The frequency of hepatotoxicity and myelotoxicity in leukemic children with different high doses of methotrexate

Int J Pediatr Adolesc Med. 2016 Dec;3(4):162-168. doi: 10.1016/j.ijpam.2016.08.008. Epub 2016 Sep 12.


Background and objectives: Methotrexate (MTX) is a chemotherapeutic agent that functions as a folic acid antagonist. The frequency of high dose methotrexate (HDMTX)-associated toxicity is variable. In this study, we investigated the frequency of myelotoxicity and hepatotoxicity 7 days after HDMTX infusion.

Patients and methods: This study included children diagnosed with acute lymphoblastic leukemia (ALL) between January 2010 and April 2015. The patient blood counts and biochemical parameters measured before and after 7 days of HDMTX infusion were retrospectively recorded. We assessed HDMTX infusions for 48 children. The number of patients and drug doses included the following: 17 children receiving 1 g/m2 (68 infusions), 14 children receiving 2 g/m2 (56 infusions), and 17 children receiving 5 g/m2 (68 infusions). The classification of toxicity was made based on the Common Terminology Criteria for Adverse Events (CTCAE) 2010 criteria. Myelotoxicity was defined as a hemoglobin level <10 g/L and absolute neutrophil count <1 × 109/L or platelet count <75 × 109/L. The presence of transaminase levels ≥5 times the upper limit was considered to be hepatotoxicity grade ≥3. The MTX levels at 42 h in patients with and without toxicity were compared to evaluate the correlation between MTX levels, hematologic parameters, and transaminase levels.

Results: Myelotoxicity was observed in 35.2%, 37.5%, and 33.8% of the infusions, and hepatotoxicity grade ≥3 was detected in 13.2%, 12.5%, and 11.7% of the infusions in patients receiving 1, 2 and 5 g/m2 HDMTX after 7 days, respectively. There was no statistically significant difference between MTX levels at 42 h in patients with and without toxicity (P > .05, for all). There was no correlation between hematologic parameters and transaminase levels and MTX levels at 42 h.

Conclusion: Hematologic toxicity was the most common toxicity observed. The data indicate the hematologic toxicity increased after repeated cycles in patients receiving 5 g/m2. However, the hepatic toxicity decreased with additional cycles. Our results show the level of MTX at 42 h is not effective to identify toxicity.

Keywords: Children; Hepatotoxicity; High dose methotrexate; Leukemia; Myelotoxicity.