Clinical Risk Factors for High-Dose Methotrexate-Induced Oral Mucositis Following Individualized Dosing

Abstract

Background: Oral mucositis affects about 20% of children undergoing high-dose methotrexate (HDMTX) for acute lymphoblastic leukemia (ALL), despite existing management strategies. Personalized HDMTX dosing, adjusted by pharmacokinetics and leukemia risk, has reduced mucositis incidence, but variations still occur with similar 24-h methotrexate levels.

Methods: This retrospective study investigated risk factors for oral mucositis under individualized methotrexate protocols. Data from patients with ≥ Grade 2 oral mucositis (CTCAE v4.0) were analyzed from the St. Jude Children's Research Hospital total 16 trial. A 1:1 case-control matching method considered age, sex, risk classification, immunophenotype, and methotrexate course. McNemar's, Bowker's symmetry, and Wilcoxon signed-rank tests were used for statistical analyses. Risk factors for recurrent mucositis were identified in a case-only analysis.

Results: The study found significant associations between methotrexate-induced mucositis and new-onset skin rashes (p = 0.0027), fever (p = 0.0016), neutropenic fever (p = 0.0008), lower absolute neutrophil count (p < 0.0001), acute kidney injury (AKI) (p = 0.0164), delayed methotrexate clearance (p = 0.0133), and higher 42-h methotrexate levels (p = 0.0179). In the standard/high-risk group, mercaptopurine dose was also linked to mucositis (p = 0.0495). Multivariable analysis showed that skin rashes (OR 6.5, p = 0.0016), fever (OR 2.8, p = 0.009), and neutropenia (OR 2.3, p = 0.0106) were independent risk factors for mucositis. Female sex (OR 7.12, p = 0.015) and AKI (OR 3.819, p = 0.037) were associated with recurrent mucositis.

Conclusions: Fever, skin rashes, AKI, delayed methotrexate clearance, and higher 42-h methotrexate levels were key risk factors for HDMTX-induced oral mucositis. Skin rashes, fever, and neutropenia were independent predictors, while female sex and AKI were linked to recurrent mucositis.

Keywords: acute kidney injury; acute lymphoblastic leukemia; delayed methotrexate clearance; high‐dose methotrexate; oral mucositis; risk factors.

FIGURE 1

The distribution of mucositis episodes. (A) The distribution of mucositis by grade during MTX courses in LR group. (B) The distribution of mucositis in detail by grade and MTX courses in LR group. (C) The distribution of mucositis by grade during MTX courses in SHR group. (D) The distribution of mucositis in detail by grade and MTX courses in SHR group. (E) The relationship between mucositis onset and MTX clearance. Yes, means mucositis onset after MTX clearance. No, means mucositis onset before MTX clearance. MTX, methotrexate. LR, low risk. SHR, stand/high risk.

FIGURE 2

Clinical symptoms during HDMTX such as new onset skin rashes, CNS side effects, fever, neutropenia, and neutropenic fever that might be associated with oral mucositis. Note: * p < 0.05, ** p < 0.01.

FIGURE 3

The effect of absolute neutrophil counts (ANC) before and after HDMTX on the MTX‐associated mucositis. (A) Box plot shows the baseline ANC before MTX was started and the lowest ANC during the MTX course. (B) Bar charts show the ANC before the MTX initial and during MTX course. Note: * p < 0.05, ** p < 0.01.

FIGURE 4

The effect of acute kidney injury and delayed methotrexate (MTX) clearance previously or during the high‐dose MTX (HDMTX) course on the oral mucositis. Note: * p < 0.05, ** p < 0.01.

FIGURE 5

MTX kinetics that might be associated with oral mucositis during HDMTX. Only 42‐h MTX level is associated with HDMTX‐induced oral mucositis in both LR and SHR groups. But 66‐h MTX level is not. *, p < 0.05 compared with control. (A) MTX levels at 42 h and 66 h compared with the controls. (B, C) Violin plot shows the MTX levels at 42 h (B) and 66 h (C) compared with the controls (n = 38) in LR group. (D, E) Violin plot shows the MTX levels at 42 h (D) and 66 h (E) compared with the controls (n = 38) in SHR group. (B–E) the box plots inside the violin show 25 percentiles, medians, and 75 percentiles; + shows the mean.

FIGURE 6

6MP dose changes during HDMTX that affect oral mucositis. Number is shown in % inside the content of the table. Note: * p < 0.05, ** p < 0.01.

FIGURE 7

The patient number in all the patients with recurrent mucositis episodes, comparing initial HDMTX courses with the recurrent courses.