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HDMTX Use in Cancer Treatment

Methotrexate: A Potent and Powerful Cancer Therapy1

Methotrexate (MTX) is an antifolate therapeutic agent that possesses potent anticancer activity against both solid tumors and leukemia.1

What Is Considered High-Dose Methotrexate?

High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers, including1:

  • Diffuse large B-cell lymphoma
  • Burkitt lymphoma
  • Adult acute lymphoblastic leukemia (ALL)
  • Pediatric ALL
  • Primary central nervous system (CNS) lymphoma
  • Osteosarcoma

High-Dose MTX (HDMTX)–Associated Acute Kidney Injury (AKI)

For patients with healthy renal function, HDMTX may be safely administered with appropriate supportive care; however, despite standard support measures, HDMTX carries the risk of severe toxicity2,3:

  • MTX is primarily cleared by the kidneys but is poorly soluble, and pH changes within the kidneys can promote its precipitation, which can result in AKI.
  • HDMTX-induced AKI leads to delayed MTX clearance, resulting in prolonged, elevated plasma MTX concentrations.

An Oncologic Emergency

Up to 12% of patients who receive HDMTX will experience delayed MTX clearance due to AKI.2,4-6 Delayed MTX clearance due to AKI is an oncologic emergency that can lead to potentially irreversible life-threatening systemic toxicity and organ damage.2-4,7

Patients who survive an episode of AKI have8:

  • Double the risk of death
  • Triple the risk of end-stage renal disease
  • Ten times the risk of developing incident or progressive chronic kidney disease

The rate of cardiovascular events is as high as 22% and mortality related to cardiovascular events is 33% in patients with AKI.9

Inadequate Elimination of MTX Due to AKI Increases the Risk of Severe Toxicities and Death2,3

Grade 3-4 toxicities in 43 patients with delayed MTX clearance due to HDMTX-induced AKI included hematologic, renal, hepatic, and CNS toxicity as well as mucositis (all in >10% of patients). Grade 3-4 hematologic toxicity occurred in 60% of patients.10

 Grade 3-4 toxicities post-HDMTX in 43 patients with delayed MTX clearance due to acute kidney injury10 
ToxicityPatients, n (%)
Hematologic26 (60%)
Mucositis15 (35%)
Renal8 (19%)
Liver7 (16%)
CNS6 (14%)
Skin1 (2%)

Assessing the Risk of Acute Kidney Injury From High-Dose Methotrexate

There are many factors associated with MTX that can increase the risk of AKI, including2,4:

  • Dose and schedule of MTX
  • Preexisting renal insufficiency
  • Host factors including patient age and cancer type
 Types of tumors* associated with higher risk of AKI3,11-13 
Tumor types Incidence of AKI
Lymphoma (N=194) 9.1%
Primary CNS lymphoma (N=154) 3-7%
Pediatric acute lymphoblastic leukemia (N=1286) 3.6%
Osteosarcoma (N=3887) 1.8%

*Tumor types included acute lymphoblastic leukemia, lymphoma, CNS lymphoma germ cell tumor, and osteosarcoma.

Patients who have one or more of the following risk factors may experience delayed MTX clearance2,4,10

  • Nephrotoxic comedication (NSAIDs, PPIs, etc)
  • BMI ≥25 kg/m2
  • Renal insufficiency prior to HDMTX (i.e., CrCl <60 mL/min)
  • Prior toxicity with HDMTX
  • Adult and elderly patients, as many as 60% of whom may have some degree of renal dysfunction
  • Third spacing (pleural effusions, ascites, intracranial fluid)
  • Volume depletion due to vomiting, diarrhea, or other factors
  • Polyuria
  • Urine pH <7

BMI, body mass index; CrCl, creatinine clearance; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor.

Trust Voraxaze® (glucarpidase) for Rapid, Nonrenal Elimination of MTX14

It may not be possible to predict who will experience kidney injury or failure during HDMTX treatment.10 Only Voraxaze reduced plasma MTX levels by ≥97% within 15 minutes.14