The impact of homocysteine level on methotrexate induced neurotoxicity in children treated with St. Jude total XV acute lymphoblastic leukemia protocol

Wael Zekri, Mohamed Sedky Mahmoud Sedky, Mona Khalifa, Sanaa Kenawy


Purpose: Methotrexate (MTX) is an antimetabolite that is routinely used in the treatment of hematological malignancies and during its metabolism leads to hyperhomocysteinemia that is associated with neurotoxicity. The purpose of this prospective study is to determine whether the increase in plasma homocysteine (Hcy) concentration is related to MTX-induced neurotoxicity.

Methods: We investigated these changes for both newly diagnosed acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) pediatric patients treated at the National Cancer Institute, Egypt. They were treated according to St. Jude total XV protocol to receive 2.5 or 5 g/m2 MTX as a phase of consolidation and were selected between October 2009 and January 2010.

Results: Twenty-nine patients were analyzed, M/F: 20/9, the mean age was 8 +/- 4.4 years. Hcy level above 15 µmol/L was considered positive. Hcy levels mean at diagnosis, pre 1st HD MTX, post 1st HDMTX, Pre 2nd HDMTX, Post 2nd HDMTX were 12.10 µmol/L ± 4.17, 6.90 µmol/L ± 3.02, 17.59 µmol/L ± 6.00, 7.21 µmol/L ± 2.73 and 13.74 µmol/L ± 4.75 respectively. Seventeen patients (58%) had features suggestive of neurotoxicity. Positive Hcy levels were associated with neurotoxicity p = 0.05, higher HDMTX 5 g/m2 P= 0.023. A highly significant relation was found between initial Hcy level at diagnosis and final Hcy level p = 0.001; the same as between Hcy level Post 1st HDMTX and that Post 2nd HDMTX with p = 0.006.

Conclusion: plasma Hcy concentration was significantly elevated after HDMTX administration and this elevation is associated with the observed neurotoxicity. Whether the elevation in Hcy concentration can prove an informative biomarker for neurotoxicity requires additional testing with other MTX regimens.


Homocysteine, High Dose Methotrexate, Neurotoxicity, Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma

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