Methotrexate-Induced Neurotoxicity in Hispanic Adolescents with High-Risk Acute Leukemia—A Case Series

Introduction

MTX is an integral component of therapy for acute lymphoblastic leukemia (ALL). The drug is given intravenously for systemic distribution and intrathecally for the treatment and/or prophylaxis of central nervous system (CNS) involvement with leukemia. The administration of high-dose intravenous methotrexate (HD MTX) (5 g/m²) has been shown to be beneficial in patients with high-risk disease and is now a component of most high-risk treatment protocols. ¹ HD MTX and intrathecal methotrexate (IT MTX) are associated with the development of neurotoxicity in a subset of patients, and the risk is increased in the adolescent population.^2–4 It is unknown whether Hispanic patients are at higher risk. Methotrexate toxicity may be related to delayed excretion or biologic differences among patients. There are no standard guidelines for the management of the acute event or subsequent provision of MTX, and the risk of recurrent neurotoxicity must be weighed against the risk of relapse of leukemia.

Case Report

We describe a series of five Hispanic adolescents with acute leukemia who developed MTX neurotoxicity (Table 1). The patients ranged in age from 14 to 21 years at the time of diagnosis of leukemia. All patients had high-risk forms of acute leukemia, including B ALL, T ALL, Philadelphia chromosome-positive ALL, and mixed phenotype acute leukemia (MPAL)(T/myeloid). Only the patient with T ALL had CNS involvement at the time of diagnosis. All patients were treated as per Children's Oncology Group high-risk ALL protocols, which were approved by the National Cancer Institute Central and Institutional IRBs. The patients did not receive any drugs or gases known to enhance the toxicity of methotrexate around the time of methotrexate administration. The patients experienced their first episode of MTX neurotoxicity during consolidation (n = 3), interim maintenance I (n = 1), and delayed intensification I (n = 1). Patient 2 had an initial episode during consolidation and recurrences during interim maintenance. Patient 4 had an initial episode during consolidation and recurrence during maintenance therapy. Neurotoxicity occurred from 4 to 10 days after the administration of IT MTX, HD MTX, or both. Patients 1, 2, and 3 had neurotoxicity after two to six weekly doses of IT MTX had been administered. Cranial irradiation was not administered to any patient before the episode of neurotoxicity. Presentations included headache, confusion, extremity paresis, dysphasia, and dysarthria. All patients had abnormal MRI findings consistent with acute methotrexate neurotoxicity, but none consistent with posterior reversible encephalopathy syndrome, and no patient had hypertension at presentation.

All patients were treated with supportive care measures during the acute presentation. Additionally, patient 3 received dextromethorphan (3 mg/kg/day divided every 12 hours for 7 days) and leucovorin, patient 4 had delayed MTX clearance at the time of presentation and received leucovorin, and patient 5 received dextromethorphan (3 mg/kg/day divided every 12 hours for 7 days) and aminophylline (10 mg/kg/day IV every 6 hours for 2 days). Patients 1–4 experienced a dramatic improvement in symptoms within 24 hours of presentation, whereas patient 5 experienced progression of symptoms over the first 24 hours, thereby prompting escalation of therapeutic intervention.

Subsequent CNS prophylaxis was generally administered along a similar algorithm for all affected patients. After an episode of neurotoxicity, the subsequent scheduled dose of HD MTX and/or IT MTX was not administered, and then the next scheduled dose of IT therapy was replaced with cytosine arabinoside. Subsequent doses of IT therapy were administered with 12 mg of MTX, followed by 5 mg/m² of oral leucovorin administered at 48 and 60 hours. Patient 4 was diagnosed with a Chiari I malformation and an ommaya reservoir was placed to facilitate the administration of intraventricular chemotherapy. He continued to receive triple intraventricular therapy as per his protocol (MTX, cytosine arabinoside, hydrocortisone), but each dose of MTX was capped at 6 mg. He developed recurrent neurotoxicity during maintenance therapy 11 days after an intraventricular administration of triple chemotherapy, for which he was treated with dextromethorphan and recovered. He went on to receive five subsequent doses of intraventricular chemotherapy without recurrent neurotoxicity. Patient 2 had recurrence of neurotoxicity on two subsequent administrations of HD MTX and so HD MTX was deleted from his subsequent therapy. Patients 1, 3, and 5 did not experience recurrent events with further IT MTX (12 mg) therapy (2–12 doses) with leucovorin rescue. Patient 3 died after a bone marrow relapse 19 months after the diagnosis of MPAL. She did not have CNS disease at the time of her relapse. The other four patients remain in remission and without neurologic deficits 3–59 months after the initial episode of neurotoxicity.

Discussion

MTX is a critical component of multiagent chemotherapy for the treatment of ALL. There is a wide dosing range recommended based on the indication for the drug. HD MTX has been shown to be beneficial in the treatment of high-risk ALL ¹ and can penetrate the blood–brain barrier. Intrathecal administration of MTX has become standard of care for prophylaxis against CNS relapse for all risk categories of ALL.

Neurotoxicity due to MTX can be acute, subacute, or delayed. ⁵ Previous studies have shown that 3–8% of patients develop acute or subacute neurotoxicity after receiving HD or IT MTX.^2,5–7 Subacute methotrexate-induced neurotoxicity can present within 2–14 days after IT MTX or HD MTX with headache, altered mental status, seizures, focal deficits, or stroke-like symptoms.^5,6,8 Magnetic resonance imaging reveals diffuse cerebral white matter changes consistent with encephalopathy. ⁹ MRI with diffusion-weighted imaging reveals restricted diffusion, which normalizes with the resolution of clinical symptoms.^8,10 Many patients will experience waxing and waning of symptoms and most will have resolution of symptoms within hours or days.

The exact mechanism behind the development of MTX neurotoxicity is unclear. Studies have evaluated pharmacogenetic polymorphisms ¹¹ as well as pharmacokinetics ⁴ in patients who have developed MTX neurotoxicity. Csordas showed that children over 14 years of age with ALL had higher blood levels of MTX and more hepatic, renal, and bone marrow toxicity. ⁴ However, Rubnitz et al. showed that pharmacokinetic data did not differ between patients who developed neurotoxicity and those who did not. ² Tsujimoto et al. showed that gene polymorphisms of the adenosine pathway, ADORA2A, were associated with MTX leukoencephalopathy. ¹² A meta-analysis by Campbell et al. studying the pharmacogenetics of MTX-induced toxicity showed significant associations between the methylenetetrahydrofolate reductase (MTHFR) C677T allele and development of MTX toxicity. ¹¹ Specifically, those with the TT genotype of the MTHFR C677T allele, with 30% enzyme activity, have a higher risk of developing methotrexate toxicity. ¹³ A study by Plaza-Plaza evaluating pharmacogenetic polymorphisms in Spanish patients with rheumatoid arthritis receiving methotrexate showed a significant association between the presence of the T allele at MTHFR C677T and the development of toxicity. ¹⁴ Children with polymorphisms in the SLCO1B1 gene, which plays a crucial role in the hepatic uptake and clearance of methotrexate, have been shown to have delayed clearance and increased toxicity.^15,16 Polymorphisms in genes related to neurogenesis may also increase the risk of MTX neurotoxicity. ⁶ These studies demonstrate that certain pharmacogenetic polymorphisms may increase the risk of developing MTX toxicity.

Drachtman and colleagues have demonstrated high levels of homocysteine in the cerebrospinal fluid (CSF) of leukemia patients who experience MTX neurotoxicity. ¹⁷ Metabolites of homocysteine are excitatory agonists of the N-methyl-D-aspartate (NMDA) receptors in the CNS. ⁹ Dextromethorphan, a noncompetitive NMDA antagonist, was administered to five patients with neurotoxicity and complete and rapid resolution of symptoms ensued. ¹⁷ Similarly, Afshar et al. gave dextromethorphan to 18 patients with MTX neurotoxicity and observed significant improvement of neurologic symptoms. ¹⁸ Several authors have evaluated the utility of aminophylline to treat MTX neurotoxicity.^19–21 Bernini et al. demonstrated high levels of adenosine in the CSF of leukemia patients after receiving MTX and hypothesized that this may contribute to the development of neurotoxicity. ²¹ They administered aminophylline, a competitive adenosine antagonist, to six leukemia patients with MTX neurotoxicity and observed significant improvement. Jaksic et al. reported a patient with severe MTX neurotoxicity who had a dramatic improvement after aminophylline and high-dose leucovorin were administered. ²⁰

Several drugs, including trimethoprim/sulfamethoxazole, nonsteroidal anti-inflammatory medications, penicillin, proton pump inhibitors, aspirin, ²² and nitrous oxide, ²³ can lead to delayed clearance of MTX and have the potential to enhance toxicity. These drugs must be avoided during and after the administration of HD MTX.

Although it is difficult to predict which patients will experience MTX neurotoxicity, most patients in the literature and all five patients in our series are adolescents or young adults. The enhanced toxicity in adolescents may be related to the known higher levels and delayed clearance of methotrexate when compared with younger children. ²⁴ There are no studies evaluating whether Hispanic patients are at higher risk. However, it is interesting to note that twelve of the eighteen patients with MTX neurotoxicity in the report by Afshar et al. were Hispanic. ¹⁸

There are no standard guidelines for the management of the acute neurotoxic event. Most patients fully recover from subacute methotrexate neurotoxicity and therefore it has been difficult to definitively demonstrate any benefit to specific therapy. As MTX is a critical component of ALL therapy, it is generally recommended that most patients who experience a neurotoxic event from MTX be rechallenged with the drug.^2,6,8,9 There is little evidence-based data regarding how and when these patients should be rechallenged. One study suggests that patients can be safely rechallenged during the maintenance phase of therapy. ⁵ A small percentage of patients will experience recurrent toxicity upon rechallenge. ⁶ There are no standard guidelines for prophylactic maneuvers to reduce the risk of recurrence of neurotoxicity upon rechallenge. We were able to rechallenge all five of our patients with MTX. Patients 2 and 4 received no further doses of HD MTX due to recurrent episodes of neurotoxicity, but they both tolerated reduced doses of intraventricular and IT MTX with leucovorin rescue without incident. Our results are consistent with previous studies that have supported the continuation of IT MTX after development of neurotoxicity.^2,6,8,9

Conclusion

Our series of five leukemia patients who experienced MTX neurotoxicity were all Hispanic adolescents. Adolescents are known to be at a higher risk of developing MTX neurotoxicity.^2–4 However, there currently is no literature regarding the incidence of MTX neurotoxicity specifically in adolescent Hispanic patients with high-risk acute leukemia, and it is possible that ours is an incidental observation. Further studies should be conducted in this population to determine if they are at an increased risk of developing MTX neurotoxicity and, if so, the biologic basis for this increased risk. Such studies could have significant therapeutic implications such as alteration of therapy or administration of prophylactic medications to prevent neurotoxicity in the Hispanic population.

Disclaimer

Four of the patients of this case series were presented as posters at the following venues:

Illinois Chapter of the American Academy of Pediatrics annual meeting, March 2016.

American Society of Pediatric Hematology Oncology annual meeting, May 2016.