Haematol: Methotrexate-Associated Central Neurotoxicity: Clinical Characteristics, Risk Factors, and Genome-Wide Association Studies in Children Treated with Acute Lymphoblastic Leukemia

Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during treatment of acute lymphoblastic leukemia (ALL) with potential long-term neurological complications
.

However, further research is currently needed regarding its risk factors and long-term outcomes

A research team conducted a systematic retrospective review of 1,251 consecutive Australian children enrolled in the Berlin-Frankfurt-Münster or Children's Oncology Group protocols between 1998 and 2013
.

Predictors of clinical risk for MTX neurotoxicity using regression analysis

Figure 1: Cumulative incidence of CNS relapse according to intrathecal methotrexate strategy
.

Children receiving intrathecal (IT) methotrexate (MTX) were permanently missed after symptomatic MTX neurotoxicity (n=48) compared with children receiving IT MTX who continued to receive ALL in the central nervous system (CNS) There was an increased risk of recurrence (n=1,174) (P=0.

Figure 1: Cumulative incidence of CNS relapse according to intrathecal methotrexate strategy

Figure 2: Time to Methotrexate Neurotoxicity and Risk of Leukemia Relapse
.

Children who experienced methotrexate (MTX) neurotoxicity early in treatment (induction/consolidation) had significantly increased rates of leukemia relapse compared to later in treatment (post-consolidation, P

Figure 2: Time to Methotrexate Neurotoxicity and Risk of Leukemia Relapse

The recurrence rate of MTX neurotoxicity was lower (12.
9%) in patients who continued intrathecal MTX after the first episode
.

^{GWAS identified single nucleotide polymorphisms (P< -6}) associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation, and cytoskeletal organization

^-6

This is the largest pediatric cohort of ALL/LBL treated with regard to the incidence, risk factors, and long-term effects of MTX toxicity
.

The independent risk factors for symptomatic MTX neurotoxicity were age ≥ 10 years at diagnosis and serum AST elevation > grade 3 during early treatment

In conclusion, elevated serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity
.

The data reported here do not support discontinuation of intrathecal MTX after the first MTX neurotoxic event

Elevated serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity
.

 

Original source:

Mateos MK, Marshall GM, Barbaro PM, Quinn MCJ, George C, Mayoh C, Sutton R, Revesz T, Giles JE, Barbaric D, Alvaro F, Mechinaud F, Catchpoole D, Lawson JA, Chenevix-Trench G, MacGregor S, Kotecha RS, Dalla-Pozza L, Trahair TN.
Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.
Haematologica.
2022 Mar 1;107(3):635-643 .
doi: 10.
3324/haematol.
2020.
268565.
PMID: 33567813; PMCID: PMC8883571.

Mateos MK, Marshall GM, Barbaro PM, Quinn MCJ, George C, Mayoh C, Sutton R, Revesz T, Giles JE, Barbaric D, Alvaro F, Mechinaud F, Catchpoole D, Lawson JA, Chenevix-Trench G, MacGregor S, Kotecha RS, Dalla-Pozza L, Trahair TN.
Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.
Haematologica.
2022 Mar 1;107(3):635-643 .
doi: 10.
3324/haematol.
2020.
268565.
PMID: 33567813; PMCID: PMC8883571.
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