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Cancer Chemotherapy and Pharmacology

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01-04-2019 | Acute Lymphoblastic Leukemia | Original Article

Folate pathway genetic polymorphisms modulate methotrexate-induced toxicity in childhood acute lymphoblastic leukemia

Authors: Al-Motassem Yousef, Rand Farhad, Daniah Alshamaseen, Abrar Alsheikh, Mohammed Zawiah, Taha Kadi

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2019

Abstract

Background

Acute lymphoblastic leukemia (ALL) is one of the major malignancies affecting children in Jordan. Methotrexate (MTX) is the cornerstone of chemotherapy for ALL, and works by targeting enzymes involved in the folate pathway. We hypothesize that genetic polymorphisms of the folate pathway are associated with MTX toxicity in children with ALL.

Methods

A total of 64 children with ALL were included in this study; 31 (48.4%) boys and 33 (51.6%) girls aged 2–16 years. The folate pathway genes were genotyped using polymerase chain reaction followed by sequencing and studying the association between genetic polymorphisms and MTX toxicity.

Results

The immunophenotype was B-lineage in 55 patients (85.9%) and T-lineage in nine patients (14.1%). All genetic polymorphisms, except for dihydropyrimidine dehydrogenase polymorphisms, were associated with hematological toxicities and did not appear to precipitate any non-hematological adverse events. Patients with ALL carrying dominant alleles of methylene tetrahydrofolate (MTHFR) C677T and dihydrofolate reductase 19 bp deletion were at a higher risk of developing severe leucopenia [OR (95% CI) = 4.5 (1.2–17), p = 0.03; 5.4 (1.6–17.8); p = 0.006] while minor allele carriers of MTHFR A1298C were more likely to develop neutropenia [OR (95% CI) = 6.1 (1.3–29.5); 0.04]. Furthermore, dominant allele carriers of thymidylate synthase 1494 del6 were at a higher risk of developing neutropenia [OR (95% CI) = 6 (1.2–31.1); p = 0.04].

Conclusion

Genetic polymorphisms of the folate pathway may modulate MTX-induced toxicity in childhood ALL.

Available only for authorised users

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Title: Folate pathway genetic polymorphisms modulate methotrexate-induced toxicity in childhood acute lymphoblastic leukemia
Authors: Al-Motassem Yousef
Rand Farhad
Daniah Alshamaseen
Abrar Alsheikh
Mohammed Zawiah
Taha Kadi
Publication date: 01-04-2019
Publisher: Springer Berlin Heidelberg
Keywords: Acute Lymphoblastic Leukemia
Methotrexate
Neutropenia
Leukopenia
Methotrexate
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03776-8

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