Abstract
PurposeThis retrospective study aimed to investigate the relationships between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C and high-dose methotrexate (HD-MTX)-related toxicities in pediatric non-Hodgkin lymphoma (NHL) patients.Patients and MethodsWe reviewed the medical records of 93 NHL patients aged under 18 years who received HD-MTX therapy at the dose of 5 g/m2 with 24-h infusion at Sun Yat-sen University Cancer Center between 2014 and 2019.ResultsThere were 61 males and 32 females, with a median age of 8.8 years (0.9–15.8 years). The tumor types included lymphoblastic lymphoma (n = 38), Burkitt’s lymphoma (n = 31), anaplastic large cell lymphoma (n = 18), diffuse large B-cell lymphoma (n = 6). Overall, 355 courses of HD-MTX therapy were prescribed. All patients were rescued with calcium folinate 12 h after the end of MTX infusion. We found that plasma MTX levels > 0.2 μmol/L at 48 h post-infusion increased the risk of developing oral mucositis (2.4% VS. 9.5%, P = 0.018). Also, patients carrying the C677T and T677T genotypes had tendencies to be more susceptible to oral mucositis (P = 0.034). Patients harboring mutant 677T allele were more likely to develop leucopenia (38.5 vs. 50.3%, P = 0.025) and thrombocytopenia (22.0 vs. 32.4%, P = 0.028). For polymorphism A1298C, the mutant genotype played a protective role in vomiting (11.1 vs. 4.3%, P = 0.018) but increased the risk of anemia (23.8 vs. 41.7%, P < 0.001) and leucopenia (38.1 vs. 50.3%, P = 0.021).ConclusionChildhood NHL patients harboring C677T genotype were more vulnerable to oral mucositis, leucopenia, and thrombocytopenia, while those with A1298C genotype were at a decreased risk of vomiting and more likely to develop anemia and leucopenia.
Highlights
Non-Hodgkin lymphoma (NHL), the fourth most common malignancy across the pediatric age spectrum, is a heterogeneous group of lymphoid malignancies [1, 2]
Other studies indicated that no significant differences in the plasma MTX concentrations were found for the different methylenetetrahydrofolate reductase (MTHFR) C677T genotype in lymphoma [19], which was in line with our results in regard to which we found that the plasma MTX levels at 48 h were independent in both C677T and A1298C polymorphisms (Table 4)
We found that MTHFR C677T/A1298C polymorphism did not significantly affect plasma MTX levels at 48 h, C677T was significantly correlated with oral mucositis (2.2 vs. 3.6 vs. 11.1%, P = 0.034, Table 5), leucopenia (38.5 vs. 50.3%, P=0.025, Table 5), and thrombocytopenia (22.0 vs. 32.4%, P = 0.028, Table 5) and that patients with C677T and T677T genotypes seemed to be more susceptible to those toxicities
Summary
Non-Hodgkin lymphoma (NHL), the fourth most common malignancy across the pediatric age spectrum, is a heterogeneous group of lymphoid malignancies [1, 2]. The current overall survival rate of pediatric NHL exceeds 80% due to dramatic progress in developing risk-adapted curative therapy [1], in which methotrexate (MTX) plays a crucial part. MTX arrests the folic acid cycle by inhibiting dihydrofolate reductase and influences other important enzymes involved in the folate pathway, such as methylenetetrahydrofolate reductase (MTHFR), an enzyme that interferes with nucleic acid synthesis and favors cell death [4, 5]. A high-dose MTX (HD-MTX) regimen, referred to the administration of a dosage ranging from 0.5 g/m2 to 12.0 g/m2 or even higher, is commonly used to treat childhood acute lymphoblastic leukemia (ALL), lymphoma and pediatric osteosarcoma [5, 10, 11]. Identifying predictors of MTX toxicity is a key to determine effective individual dosage adjustment and to minimize adverse events [13]
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