Table 1.
Treatments used in ALL and associated neurotoxicity.
| Phase of Treatment | Drugs | Toxicity-Related Gene | Mechanism of Neurotoxicity | Neurotoxicity | References |
|---|---|---|---|---|---|
| Induction | Vincristine | ABCC11 1, ABCC2 2, ABCC4 3, ABCC5 4, ABCB1 5, ABCC10 6, CEP72 7, SLC5A7 8, TUBB1 9, TUBB2A 10, TUBB2B 11, TUBB3 12, TUBB4A 13, MAP4 14, CYP3A4 15, CYP2C8 16, CYP3A5 17, CEP72 18 | Interferes with the assembly of microtubule structures leading to cell apoptosis. It affects the peripheral nerves but can also contribute to dysfunction of the cranial nerves and autonomic nervous system. | Peripheral neuropathy, sensory neuropathy: symmetry sensory/tactile impairment, numbness, and tingling in the hands and feet, paresthesia, decreased balance, tendon weakening, visual and hearing problems. | [8,9] |
| L-asparaginase | ZBTB1 19, GRIA1 20, HLA-DRB1 21 | L-asparaginase produces three neurotoxic agents: ammonia, L-aspartic acid, and glutamic acid. These two amino acids can induce cell death in CNS neurons by excessive stimulation through NMDA (N-methyl-D-aspartate) receptor, leading to a major intracellular calcium influx and apoptosis. | Myelosuppression, encephalopathy, hepatic toxicity. | [10,11,12] | |
| Consolidation | Methotrexate (intravenous infusion and intrathecally) | DHFR19bp 22, MTHFR 677C > T 23, MTHFR 677TT 24, SLC19A1 25, TYMS 26, ADORA2A 27 | Methotrexate is an antimetabolite that inhibits Dihydrofolate Reductase and thus tetrahydrofolate formation. This affects the synthesis of macromolecules such as myelin, and reversible leukoencephalopathy has been suggested to be secondary to impaired myelin turnover. Dihydrofolate Reductase inhibition leads to lack of folate and cobalamin, and increase in homocysteine, which is toxic to vascular endothelium may cause seizures and vascular disease. Dihydrofolate Reductase inhibition results in decreased levels of S-adenosylmethionine, which in turn plays a role in maintaining the myelin sheath, and this deficiency may lead to demyelination after intrathecal methotrexate administration. |
Transverse myelopathy-symptoms include back pain with subsequent weakness, sensory loss and bladder or bowel incontinence, blurred vision, aphasia, anarthria, seizures, aphasia, mental status disorder, stroke-like episodes, delirium, leukoencephalopathy septic meningitis characterized by headache, neck stiffness, nausea, vomiting and potential fever and encephalopathy. | [13,14,15] |
| Cytarabine | DCK 28, NT5C2 29, CDA 30, RRM1 31, GIT1 32, NT5C 3 33, ENT1 34, SCL29A1 25 | Cytarabine exhibits preferential toxicity for CNS 35 progenitor cells and oligodendrocytes, compromises cell division in vitro, and causes cell death and reduced cell division in vivo. | Myelosuppression, neurotoxicity. | [16,17,18,19] | |
| Maintenance | Methotrexate (orally) | Genes have been described above. | Mechanism has been described above. | Seizures, aphasia, mental status disorder, stroke-like episodes, delirium, leukoencephalopathy, cognitive dysfunction, personality changes. | [13,14,15,20] |
1 ABCB11, ATP Binding Cassette Subfamily C Member 11; 2 ABCC2, ATP Binding Cassette Subfamily C Member 2; 3 ABCC4, ATP Binding Cassette Subfamily C Member 4; 4 ABCC5, ATP Binding Cassette Subfamily C Member 1; 5 ABCB1, ATP Binding Cassette Subfamily B Member 1; 6 ABCC10, ATP Binding Cassette Subfamily C Member 10; 7 CEP72, Centrosomal Protein 72; 8 SLC5A7, Solute Carrier Family 5 Member 7; 9 TUBB1, Tubulin Beta 1 Class VI; 10 TUBB2A, Tubulin Beta 2A Class IIa; 11 TUBB2B, Tubulin Beta 2B Class IIb; 12 TUBB3, Tubulin Beta 3 Class III; 13 TUBB4A, Tubulin Beta 4A Class Iva; 14 MAP4, Microtubule-Associated Protein 4; 15 CYP3A4, Cytochrome P450 Family 3 Subfamily A Member 4; 16 CYP2C8, Cytochrome P450 Family 2 Subfamily C Member 8; 17 CYP3A5, Cytochrome P450 Family 3 Subfamily A Member 5; 18 CEP72, Centrosomal Protein 72; 19 ZBTB1, Zinc Finger and BTB Domain Containing 1; 20 GRIA1, Glutamate Ionotropic Receptor AMPA Type Subunit 1; 21 HLA-DRB1, Major Histocompatibility Complex Class II, DR Beta1; 22 DHFR19bp, Dihydrofolate Reductase 19 bp polymorphism; 23 MTHFR 677C > T, Methylenetetrahydrofolate Reductase polymorphism; 24 MTHFR 677TT, Methylenetetrahydrofolate Reductase polymorphism; 25 SCL29A1, Solute Carrier Family 29, member 1; 26 TYMS, Thymidylate Synthetase; 27 ADORA2A, Adenosine A2a Receptor; 28 DCK, Deoxycytidine Kinase; 29 NT5C2, 5’-Nucleotidase, Cytosolic II; 30 CDA, Cytidine Deaminase; 31 RRM1, Ribonucleotide Reductase Catalytic Subunit M1; 32 GIT1, G Protein-Coupled Receptor Kinase Interacting ArfGAP 1; 33 NT5C3, 5’-Nucleotidase, Cytosolic IIIA; 34 ENT1, Equilibrative nucleoside transporter 1; 35 CNS, central nervous system.