The effects of genetic polymorphism on toxicity and pharmacokinetics of methotrexate in Egyptian adult patients with leukaemia or lymphoma

Abstract

1. Polymorphisms in genes coding folate-metabolising enzymes might alter the pharmacokinetics and sensitivity for methotrexate “MTX”.

2. The aim of the study aimed to investigate the influence of MTHFR C677T, DHFR19 Ins/del, GGH −401 C > T, and MTR A2756G polymorphisms on MTX toxicity and pharmacokinetics in Egyptian patients with Acute lymphoblastic leukaemia (ALL) or Non-Hodgkin lymphoma (NHL).

3. Fifty adult Egyptian patients with ALL and NHL, treated with high dose MTX, were prospectively enrolled in the study. Clinical and biochemical data was collected objectively from medical records after each cycle of MTX. Plasma concentrations of MTX were measured after 72 h of initiation of infusion. Genotyping was done with a PCR-ARMS and PCR-RFLP assays.

4. The MTHFR C677T T variants significantly increased the risk of leukopoenia, whereas the genotype MTHFR 677 C > T TT significantly associated with lymphocytopenia, thrombocytopenia, and anaemia. The genotype GGH-401 TT was significantly correlated with anaemia. Plasma MTX level was significantly higher in patients with MTR A2756G G variants.

5. MTHFR polymorphism played the main role in MTX toxicities. The pharmacokinetics of MTX was affected by MTR polymorphism. GGH mutation was mainly concerned with anaemia. Pharmacogenetic testing are recommended to optimise MTX therapy.

Keywords:

• Genetic polymorphism
• MTHFR
• DHFR
• GGH
• MTR
• methotrexate
• toxicity
• pharmacokinetics

Author contributions

Study design: Khaled Abdelkawy, Ahmed Amin Ali, Fathalla Belal

Experimental work: Khloud Shendy, Galal Magdy, Mostafa Abdelhakiem, Nahla Anber

Data analysis: Fawzy Elbarbry, Khloud Shendy, Khaled Abdelkawy, Ahmed Amin Ali

Resources: Fawzy Elbarbry, Khloud Shendy, Khaled Abdelkawy, Fathalla Belal

Manuscript draft writing and revision: Fawzy Elbarbry, Khaled Abdelkawy, Khloud Shendy

Disclosure statement

The authors report no declarations of interest. The authors declare that they have no financial or non-financial interests that are directly or indirectly related to the work submitted for publication.

Data availability statement

The authors declare that the data supporting the findings of this study are available within the paper. Should any raw data files be needed in another format they are available from the corresponding author upon reasonable request.

Additional information

Funding

The study did not receive any specific grant from funding agencies in the public. Commercial, or not-for-profit sectors.