TY - JOUR
T1 - Intestinal mucositis, systemic inflammation and bloodstream infections following high-dose methotrexate treatment in childhood acute lymphoblastic leukaemia
T2 - Comparison between the NOPHO ALL 2008 protocol and the ALLTogether1 protocol
AU - Weischendorff, Sarah
AU - de Pietri, Silvia
AU - Rathe, Mathias
AU - Schmiegelow, Kjeld
AU - Frandsen, Thomas Leth
AU - Petersen, Malene Johanne
AU - Weimann, Allan
AU - Nielsen, Claus Henrik
AU - Enevold, Christian
AU - Kocadag, Helin Berna
AU - Moser, Claus
AU - Müller, Klaus
PY - 2025/1/1
Y1 - 2025/1/1
N2 - 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
s = -0.44, p = 0.0016 and r
s = 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.
AB - 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
s = -0.44, p = 0.0016 and r
s = 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.
KW - CCL20
KW - Citrulline
KW - acute lymphoblastic leukaemia
KW - bloodstream infections
KW - high-dose methotrexate
KW - intestinal mucositis
KW - systemic inflammation
KW - Humans
KW - Child, Preschool
KW - C-Reactive Protein/analysis
KW - Male
KW - Infant
KW - Mucositis/chemically induced
KW - Inflammation
KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects
KW - Adolescent
KW - Female
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Methotrexate/adverse effects
KW - Child
U2 - 10.1002/ijc.35136
DO - 10.1002/ijc.35136
M3 - Journal article
C2 - 39150399
SN - 0020-7136
VL - 156
SP - 164
EP - 173
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 1
ER -