Novel and replicated clinical and genetic risk factors for toxicity from high‐dose methotrexate in pediatric acute lymphoblastic leukemia

Zobeck, Mark; Bernhardt, M. Brooke; Kamdar, Kala Y.; Rabin, Karen R.; Lupo, Philip J.; Scheurer, Michael E.

doi:10.1002/phar.2779

Cited by 4 publications

(1 citation statement)

References 45 publications

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“…Finally, a large number of studies propose that pathogenesis and the phenotypic characteristics of B-acute lymphoblastic leukemia are connected with the conjunction of specific targets and DNA variations promoted by epigenetic alterations such as methylation [ 184 , 185 , 186 ]. hTERT promoter methylation is infrequent in B-ALL cases with remission, and there is no association with TL.…”

Section: Discussionmentioning

confidence: 99%

The Relevance of Telomerase and Telomere-Associated Proteins in B-Acute Lymphoblastic Leukemia

Mota

Camargo

Biojone

et al. 2023

Genes

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Telomeres and telomerase are closely linked to uncontrolled cellular proliferation, immortalization and carcinogenesis. Telomerase has been largely studied in the context of cancer, including leukemias. Deregulation of human telomerase gene hTERT is a well-established step in leukemia development. B-acute lymphoblastic leukemia (B-ALL) recovery rates exceed 90% in children; however, the relapse rate is around 20% among treated patients, and 10% of these are still incurable. This review highlights the biological and clinical relevance of telomerase for B-ALL and the implications of its canonical and non-canonical action on signaling pathways in the context of disease and treatment. The physiological role of telomerase in lymphocytes makes the study of its biomarker potential a great challenge. Nevertheless, many works have demonstrated that high telomerase activity or hTERT expression, as well as short telomeres, correlate with poor prognosis in B-ALL. Telomerase and related proteins have been proven to be promising pharmacological targets. Likewise, combined therapy with telomerase inhibitors may turn out to be an alternative strategy for B-ALL.

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Section: Discussionmentioning

confidence: 99%

The Relevance of Telomerase and Telomere-Associated Proteins in B-Acute Lymphoblastic Leukemia

Mota

Camargo

Biojone

et al. 2023

Genes

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

Hu,

Escalera‐Joy,

Ashcraft

et al. 2024

Cancer Medicine

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BackgroundOral 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.MethodsThis 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.ResultsThe 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.ConclusionsFever, 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.

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Glucarpidase (carboxypeptidase G2): Biotechnological production, clinical application as a methotrexate antidote, and placement in targeted cancer therapy

Moradbeygi

Ghasemi

Farmani

et al. 2023

Biomedicine & Pharmacotherapy

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Novel and replicated clinical and genetic risk factors for toxicity from high‐dose methotrexate in pediatric acute lymphoblastic leukemia

Cited by 4 publications

References 45 publications

The Relevance of Telomerase and Telomere-Associated Proteins in B-Acute Lymphoblastic Leukemia

The Relevance of Telomerase and Telomere-Associated Proteins in B-Acute Lymphoblastic Leukemia

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

Glucarpidase (carboxypeptidase G2): Biotechnological production, clinical application as a methotrexate antidote, and placement in targeted cancer therapy

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