Prediction of Excretion and Toxicity of High Dose Methotrexate in Children and Adolescents With ALL
Condition: ALL
Study type: Interventional

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.
    

Detailed description: 
      Using this approach, retrospective clinical data from our patient population has identified a
      significant number of HDMTX treatments associated with delayed MTX excretion (defined as a
      MTX level of >1 µmol/L at 42 hours and > 0.40 µmol/L at 48 hours) and secondary toxicity.
      From January 2012-May 2013, 16 ALL patients received 64 total HDMTX doses (4 cycles each). At
      48 hours post-HDMTX infusion, 27 doses (42%) exhibited delayed MTX clearance [median plasma
      MTX level 0.41 µmol/L (range, 0.01-1.6 µmol/L) above the 48-hour clearance level of 0.40
      µmol/L]. Mucositis, cytopenias, skin rashes, and subsequent chemotherapy delays were noted in
      31%, 31%, 6%, and 34% of doses respectively. Toxicities in combination with delayed MTX
      clearance occurred in 17 doses (27%) and toxicity without delayed clearance occurred in 18
      doses (28%). Also, a mean increase in sCr of 17% (range 0-57.6%) above pre-HDMTX baseline was
      observed. Although measurements of sCr are used per the standard of care as an indirect
      marker of kidney injury, the known delay in sCr rise following nephrotoxic (drug-induced)
      kidney injury (KI) eliminates its use as a point of care surrogate marker for kidney
      toxicity. Therefore, 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.

      Substantial evidence demonstrates sCr, alone or used to estimate glomerular filtration rate
      (eGFR), overestimates kidney filtering function when compared with direct measurement of GFR
      [3]. A new, commonly used equation for estimating the GFR uses values of sCr, blood urea
      nitrogen (BUN), and cystatin C. Conversely, a direct measurement of kidney filtering function
      (mGFR) can be accomplished by determining the plasma (part of the blood) iohexol
      (Omnipaque300, GE Healthcare) clearance rate (rate at which the iohexol is removed from the
      body by the kidneys) over a period of 300 minutes, and has been documented as a sensitive and
      accurate measure of renal filtering function [4]. Plasma clearance of iohexol is an optimal
      method of determining mGFR, particularly in children, because it is not radioactive, is
      non-ionic, has a low osmolality, has been proven to be a safe and non-toxic X-ray contrast
      medium, and is excreted from the plasma exclusively by the kidneys [5]. Iohexol is a
      well-known contrast agent that is already FDA-approved for use in urographic procedures,
      angiographic procedures, and for the measurement of GFR (See Appendix I for more information
      on the history and safety of iohexol use for GFR measurement). Iohexol clearance from plasma
      has been shown in several studies to be a suitable method of determining GFR in adults [6]
      and children [7, 8, 9].

      Given that standard oncology care relies on sCr values and eGFR, the kidney filtering
      function is likely often overestimated, which can result in an increased incidence of delayed
      MTX excretion and subsequent toxicity. Therefore, mGFR may provide an optimal method to more
      accurately determine kidney filtering function and thereby allow prediction of which ALL
      patients will develop delayed MTX excretion and/or toxicity. The utility of mGFR in
      predicting MTX excretion delay and/or toxicity has not been previously studied.

      In addition, earlier recognition of kidney injury following HDMTX administration could also
      be evaluated using biomarkers in blood and urine. If these biomarkers are found to be useful
      in diagnosing early kidney injury, these tests may become a new clinical point of care in the
      future that could allow earlier and thus more effective clinical intervention in ALL
      patients. These interventions include increased intravenous hydration, which decreases the
      associated end-organ toxicities.

      Urinary kidney injury molecule-1 (KIM-1) and clusterin, serum cystatin C, and plasma
      fibroblast growth factor 23 (pFGF23) are biomarkers that appear earlier and are more
      sensitive than sCr in the setting of kidney injury. In fact, a detectable increase in sCr
      does not occur until 24-48 hours after a primary renal injury [2]. KIM-1, a type 1
      transmembrane glycoprotein, is not expressed in normal kidneys, but is exhibited at high
      levels in proximal tubule epithelial cells and is excreted into the urine within 6-12 hours
      after toxic or ischemic injury [10, 11, 12]. Similarly, clusterin expression is induced by
      glomerular, tubular, or papillary kidney injury, with increased urine concentrations at 8,
      24, and 48 hours post-toxic exposure [12, 13]. Cystatin C, a cysteine protease inhibitor, is
      not affected by age, gender, race, or overall muscle mass, making it a useful glomerular
      filtration marker in early KI. In a prospective study, cystatin C rise preceded an increase
      in sCr by 1-2 days [14]. FGF23 increases as early as within one hour of acute KI induction in
      mice and remains elevated in chronically compromised GFR, thereby serving as a useful
      biomarker in both acute and chronic KI [15]. In addition, plasma FGF23 has recently been show
      to be a strong predictor for risk of adverse outcomes in adults with acute kidney injury
      (AKI), with the median FGF 23 level obtained within 24 hours of admission being 5.5 times
      higher in patients with AKI compared to "control" ICU patients without kidney injury and
      almost 20 times higher than the upper limit of normal [16]. Therefore, KIM-1, clusterin,
      cystatin C, and FGF23 could provide earlier detection of kidney injury related to HDMTX when
      compared with sCr measurements. The utility of these biomarkers in identifying early kidney
      injury following treatment with HDMTX has not been previously studied. This study will
      compare these biomarkers with sCr pre-, intra-, and post-HDMTX treatment to determine their
      utility in detecting early kidney injury.
    

Intervention name(s): IOHEXOL
Intervention type(s): Drug
Intervention description(s): Patients receive 5 mL of Iohexol prior to cycle 1 and 4 of HDMTX
Other intervention name(s): Iohexol, Omnipaque 300
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic