Prediction of Excretion and Toxicity of High Dose Methotrexate in Children and Adolescents With ALL

Summary

Each year approximately 2,900 children and adolescents less than 20 years old are diagnosed with acute lymphoblastic leukemia or acute lymphoblastic lymphoma in the United States. (For the purposes of this protocol, ALL will be used to refer to patients with either acute lymphoblastic leukemia or acute lymphoblastic lymphoma as patients are treated in the same manner.) High-dose methotrexate (HDMTX; 5 g/m2) remains an important component of standard treatment for most ALL patients. However, high plasma and intracellular MTX concentrations (defined as a MTX level of \>1 µmol/L at 42 hours and \> 0.40 µmol/L at 48 hours) can quickly lead to acute kidney, bone marrow, liver, skin, central nervous system, and gastrointestinal toxicities requiring extended hospitalization and delays in subsequent chemotherapy treatments. This study seeks to identify more sensitive markers of kidney injury that could serve as better predictors of delayed excretion and/or toxicity of HDMTX. This study is a pilot repeated-measures feasibility study. Hypothesis 1: Directly measured GFR (mGFR, a type of test to measure the filtering rate of kidneys) by iohexol clearance obtained prior to HDMTX will demonstrate greater sensitivity and specificity for prediction of delayed MTX excretion and/or toxicity in children and adolescents with ALL than serum creatinine (sCr) alone or sCr used for eGFR calculation. If this study proves that mGFR is a better predictor of delayed MTX excretion and/or toxicity, then another study will be developed in the future to determine if modifying the HDMTX dose or adjusting supportive care based on mGFR will prevent delayed clearance and toxicity without impacting patient survival. Hypothesis 2: Those participants prospectively demonstrating delayed MTX excretion or toxicity will exhibit elevation of kidney injury biomarkers less than 24 hours following initiation of HDMTX infusion compared to pre-chemotherapy measurements. These biomarkers will increase prior to a measurable sCr elevation.

Timeline

Start

2014-07-24

Primary completion

2019-02-26

Completion

2019-02-27

Publications

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• Background Herget-Rosenthal S, Marggraf G, Husing J, Goring F, Pietruck F, Janssen O, Philipp T, Kribben A. Early detection of acute renal failure by serum cystatin C. Kidney Int. 2004 Sep;66(3):1115-22. doi: 10.1111/j.1523-1755.2004.00861.x.
• Background Christov M, Waikar SS, Pereira RC, Havasi A, Leaf DE, Goltzman D, Pajevic PD, Wolf M, Juppner H. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int. 2013 Oct;84(4):776-85. doi: 10.1038/ki.2013.150. Epub 2013 May 8.
• Background Leaf DE, Wolf M, Waikar SS, Chase H, Christov M, Cremers S, Stern L. FGF-23 levels in patients with AKI and risk of adverse outcomes. Clin J Am Soc Nephrol. 2012 Aug;7(8):1217-23. doi: 10.2215/CJN.00550112. Epub 2012 Jun 14.

Drugs

Indications

No indication recorded.