Evaluation, Identification, and Management of Acute Methotrexate Toxicity in High-dose Methotrexate Administration in Hematologic Malignancies.

Doron Feinsilber,Roberto J Leoni,Katrina A Mears,Julianne Leuck,Duminda Siripala

doi:10.7759/cureus.2040

Abstract

The pharmacological and medical management of complex chemotherapy regimens are vast and complex, requiring an intimate understanding of physiology, particularly when novel biologic agents are utilized with commonly used regimens. The molecular classification in patients with diffuse large B-cell lymphoma (DLBCL) is multifaceted, particularly with the expansion of novel molecular targets. The pharmacological and medical management of hematologic malignancies with a tendency to have central nervous system (CNS) involvement is complex and requires an understanding of physiology and pharmacology. Many chemotherapy regimens used to treat hematologic malignancies with either CNS involvement or high risk for CNS disease will include the administration of high dose methotrexate. This requires having physiological understanding with respect to the standard regimens for DLBCL in addition to understanding cytogenetic markers, such as c-myc and bcl-2, the expression of which displays increased likelihood of CNS involvement. In patients with documented CNS disease and active neurological manifestations such as myclonus, headaches, nystagmus, and blurred vision, the utilization of high dose methotrexate has become an essential standard of care. We examine the pharmacologic mechanisms of high dose methotrexate in patients with hematologic malignancies such as DLBCL and review the most common toxicities on a multidisciplinary level.

Highlights

BackgroundPharmacology and metabolismIn order to have a more complete concept of the multifactorial aspects of methotrexate toxicity, we must first characterize the pharmacologic mechanism of the action of methotrexate (MTX)
We examine the pharmacologic mechanisms of high dose methotrexate in patients with hematologic malignancies such as diffuse large B-cell lymphoma (DLBCL) and review the most common toxicities on a multidisciplinary level
With respect to evaluation of renal toxicity, glucoparidase, high-flux hemodialysis, and continuous renal replacement therapy (CRRT) may be considered in the management of methotrexate nephrotoxicity in certain cases

Summary

Introduction

In order to have a more complete concept of the multifactorial aspects of methotrexate toxicity, we must first characterize the pharmacologic mechanism of the action of methotrexate (MTX). One case involved a 20-year-old male with pre T-cell acute lymphoblastic leukemia (ALL) who had developed a rise in serum creatinine levels to 8.3 mg/dL three days following administration of high-dose methotrexate. After the patient had received four daily sessions of highflux hemodialysis, his serum methotrexate levels had dropped to 0 umol/L and his GFR had not dropped significantly [6] These case reports demonstrate plasma clearance of methotrexate using high-flux hemodialysis, and recovery of renal function. While CRRT does have the advantage of avoiding rebound of serum methotrexate levels due to being continuous over a long period of time and of less likelihood of hypotension, in comparison with intermittent hemodialysis, due to slower blood flow rates and more gentle fluid removal, it did not appear to provide a mortality benefit nor a benefit in terms of renal recovery in either case described above. High dose methotrexate 3.5 g/m2 and/or highdose cytarabine at 3g/m2 or higher can be combined with ocular radiation therapy leading to remission in several studies [11]

Conclusions

Findings

Disclosures