Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Institute for Inflammation Research, Centre for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Int J Cancer. 2025 Jan 1;156(1):164-173. doi: 10.1002/ijc.35136. Epub 2024 Aug 16.
Severe intestinal mucositis (IM) increases the risk of bloodstream infections (BSI) and inflammatory toxicity during acute lymphoblastic leukaemia (ALL) induction treatment. However, the implications of IM in subsequent ALL therapy phases after achieving remission remain unknown. This study investigated the relationship between IM (measured by plasma citrulline and the chemokine CCL20) and the development of BSI and systemic inflammation (reflected by C-reactive protein, CRP) in children with ALL during high-dose methotrexate (HDMTX) treatment, an important part of ALL consolidation therapy. The study compared patients treated according to the NOPHO ALL 2008 protocol (n = 52) and the ALLTogether1 protocol (n = 42), both with identical HDMTX procedures but different scheduling. One week post-HDMTX, citrulline dropped to median levels of 14.5 and 16.9 μM for patients treated according to the NOPHO ALL 2008 and ALLTogether1 protocols, respectively (p = 0.11). In a protocol and neutrophil count-adjusted analysis, hypocitrullinaemia (<10 μmol/L) was associated with increased odds of BSI within 3 weeks from HDMTX (OR = 26.2, p = 0.0074). Patients treated according to the NOPHO ALL 2008 protocol exhibited increased mucosal- and systemic inflammation post-HDMTX compared to patients treated according to ALLTogether1, with increased CCL20 (14.6 vs. 3.7 pg/mL, p < 0.0001) and CRP levels (10.0 vs. 1.0 mg/L, p < 0.0001). Both citrulline and CCL20 correlated with CRP for these patients (r = -0.44, p = 0.0016 and r = 0.35, p = 0.016, respectively). These results suggest that hypocitrullinaemia following HDMTX increases the risk of BSI, confirming previous observations from more intensive treatments. Moreover, these data indicate that the patients' vulnerability to mucositis and inflammatory toxicity after chemotherapy varies with treatment protocol.
严重的肠道黏膜炎（IM）会增加急性淋巴细胞白血病（ALL）诱导治疗期间血流感染（BSI）和炎症毒性的风险。然而，在缓解后随后的 ALL 治疗阶段，IM 的影响仍不清楚。本研究调查了 IM（通过血浆瓜氨酸和趋化因子 CCL20 测量）与接受高剂量甲氨蝶呤（HDMTX）治疗期间 ALL 患儿 BSI 和全身炎症（反映 C 反应蛋白，CRP）发展之间的关系，HDMTX 是 ALL 巩固治疗的重要组成部分。该研究比较了根据 NOPHO ALL 2008 方案（n=52）和 ALLTogether1 方案（n=42）治疗的患者，这两个方案均采用相同的 HDMTX 程序，但方案不同。HDMTX 治疗后一周，根据 NOPHO ALL 2008 和 ALLTogether1 方案治疗的患者瓜氨酸分别降至 14.5 和 16.9μM 的中位水平（p=0.11）。在方案和中性粒细胞计数调整分析中，低瓜氨酸血症（<10μmol/L）与 HDMTX 后 3 周内 BSI 的发生几率增加相关（OR=26.2，p=0.0074）。与 ALLTogether1 方案相比，根据 NOPHO ALL 2008 方案治疗的患者在接受 HDMTX 后表现出更高的黏膜和全身炎症，CCL20 增加（14.6 对 3.7pg/mL，p<0.0001）和 CRP 水平（10.0 对 1.0mg/L，p<0.0001）。对于这些患者，瓜氨酸和 CCL20 与 CRP 均相关（r=-0.44，p=0.0016 和 r=-0.35，p=0.016）。这些结果表明，HDMTX 后低瓜氨酸血症会增加 BSI 的风险，证实了来自更强化治疗的先前观察结果。此外，这些数据表明，患者在化疗后对黏膜炎和炎症毒性的易感性因治疗方案而异。
