ALL患儿大剂量甲氨蝶呤化疗和亚叶酸解救治疗期间红细胞内叶酸和甲氨蝶呤代谢的变化

Changes of folate and methotrexate metabolism in erythrocyte during high-dose methotrexate and folinic acid rescue treatment in children with ALL

目的 探讨急性淋巴细胞白血病(ALL)儿童在给予大剂量甲氨蝶呤(HDMTX)化疗和亚叶酸(LV)解救后红细胞(REC)内叶酸(FA)和甲氨蝶呤(MTX)代谢产物的变化。方法 2021年5月至2022年12月,前瞻性测定72例ALL儿童在HDMTX开始前(T0)和LV解救停止后(T1)红细胞内叶酸(REC-FA)和REC内MTX聚谷氨酸盐(REC MTX-PG_(2-5))的水平。结果 在T0和T1之间,REC MTC-PG_(2-5)和REC-FA水平显著增加(P<0.001),ΔT1-T0值分别为180.50(79.50,362.00)nmol/L和92.52(60.96,117.01)nmol/L;这是由于5-甲基四氢叶酸(THF)水平增加(P<0.001),其ΔT1-T0值为172.50(76.50,361.00)nmol/L,而非甲基THF水平没有变化(P>0.05)。REC-FA在T0和T1之间增加(P<0.001),结果不受年龄、性别、MTHFR677C>T基因型、ALL表型和T0血浆FA水平的显著影响。MTX诱导的≥3级口腔粘膜炎与REC MTX-PG_(2-5)ΔT1-T0更高以及REC 5-甲基THF、REC-FA水平和REC-FA/REC MTX-PG_(2-5)ΔT1-T0更低有关(P<0.05)。结论 ALL儿童经HDMTX化疗和LV解救治疗后,REC-FA水平积累,表明LV可恢复细胞内叶酸库;另一方面REC-FA水平的增加似乎对REC内MTX水平没有太大影响。

Objective To investigate the changes of folate(FA) and methotrexate(MTX) metabolism in red blood cells(REC) of children with acute lymphoblastic leukemia after high-dose methotrexate(HD-MTX) and leucovorin(LV) rescue treatment.Methods From May 2021 through December 2022,the levels of REC-FA and REC-MTX-PG_(2-5) in 72 children with ALL were prospectively measured before HD-MTX and LV treatment began(T0) and after discontinuation(T1).Results Between T0 and T1,the levels of MTC-PG_(2-5) and REC-FA in REC were significantly increased(P<0.001),ΔT1-T0 values were 180.50(79.50,362.00) nmol/L and 92.52(60.96,117.01) nmol/L,respectively.This was due to an increase in 5-methyltetrahydrofolate(THF) levels(P<0.001) with a ΔT1-T0 value of 172.50(76.50,361.00) nmol/L,while non-methylTHF levels did not change(P>0.05).REC-FA levels increased between T0 and T1,and results were not significantly affected by age,sex,MTHFR677C>T genotype,ALL phenotype,and T0 plasma FA(P<0.001).Finally,the development of MTX-induced grade ≥3 oral mucositis was associated with higher ΔT1-T0 changes in REC MTX-PG_(2-5) and lower ΔT1-T0 changes in 5-methyl THF,REC-FA levels,and REC-FA/MTX-PG_(2-5) ratio(P<0.05).Conclusions In ALL children,the level of REC-FA accumulates after rescue treatment of HD-MTX and LV,which indicates that LV can restore intracellular folate pool.On the other hand,the increase in REC-FA levels did not affect the REC-MTX levels.