High Dose Methotrexate Treatment in Childhood ALL: Pilot Study on the Impact of the MTHFR 677C>T and 1298A>C Polymorphisms on MTX-related Toxicity

Abstract

Background:

Methotrexate (MTX) is commonly administered in high doses for treatment of childhood acute lymphoblastic leukemia (ALL). The aim of this analysis was to study the influence of 2 common MTHFR polymorphisms (MTHFR 677C>T and 1298 A>C) on MTX toxicity in children with ALL.

Patients and methods:

Retrospective analysis of 129 MTX courses in 34 pediatric patients with ALL.

Results:

677C>T variants (CT or TT) were found in 19 (14 heterozygous, 5 homozygous) and 1298A>C variants (AC or CC) in 20 (16 heterozygous, 4 homozygous) patients. The MTHFR 677C>T wild type was associated with an increased frequency of grade III and IV leukopenia (60% vs. 31%, p<0.05) compared to the variants. The rate of severe infections (21% vs. 0%, p<0.05) and grade III–IV anemia (26% vs. 5%, p<0.05) was increased in carriers of the MTHFR 677C>T wild type compared to patients with the TT variant. Grade III–IV anemia was more frequent in patients with the MTHFR 1298A>C CC variant compared to the wild type (56% vs. 21%, p<0.05). The differences were not significant in a patient-based analysis.

Conclusions:

MTX related toxicity might be influenced by the MTHFR 677C>T or the MTHFR 1298A>C polymorphisms. Differences in MTX toxicity are only partially explainable by these 2 polymorphisms.

Zusammenfassung

Hintergrund:

Hochdosis-Methotrexat (MTX) wird zur Behandlung der akuten lymphatischen Leukämie (ALL) des Kindesalters eingesetzt. Ziel der vorliegenden Arbeit war die Analyse des Einflusses des MTHFR 677C>T- und des 1298 A>C- Polymorphismus auf die MTX-induzierte Toxizität bei Kindern mit ALL.

Patienten und Methoden:

34 Kinder mit ALL und 129 Hochdosis-MTX-Zyklen wurden retrospektiv ausgewertet.

Ergebnisse:

MTHFR 677C>T-Varianten (CT/TT) wurden bei 19 Patienten (14 heterozygot, 5 homozygot) und MTHFR 1298 A>C-Varianten (AC/CC) bei 20 Patienten (16 heterozygot, 4 homozygot) gefunden. Träger des MTHFR 677C>T-Wildtyps hatten im Vergleich zu den Varianten häufiger Grad-III/IV-Leukopenien (60% vs. 31%, p<0,05) und im Vergleich zu MTHFR 677C>T TT-Trägern häufiger Grad-III/IV-Infektionen (21% vs. 0%, p<0,05) und Anämien (26% vs. 5%, p<0,05). Grad-III/IV-Anämien traten häufiger bei Trägern der MTHFR1298A>C-CC-Variante als beim Wildtyp auf (56% vs. 21%, p<0,05). In der patientenbezogenen Analyse waren die Unterschiede nicht signifikant.

Schlussfolgerung:

Die genannten Polymorphismen könnten die MTX-Toxizität beeinflussen, erklären aber interindividuelle Unterschiede nur teilweise.

Key words

methotrexate - toxicity - MTHFR - polymorphism

Schlüsselwörter

Methotrexat - Toxizität - MTHFR - Polymorphismus

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