12%
Tumor types included ALL, lymphoma, CNS lymphoma germ cell tumor, and osteosarcoma.
High-dose Methotrexate (HDMTX) Use in Cancer Treatment
High-Dose Methotrexate: A Cornerstone of Cancer Therapy1
Methotrexate (MTX) is an antifolate therapeutic agent that possesses anticancer activity against both solid tumors and leukemia.1
What Is Considered High-Dose Methotrexate and What Does it Treat?
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 lymphoma
- Osteosarcoma
HDMTX–Associated Acute Kidney Injury (AKI)
For patients with healthy renal function, HDMTX is usually tolerated with appropriate supportive care; however, despite standard support measures, HDMTX carries the risk of severe toxicity2:
- 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 AKI2
- HDMTX-induced AKI leads to delayed MTX clearance, resulting in prolonged, elevated plasma MTX concentrations2
An Oncologic Emergency
Up to 12% of patients who receive HDMTX will experience toxic MTX levels with delayed MTX clearance due to AKI.2 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
Systemic toxicities may include2,3:
Myelosuppression
Mucositis
Neurotoxicity
Hepatotoxicity
GI toxicity
Nephrotoxicity
Up to 12% of patients who receive HDMTX will experience toxic
Inadequate Elimination of MTX Due to AKI Increases the Risk of Severe Toxicities and Death2,3
Severe Toxicities
In a study of 43 adult patients receiving HDMTX for a solid tumor or hematopoietic malignancy with delayed MTX clearance due to HDMTX-induced AKI, Grade 3-4 toxicities included hematologic, renal, liver, and CNS toxicity as well as mucositis (all in >10% of patients). Grade 3-4 hematologic toxicity occurred in 60% of patients.3
with delayed MTX clearance due to AKI3
| Toxicity | Patients, n (%) |
|---|---|
| Hematologic | 26 (60%) |
| Mucositis | 15 (35%) |
| Renal | 8 (19%) |
| Liver | 7 (16%) |
| CNS | 6 (14%) |
| Skin | 1 (2%) |
Death
10 of 43 patients (23%) died due to complications associated with HDMTX, including infection (n=7), uremia and seizures (n=1), MTX neurotoxicity (n=1), peritonitis with multiorgan failure (n=1).3
Patients who survive an AKI episode (all-cause) have5:
- Double the risk of death
- Triple the risk of end-stage renal disease
- 10 times the risk of developing incident or progressive chronic kidney disease
Cardiovascular Events
The rate of cardiovascular events is as high as 22%, and mortality related to cardiovascular events is 33% in patients with all-cause AKI.6
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:
- Dose and schedule of MTX
- Preexisting renal insufficiency
- Host factors, including patient age and cancer type
| 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% |
Despite Known Risk Factors for Delayed MTX Clearance, HDMTX-Induced AKI Can Be Hard to Predict3
9%(n=4)
Delayed MTX clearance can occur in any patient receiving HDMTX
In a study of 43 adult patients receiving HDMTX for a solid tumor or hematopoietic malignancy, 9% (n=4) did not exhibit any risk factors and still experienced delayed MTX clearance with AKI.3
Risk factors for delayed MTX clearance
- Medications that can interfere with MTX clearance (NSAIDs, PPIs, platinum-based chemotherapy, etc)2,11
- BMI ≥25 kg/m2 and BSA >2 m2 3,12
- Renal insufficiency prior to HDMTX, or CrCl <60 mL/min2
- Prior toxicity with HDMTX2
- Adult and elderly patients2
- Third spacing (pleural effusions, ascites, intracranial fluid)2
- Volume depletion due to vomiting, diarrhea, or other factors2
- Urine pH <72,3
- Hypoalbuminemia11,13
- Down syndrome13
*
AKI, acute kidney injury; BMI, body mass index; BSA, body surface area; CNS, central nervous system; CrCl, creatinine clearance; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor.