NCCN Issues Guideline Update on the Use of High-Dose Methotrexate, Glucarpidase in ALL/B-Cell Lymphoma

Laura Ramsey, PhD

The National Comprehensive Cancer Network (NCCN) has announced a guideline update concerning the treatment of patients with acute lymphoblastic leukemia (ALL), B-cell lymphomas, pediatric ALL, and pediatric aggressive mature B-cell lymphoma.¹

The modified guidelines provide instruction on treatments for patients who are receiving high-dosemethotrexate and have delayed elimination because of renal impairment. The NCCN also offered guidance on the proper use of glucarpidase (Voraxaze) and provided safety information pertaining to the use of the agent in the new guidelines.¹

The new guidelines recommend administering glucarpidase when the plasma methotrexate concentrations rise 2 standard deviations above the expected mean per the MTXPK.org online tool. Alternatively, glucarpidase therapy is advised if the plasma level of methotrexate is above 30 μM at 36 hours, above 10 μM at 42 hours, or above 5 μM at 48 hours. These recommendations for best supportive care were identical across ALL, pediatric ALL, B-cell lymphoma, and pediatric aggressive mature B-cell lymphoma.^2-5

In terms of glucarpidase, the NCCN guidelines specify that the most advantageous time to administer glucarpidase is 48 hours to 60 hours from the commencement of methotrexate therapy. Additionally, patients should be given leucovorin on a pre-glucarpidase plasma methotrexate and treatment with the agent should be ongoing for a minimum of 2 days, but not within 2 hours before or after glucarpidase since leucovorin is a substrate for glucarpidase. These recommendations also pertained to the best supportive care of ALL, pediatric ALL, B-cell lymphoma, and pediatric aggressive mature B-cell lymphoma.^2-5

“The updated guidelines will help ensure that health care professionals understand the current best practice for managing delayed methotrexate elimination due to acute kidney injury, and can identify, and appropriately treat patients at risk of methotrexate toxicity,” Suzanne Ward, PharmD, MBA, the senior director of Medical Strategy for BTG Pharmaceuticals said in a news release.¹ “The updates also bring attention to MTXPK.org, an online tool designed to help clinicians understand the pharmacokinetics of high-dose methotrexate, especially with regard to delayed clearance.”

High-dose (> 500 mg/m2) methotrexate is often the frontline treatment option for many pediatric and adult patients with hematologic and solid malignancies. However, the agent has been noted to cause renal toxicity in as many as 12% of patients, because of the way it crystalizes in the renal tubular lumen, thus causing tubular toxicity. This renal toxicity can cause reduced clearance of methotrexate, lengthening exposure to toxic concentrations of the drug, which can in turn further exacerbate renal function and lead to the worsening of other adverse effects.6

The updated NCCN guidelines also called special attention to MTXPK.org, an online pharmacokinetic model that was developed using over 30,000 methotrexate plasma concentrations from more than 700 pediatric patients with who were treated with methotrexate. The tool can incorporate and synthesize individual patient demographics, serum creatine levels, and real-time drug concentrations to produce a prediction for clinicians concerning the elimination profile of methotrexate for patients and provide an informed recommendation for glucarpidase therapy. The model has since been validated in both adult and pediatric patients with a variety of doses and infusion durations.⁷

“The inclusion of MTXPK.org in several NCCN Guidelines is an important milestone for our team after launching this free, open-access tool in 2019,” Laura Ramsey, PhD, an associate professor at Cincinnati Children’s Hospital Medical Center in Ohio said in the release.¹ “We are pleased to be able to provide a user-friendly tool for clinicians managing patients receiving [high-dose methotrexate] for them to understand whether their patients are eliminating methotrexate as expected.”

References

1. BTG Pharmaceuticals statement on NCCN clinical practice guidelines in oncology (NCCN Guidelines) recommendation for use of glucarpidase (Voraxaze) and MTXPK.org. BTG Pharmaceuticals. June 22, 2023. Accessed June 28, 2023. https://btgsp.com/en-us/about/news/btg-pharmaceuticals-statement-on-nccn-clinical-pra
2. NCCN. Clinical Guidelines in Oncology. Acute lymphoblastic Leukemia, version 1.2023. Accessed June 28, 2023. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf
3. NCCN. Clinical Guidelines in Oncology. B-cell lymphomas, version 4.2023. Accessed June 28, 2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
4. NCCN. Clinical Guidelines in Oncology. Pediatric acute lymphoblastic leukemia, version 2.2023. Accessed June 28, 2023. https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf
5. NCCN. Clinical Guidelines in Oncology. Pediatric aggressive mature B-cell lymphoma, version 1.2023. Accessed June 28, 2023. https://www.nccn.org/professionals/physician_gls/pdf/ped_b-cell.pdf
6. Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and Managing Toxicities of High-Dose Methotrexate. Oncologist. 2016;21(12):1471-1482. doi:10.1634/theoncologist.2015-0164
7. Taylor ZL, Mizuno T, Punt NC, et al. MTXPK.org: a clinical decision support tool evaluating high-dose methotrexate pharmacokinetics to inform post-infusion care and use of glucarpidase. Clin Pharmacol Ther. 2020;108(3):635-643. doi:10.1002/cpt.1957