3 | Ph+ ALL | 2015–2018 | 97 (ima) + 92 (dasa)/0–18 | 4-year EFS 49% (imatinib) vs. 71% (dasatinib) (p 0.005) | Shen et al. [21] |
NCT03117751 | Total therapy XVII | Active, not recruiting | 2/3 | ABL-class ALL (B- and T-ALL) | 2017–2023 | 790/1–18 | - | - |
NCT01406756 | COG AALL1131 | Active, not recruiting | 3 | ABL-class ALL | 2016–2019 | 22/1–31 | 4-year EFS 52.5% | Salzer et al. [32] |
NCT03020030 | DFCI 16-001 | Active, not recruiting | 3 | ABL-class ALL | 2017–2022 | 560/1–21 | - | - |
NCT06336395 | MA-Spore 2020 | Recruiting | 3 | Ph+ ALL, ABL-class ALL | 2020–present | 500/up to 40 | - | - |
NCT06257394 | - | Recruiting | 2 | Ph+ ALL | 2024–present | 74/1–19 | - | - |
NCT05192889 | RAVEN | Active, not recruiting | 1/2 | R/R ABL-class ALL, R/R non-ETP ALL | 2022–2024 | 35/4–30 | - | - |
NCT06124157 | EsPhALL 2022/ COG AALL2131 | Not yet recruiting | 3 | Ph+ ALL, ABL-class ALL | - | 222/1–46 | - | - |
NCT06390319 | SJALL23T | Not yet recruiting | 2 | Non-ETP T-ALL | - | 100/1–18 | - | - |
NCT05751044 | HEM-iSMART-B | Not yet recruiting | 1/2 | T-ALL R/R | - | 26/1–21 | - | - |
Nilotinib | ||||||||
NCT01077544 | - | Completed | 1 | R/I CML, Ph+ ALL | 2011–2015 | 15/1–18 | RP2D 230 mg/m2 (twice daily) | Hijiya et al. [33] |
Ponatinib | ||||||||
NCT04501614 | - | Terminated | 1|2 | R/R Ph+ ALL, ABL-class ALL | 2020–2024 | 11/1–21 | - | Matloub et al. [34] |
NCT03934372 | - | Recruiting | 1|2 | R/R leukemia, lymphomas, solid tumors | 2020-present | 60/1–17 | - | - |
NCT05268003 | MDACC 2021-0802 | Active, not recruiting | 2 | R/R T-ALL | 2020-present | 26/12 and older | - | - |
Olverembatinib | ||||||||
NCT05495035 | - | Active, not recruiting | 1 | Ph+ ALL | 2022–2024 | 10/0–18 | - | Zhang et al. [35] |
JAK inhibitors | ||||||||
Ruxolitinib | ||||||||
NCT01164163 | ADVL1011 | Completed | 1 | R/R leukemia and solid tumors | 2010–2012 | 49/1–18 | RP2D 50 mg/m2 (BID) | Loh et al. [36] |
NCT02723994 | AALL1521 (INCB18424-269) | Active, not recruiting | 2 | HR Ph-like B-ALL | 2016–2022 | 171/1–21 | - | Tasian et al. [37] |
NCT03117751 | Total therapy XVII | Active, not recruiting | 2/3 | HR Ph-like B-ALL (B- and T-ALL) | 2017–2023 | 790/1–18 | - | - |
NCT05745714 | HEM-iSMART-C | Not yet recruiting | 1/2 | R/R T-ALL | - | 26/1–21 | - | - |
Proteasome inhibitors | ||||||||
Bortezomib | ||||||||
NCT00077467 | COG-ADVL0317 | Completed | 1 | R/R ALL | 2004–2005 | 12/1–18 | RP2D 1.3 mg/m2/dose (twice weekly for 2 weeks followed by a 1-week rest) | Horton et al. [38] |
NCT00440726 | T2005-003 | Completed | 1/2 | R/R ALL | 2006–2011 | 22/1–22 | ORR 73% | Messinger et al. [39,40] |
NCT00873093 | COG AALL07P1 | Completed | 2 | 1st R ALL | 2009–2013 | 135/1–18 | ORR 68 ± 5% B-ALL; 68 ± 10% T-ALL | Horton et al. [41] |
2009-014037-25 (EudraCTnumber) | ITCC 021/I-BFM-SG | Completed | 2 | R/R ALL | 2010–2014 | 29/0.5–19 | ORR 60% | Kaspers et al. [22] |
NCT03590171 | IntReALL HR 2010 | Recruiting | 2 | 1st R ALL | 2017–present | 250/0–17 | - | - |
NCT02112916 | COG AALL1231 | Active, not recruiting | 3 | T-ALL and T-LLy (1st line) | 2014–2017 | 824/1–30 | 4-year EFS 80.1% (no bortezomib) vs. 83.8% (bortezomib) (p 0.131) | Teachey et al. [42] |
NCT04224571 | CCCG-ALL-2017 relapse | Completed | 2 | R/R ALL | 2018–2023 | 208/3 months-21 yrs | - | - |
NCT03643276 | AIEOP-BFM ALL 2017 | Active, not recruiting | 3 | B- and T-ALL (1st line) | 2018–2024 | 5000/0–17 | - | - |
NCT03117751 | Total therapy XVII | Active, not recruiting | 2/3 | B- and T-ALL (1st line) | 2017–2023 | 790/1–18 | - | - |
NCT06390319 | SJALL23T | Not yet recruiting | 2 | Non-ETP T-ALL | - | 100/1–18 | - | - |
NCT05681260 | CCCG-T-LBL-2023 | Recruiting | 3 | T-LLy | 2023–present | 200/12–18 | - | - |
NCT02553460 | TINI I | Active, not recruiting | 1/2 | Infant ALL | 2017–2021 | 50/up to 1 year | 3-year EFS 56.5% | Gruber et al. [43] |
NCT05848687 | TINI II | Not yet recruiting | 1/2 | Infant ALL | - | 90/up to 1 year | - | - |
Carfilzomib | ||||||||
NCT02303821 | CFZ008 | Completed | 1/2 | R/R ALL | 2015–2024 | 141/1–21 | ORR 50% | Burke et al. [44] |
Ixazomib | ||||||||
NCT03817320 | T2017-002 | Active, not recruiting | 1/2 | R/R ALL | 2019–2024 | 24/1–21 | RP2D 2 mg/m2/dose | Schafer et al. [45] |
BH3 mimetics | ||||||||
Venetoclax | ||||||||
NCT03236857 | M13–833 | Completed | 1/2 | R/R ALL | 2017–2023 | 31/0–25 | ORR 55% | Place et al. [46] |
NCT03181126 | - | Completed | 1/2 | R/R ALL and LLy | 2017–2019 | 47/4 yrs and older | ORR 60% | Pullarkat et al. [47] |
NCT05192889 | RAVEN | Active, not recruiting | 1/2 | R/R ALL | 2022–2024 | 35/4–30 | - | - |
NCT05268003 | MDACC 2021-0802 | Active, not recruiting | 2 | R/R T-ALL | 2022–present | 26/12 yrs and older | - | - |
NCT05292664 | - | Active, not recruiting | 1 | R/R ALL | 2023–present | 13/1–40 | - | - |
NCT06317662 | AALL2321 | Not yet recruiting | 2 | Front line Infant ALL | - | 153/up to 1 year | - | - |
NCT06390319 | SJALL23T | Not yet recruiting | 2 | Front line ETP/near ETP ALL | - | 100/1–18 | - | - |
NCT05751044 | HEM-iSMART-B | Not yet recruiting | 1/2 | R/R T-ALL | - | 26/1–21 | - | - |
NCT05745714 | HEM-iSMART-C | Not yet recruiting | 1/2 | R/R T-ALL | - | 26/1–21 | - | - |
NCT06561074 | MDACC 2022-0416 | Not yet recruiting | 2 | R/R T-ALL | - | 22/1–21 | - | - |
Navitoclax | ||||||||
NCT03181126 | - | Completed | 1/2 | R/R ALL and LLy | 2017–2019 | 47/4 yrs and older | ORR 60% | Pullarkat et al. [47] |
NCT05192889 | RAVEN | Active, not recruiting | 1/2 | R/R ALL | 2022–2024 | 35/4–30 | - | - |
Lisaftoclax | ||||||||
NCT05495035 | - | Active, not recruiting | 1 | Ph+ ALL | 2022–2024 | 10/0–18 | - | Zhang et al. [35] |
MEK inhibitors | ||||||||
Selumetinib | ||||||||
NCT03705507 | SeluDex, ITCC-063 | Terminated | 1 | R/R ALL | 2018–2023 | 12/All ages | CR 44% | Vormoor et al. [48] |
Trametinib | ||||||||
NCT05658640 | HEM-iSMART D | Recruiting | 1/2 | R/R T-ALL | 2024–present | 26/1–21 | - | - |
CDK4/6 inhibitors | ||||||||
Palbociclib | ||||||||
NCT03792256 | AINV18P1 | Completed | 1 | R/R ALL | 2019–2021 | 12/1–31 | 50 mg/m2/day for 21 days; ORR 42% | Raetz et al. [49] |
NCT03515200 | RELPALL | Terminated | 1 | R/R ALL | 2018–2020 | 12/up to 21 | - | - |
NCT04996160 | RELPALL2 | Recruiting | 1 | R/R ALL | 2021–present | 22/up to 25 | - | - |
Ribociclib | ||||||||
NCT02813135 | AcSé-ESMART sub-trial B | Completed | 1/2 | R/R leukemia | 2016–2019 | 31/up to 18 | - | Bautista et al. [50] |
NCT02813135 | AcSé-ESMART sub-trial M | Recruiting | 1/2 | R/R leukemia | 2021–present | 35/up to 18 | - | Geoerger et al. [51] |
NCT03740334 | 18-328 | Active, not recruiting | 1 | R/R ALL | 2019–2023 | 45/1–30 | - | - |
mTOR inhibitors | ||||||||
Sirolimus | ||||||||
NCT00068302 | - | Terminated | 1 | R/R ALL | 2003–2009 | 10/Up to 21 | - | Rheingold et al. [52] |
NCT00874562 | - | Completed | 1 | R/R ALL | 2007–2009 | 6/1 year and older | - | Schlis et al. [53] |
NCT01162551 | - | Completed | 2 | R/R ALL | 2010–2017 | 5/up to 25 | - | - |
NCT01658007 | - | Terminated | 1 | R/R ALL | 2012–2017 | 3/up to 30 | - | - |
Everolimus | ||||||||
NCT01523977 | - | Completed | 1 | R/R ALL | 2012–2017 | 22/18 months-21 years | RP2D 5 mg/m2/day; CR 86% | Place et al. [54] |
NCT03328104 | Aflac LL1602 ENCERT | Completed | 1 | R/R T-ALL | 2018–2023 | 8/2–29 | - | - |
NCT03740334 | 18-328 | Active, not recruiting | 1 | R/R ALL | 2019–2023 | 45/1–30 | - | - |
Temsirolimus | ||||||||
NCT01403415 | ADVL1114 | Completed | 1 | R/R ALL | 2012–2014 | 13/1–21 | - | Rheingold et al. [55] |
NCT01614197 | TACL 2014-001 | Completed | 1 | R/R ALL | 2015–2019 | 16/1–21 | RP2D 15 mg/m2; ORR of 47% | Tasian et al. [56] |
HDAC inhibitors | ||||||||
Vorinostat | ||||||||
NCT00217412 | - | Completed | 1 | Solid/hematologic cancers | 2005–2009 | 64/1–21 | RP2D 230 mg/m2/d | Fouladi et al. [57] |
NCT00882206 | - | Terminated | 2 | R/R ALL | 2009–2013 | 13/2–60 | ORR 46.2% | Burke et al. [58] |
NCT01483690 | TACL T2009-003 | Terminated | 1/2 | R/R ALL | 2011–2015 | 23/1–21 | - | Burke et al. [59] |
NCT02553460 | TIN I | Active, not recruiting | 1/2 | Infant ALL | 2017–2021 | 50/up to 1 year | 3-year EFS 56.5% | Gruber et al. [43] |
NCT05848687 | TINI II | Not yet recruiting | 1/2 | Infant ALL | - | 90/up to 1 year | - | - |
NCT03117751 | Total therapy XVII | Active, not recruiting | 2/3 | B- and T-ALL (1st line) | 2017–2023 | 790/1–18 | - | - |
DNA methyltransferase inhibitors | ||||||||
Azacitidine | ||||||||
NCT01861002 | TACL T2011-002 | Completed | 1 | R/R ALL | 2013–2014 | 15/1–21 | RP2D 75 mg/m2/day | Sun et al. [60] |
NCT02828358 | COG AALL15P1 | Completed | 2 | KMT2A-r infant R/R ALL | 2017–2022 | 78/up to 1 year | 3-year EFS 34.7% | Guest et al. [61] |
NCT06397027 | - | Recruiting | 1 | R/R AML and ALL (KMT2A-r, NPM1-m or NUP98-r) | 2024–present | 22/2–21 | - | - |
Decitabine | ||||||||
NCT00042796 | - | Terminated | 1 | R/R leukemia | 2002–2005 | 21/up to 21 | - | - |
NCT00349596 | - | Completed | 1/2 | R/R ALL | 2006–2014 | 40/All ages | - | Benton at al. [62] |
NCT00882206 | - | Terminated | 2 | R/R ALL | 2009–2013 | 13/2–60 | ORR 46.2% | Burke et al. [58] |
NCT01483690 | TACL T2009-003 | Terminated | 1/2 | R/R ALL | 2011–2015 | 23/1–21 | - | Burke et al. [59] |
NCT06561074 | MDACC 2022-0416 | Not yet recruiting | 2 | R/R T-ALL | - | 22/1–21 | - | - |
FLT3 inhibitors | ||||||||
Midostaurin | ||||||||
NCT00866281 | CPKC412A2114 | Terminated | 1/2 | R/R AML and ALL | 2009–2014 | 22/2–18 | RDE 60 mg/m2 BID | Zwaan et al. [63] |
Lestaurtinib | ||||||||
NCT00557193 | COG AALL0631 | Completed | 3 | KMT2A-r ALL | 2008–2014 | 210/up to 1 year | 3-year EFS 36 ± 6% (chemo + lestaurtinib) vs. 39 ± 7%, (chemo-only) (p 0.67) | Brown et al. [64] |
Menin inhibitors | ||||||||
Revumenib | ||||||||
NCT04065399 | AUGMENT-101 | Recruiting | 1/2 | R/R AML and ALL (KMT2A-r, NPM1 or NUP98-r) | 2019-present | 94/30 days and older | CR + CRh 22.8% and ORR 63.2% (57 patients) | Issa et al. [65,66] |
NCT05326516 | AUGMENT-102 | Completed | 1 | R/R AML and ALL (KMT2A-r, NPM1-m or NUP98-r) | 2022–2024 | 30/30 days and older | - | Shukla et al. [67] |
NCT05761171 | COG AALL2121 | Active, not recruiting | 2 | R/R KMT2A-r ALL | 2024–present | 78/1 month- 6 years | - | - |
NCT06575296 | - | Recruiting | 1 | KMT2A-r and NPM1-m ALL | 2025-present | 27/2 years and older | - | - |
Ziftomenib | ||||||||
NCT06397027 | - | Recruiting | 1 | R/R AML and ALL (KMT2A-r, NPM1-m or NUP98-r) | 2024–present | 22/2–21 | - | - |
NCT06376162 | ITCC-101/APAL2020K | Recruiting | 1 | R/R AML and ALL (KMT2A-r, NPM1-m or NUP98-r) | 2024–present | 20/0–21 | - | Salzer et al. [68] |
NCT05848687 | TINI II | Not yet recruiting | 1/2 | Infant ALL | - | 90/up to 1 year | - | |
Bleximenib | ||||||||
NCT04811560 | cAMeLot-1 | Recruiting | 1/2 | R/R AML and ALL (KMT2A-r, NPM1-m or NUP98-r) | 2024–present | 400/12 years and older | - | - |
Main Toxicities | References | |
---|---|---|
BCR::ABL1-direcetd tyrosine kinase inhibitors | Hematologic: cytopenia. Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain. Musculoskeletal: muscle cramps, musculoskeletal pain, myalgia. Dermatologic: skin rash, pruritus, depigmentation, photosensitivity. Constitutional: fatigue, headache. Fluid retention: edema, pleural or pericardial effusion (particularly associated with dasatinib). Cardiovascular: arterial/venous thrombosis (specifically for ponatinib). Endocrinologic: thyroid dysfunction, metabolic bone disorders, growth retardation. | [23,29,69,70,71,72] |
JAK inhibitors | Hematologic: cytopenia. Increased infection risk. Gastrointestinal: diarrhea, nausea. Constitutional: fatigue, headache. Skin: rash | [36,73] |
Proteasome inhibitors | Hematologic: cytopenia. Neurologic: Peripheral neuropathy (mainly with bortezomib; dose-limiting; sensory or painful). Cardiovascular: heart failure, hypertension, arrhythmias, and acute coronary syndromes (specifically for carfilzomib) | [74,75] |
BH3 mimetics | Hematologic: cytopenia. Thrombocytopenia, especially associated with navitoclax (dose-limiting). Increased infection risk. Other: tumor lysis syndrome. | [47] |
MEK inhibitors | Hematologic: mild cytopenia. Dermatologic: skin rash, pruritus, alopecia, hand-foot skin reaction (palmar-plantar erythrodysesthesia). Ocular: retinal disorders | [76] |
CDK4/6 inhibitors | Hematologic: cytopenia, especially neutropenia (dose-limiting). Mild gastrointestinal and hepatic toxicity. | [49,50] |
mTOR inhibitors | Hematologic: mild cytopenia. Dermatologic: skin rash. Metabolic: hyperlipidemia, hyperglycemia. | [77] |
HDAC | Hematologic: cytopenia, especially thrombocytopenia (dose-limiting). Gastrointestinal: nausea, vomiting, diarrhea, anorexia. Constitutional: fatigue, headache. Cardiovascular: QT prolongation. | [57,58] |
DNA methyltransferase inhibitors | Hematologic: cytopenia. Increased infection risk. Gastrointestinal: Nausea, vomiting, diarrhea, constipation. | [60,62] |
FLT3 inhibitors | Hematologic: cytopenia. Cardiovascular: QT prolongation (especially with quizartinib). Gastrointestinal: nausea, vomiting, diarrhea, anorexia. Hepatic: elevated liver enzymes. | [78] |
Menin inhibitors | Hematologic: cytopenia. Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain. Other: differentiation syndrome | [79] |
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Peccatori, N.; Brivio, E.; Lissat, A.; Bautista Sirvent, F.; Salzer, E.; Biondi, A.; Fazio, G.; Rizzari, C.; Tasian, S.K.; Zwaan, C.M. Molecularly Targeted Small Molecule Inhibitor Therapy for Pediatric Acute Lymphoblastic Leukemia: A Comprehensive Review of Clinical Trials. Cancers 2025, 17, 3322. https://doi.org/10.3390/cancers17203322
Peccatori N, Brivio E, Lissat A, Bautista Sirvent F, Salzer E, Biondi A, Fazio G, Rizzari C, Tasian SK, Zwaan CM. Molecularly Targeted Small Molecule Inhibitor Therapy for Pediatric Acute Lymphoblastic Leukemia: A Comprehensive Review of Clinical Trials. Cancers. 2025; 17(20):3322. https://doi.org/10.3390/cancers17203322
Chicago/Turabian StylePeccatori, Nicolò, Erica Brivio, Andrej Lissat, Francisco Bautista Sirvent, Elisabeth Salzer, Andrea Biondi, Grazia Fazio, Carmelo Rizzari, Sarah K. Tasian, and Christian Michel Zwaan. 2025. "Molecularly Targeted Small Molecule Inhibitor Therapy for Pediatric Acute Lymphoblastic Leukemia: A Comprehensive Review of Clinical Trials" Cancers 17, no. 20: 3322. https://doi.org/10.3390/cancers17203322
APA StylePeccatori, N., Brivio, E., Lissat, A., Bautista Sirvent, F., Salzer, E., Biondi, A., Fazio, G., Rizzari, C., Tasian, S. K., & Zwaan, C. M. (2025). Molecularly Targeted Small Molecule Inhibitor Therapy for Pediatric Acute Lymphoblastic Leukemia: A Comprehensive Review of Clinical Trials. Cancers, 17(20), 3322. https://doi.org/10.3390/cancers17203322