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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. [ABSTRACT FROM AUTHOR]

Introduction: High‐dose methotrexate (HDMTX) use can be limited by the development of acute kidney injury (AKI). Early AKI detection is paramount to prevent further renal injury and irreversible toxicities. This study sought to determine whether early elimination patterns of MTX would be useful as a biomarker of AKI in HDMTX treatment. Methods: This retrospective cohort study included two sites that collected ≥2 MTX levels within 16 h from completion of MTX infusion. Early levels were tagged and MTX elimination half‐life (t½) were calculated from combinations of two of three different early time periods. Receiver operating characteristic (ROC) curves were synthesized for each elimination t½ (biomarker) with respect to AKI and delayed methotrexate elimination (DME); the biomarker with the highest area under the ROC curve (AUC) was tested in a multiple variable logistic regression model. Results: Data from 169 patients who received a total of 556 courses of HDMTX were analyzed. ROC analysis revealed MTX elimination t½ calculated from the second and third time periods had the highest AUC for AKI at 0.62 (interquartile range [IQR] 0.56–0.69) and DME at 0.86 (IQR 0.73–1.00). After adjusting for age, sex, dose (mg/m2), infusion duration, HDMTX course, and baseline estimated glomerular filtration rate, it remained significant for AKI with an OR of 1.29 and 95% confidence interval of 1.03–1.65. Conclusion: Early MTX elimination t½ measured within 16 h of infusion completion was significantly associated with the development of AKI and serves as an early clearance biomarker that may identify patients who benefit from increased hydration, augmented leucovorin rescue, and glucarpidase administration. [ABSTRACT FROM AUTHOR]

Abstract Background Primary breast diffuse large B‐cell lymphoma (PB‐DLBCL) is a rare subtype of extranodal DLBCL, and the standard treatment remains controversial. In this study, we aimed to define the optimal treatment management in the rituximab era. Methods A total of 5089 newly diagnosed DLBCL patients treated with rituximab‐containing immunochemotherapy between 2008 and 2019 from the Chinese Southwest Oncology Group‐affiliated institutes were identified, of whom 135 diagnosed with PB‐DLBCL were eligible for this analysis. Results PB‐DLBCL accounted for 2.7% of all DLBCLs. With a median follow‐up of 4.2 years, the 5‐year overall survival and progression‐free survival rates were 84.8% and 71.6%, respectively. Breast and central nervous system (CNS) relapses were the main cause of treatment failure. We observed that consolidative breast radiotherapy (RT) significantly decreased breast relapse risk (5‐year risk, 2.9% vs. 20.1%, p = 0.007). The CNS relapse risk was lower for patients who received high‐dose methotrexate (HD‐MTX) than for patients who did not (5‐year risk, 0% vs. 15.2%, p = 0.015). We further screened the genetic mutation profile of 20 patients from two institutes, and found that MYD88 (25%) and CD79B mutations (25%) frequently occur in PB‐DLBCL. In addition, four patients with MYD88 and/or CD79B mutations experienced CNS relapse, while three patients with MYD88 and/or CD79B mutations who received HD‐MTX did not experience CNS relapse. Conclusion Collectively, our results indicate combined modality therapy including rituximab‐containing immunochemotherapy and consolidative breast RT is a promising approach for PB‐DLBCL, while HD‐MTX is useful for preventing CNS relapse.

Background: Primary breast diffuse large B‐cell lymphoma (PB‐DLBCL) is a rare subtype of extranodal DLBCL, and the standard treatment remains controversial. In this study, we aimed to define the optimal treatment management in the rituximab era. Methods: A total of 5089 newly diagnosed DLBCL patients treated with rituximab‐containing immunochemotherapy between 2008 and 2019 from the Chinese Southwest Oncology Group‐affiliated institutes were identified, of whom 135 diagnosed with PB‐DLBCL were eligible for this analysis. Results: PB‐DLBCL accounted for 2.7% of all DLBCLs. With a median follow‐up of 4.2 years, the 5‐year overall survival and progression‐free survival rates were 84.8% and 71.6%, respectively. Breast and central nervous system (CNS) relapses were the main cause of treatment failure. We observed that consolidative breast radiotherapy (RT) significantly decreased breast relapse risk (5‐year risk, 2.9% vs. 20.1%, p = 0.007). The CNS relapse risk was lower for patients who received high‐dose methotrexate (HD‐MTX) than for patients who did not (5‐year risk, 0% vs. 15.2%, p = 0.015). We further screened the genetic mutation profile of 20 patients from two institutes, and found that MYD88 (25%) and CD79B mutations (25%) frequently occur in PB‐DLBCL. In addition, four patients with MYD88 and/or CD79B mutations experienced CNS relapse, while three patients with MYD88 and/or CD79B mutations who received HD‐MTX did not experience CNS relapse. Conclusion: Collectively, our results indicate combined modality therapy including rituximab‐containing immunochemotherapy and consolidative breast RT is a promising approach for PB‐DLBCL, while HD‐MTX is useful for preventing CNS relapse. [ABSTRACT FROM AUTHOR]

Abstract Background Taiwanese patients frequently experience severe hepatotoxicity associated with high‐dose methotrexate (HD‐MTX) treatment, which interferes with subsequent treatment. Drug–drug interactions occur when MTX is used in combination with proton pump inhibitors (PPIs), trimethoprim‐sulfamethoxazole (TMP‐SMX), or non‐steroidal anti‐inflammatory drugs (NSAIDs). In East Asia, real‐world analyses on the effects of co‐medication and other potential risk factors on the clinical course of HD‐MTX‐mediated acute hepatotoxicity in patients with osteogenic sarcoma (OGS) are limited. Methods This cohort study included patients with newly diagnosed OGS who were treated with HD‐MTX between 2009 and 2017 at Taipei Veterans General Hospital. We collected data on the clinical course of HD‐MTX‐mediated acute hepatotoxicity, co‐medications, and other potential risk factors, and analyzed the effects of these factors on the clinical course of HD‐MTX‐mediated acute hepatotoxicity. Results Almost all patients with OGS treated with HD‐MTX developed acute hepatotoxicity with elevated alanine aminotransferase (ALT) levels. Most patients with Grade 3–4 ALT elevation failed to recover to Grade 2 within 7 days. Women and children are high‐risk subgroups for HD‐MTX‐mediated elevation of ALT levels. Age is a factor that contributes to the pharmacokinetic differences of HD‐MTX. However, the concurrent use of PPIs, TMP‐SMX, or NSAIDs did not affect the elimination of MTX when administered with adequate supportive therapy. Conclusions Co‐administration of PPIs, TMP‐SMX, or NSAIDs may have limited effects on acute hepatotoxicity in well‐monitored and adequately pre‐medicated patients with OGS undergoing chemotherapy with HD‐MTX. Clinicians should pay particular attention to ALT levels when prescribing HD‐MTX to children and women.

Background: Taiwanese patients frequently experience severe hepatotoxicity associated with high‐dose methotrexate (HD‐MTX) treatment, which interferes with subsequent treatment. Drug–drug interactions occur when MTX is used in combination with proton pump inhibitors (PPIs), trimethoprim‐sulfamethoxazole (TMP‐SMX), or non‐steroidal anti‐inflammatory drugs (NSAIDs). In East Asia, real‐world analyses on the effects of co‐medication and other potential risk factors on the clinical course of HD‐MTX‐mediated acute hepatotoxicity in patients with osteogenic sarcoma (OGS) are limited. Methods: This cohort study included patients with newly diagnosed OGS who were treated with HD‐MTX between 2009 and 2017 at Taipei Veterans General Hospital. We collected data on the clinical course of HD‐MTX‐mediated acute hepatotoxicity, co‐medications, and other potential risk factors, and analyzed the effects of these factors on the clinical course of HD‐MTX‐mediated acute hepatotoxicity. Results: Almost all patients with OGS treated with HD‐MTX developed acute hepatotoxicity with elevated alanine aminotransferase (ALT) levels. Most patients with Grade 3–4 ALT elevation failed to recover to Grade 2 within 7 days. Women and children are high‐risk subgroups for HD‐MTX‐mediated elevation of ALT levels. Age is a factor that contributes to the pharmacokinetic differences of HD‐MTX. However, the concurrent use of PPIs, TMP‐SMX, or NSAIDs did not affect the elimination of MTX when administered with adequate supportive therapy. Conclusions: Co‐administration of PPIs, TMP‐SMX, or NSAIDs may have limited effects on acute hepatotoxicity in well‐monitored and adequately pre‐medicated patients with OGS undergoing chemotherapy with HD‐MTX. Clinicians should pay particular attention to ALT levels when prescribing HD‐MTX to children and women. [ABSTRACT FROM AUTHOR]