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

  • Al-Motassem YousefEmail author
  • Rand Farhad
  • Daniah Alshamaseen
  • Abrar Alsheikh
  • Mohammed Zawiah
  • Taha Kadi
Original Article



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.


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.


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].


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


ALL MTX Toxicity Genetic polymorphisms Folate 




Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

The protocol of the study was approved by the institutional review board (IRB) of Royal Medical Services (IRB no. 1762, 14/2/2017), and conducted in concordance with the principles of the Declaration of Helsinki 1964 and its later amendments or comparable ethical standards.

Informed consent

Each patient provided their written informed consent.

Supplementary material

280_2019_3776_MOESM1_ESM.docx (27 kb)
Supplementary material 1 (DOCX 26 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Biopharmaceutics and Clinical Pharmacy, School of PharmacyThe University of JordanAmmanJordan

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