Aminophylline for Methotrexate Induced Leukoencephalopathy?

 Amy Smith, as part of her Green Oncology series

 

The severe neurotoxicities that may occur with methotrexate (MTX) therapy are unpredictable and troubling (to say the least).  During a recent experience, a patient with high dose MTX induced leukoencephalopathy presenting with concurrent disorientation and confusion left me seeking ways to resolve these concerning symptoms.  Although the benefits of aminophylline have been discussed on list servers or email threads, I sought to briefly review the primary literature available (although limited).  Below is a brief overview the next time a patient presents with severe MTX induced neurotoxicities. 

 

Proposed Mechanism of Action:

Patients experiencing methotrexate (MTX) induced neurotoxicities display increased CSF adenosine (CNS depressant).(1)  There is a hypothesized link between MTX neurotoxicities and adenosine as it dilates cerebral vessels, alters neurotransmitters release, and slows neuron discharge rate.(1)(2)  Aminophylline is an adenosine antagonist therefore displacing adenosine from its receptor.(1) 

Adenosine also decreases the glomerular filtration rate and as an adenosine antagonist and diuretic, aminophylline may increase methotrexate clearance and potentially decrease renal insult.(2) 

 

Approved Therapeutic Uses:

Asthma, chronic obstructive pulmonary disease, neonatal apnea of prematurity

 

Suggested Dosing for MTX Induced Neurotoxicity:

  • 2.5 mg/kg IV over 60 minutes (0.5 mg/kg/hr continuous infusion or 300 mg PO dosing have also been reported)(1)(2)
  • Suggested aminophylline target concentrations for MTX induced neurotoxicity ~10-30 mmol/L.(1) 
  • Obtain steady state peak concentration 30 mins post infusion to measure for potential toxicity.(3) (Conventional asthma target concentrations 55-110 mmol/L)(4). 

 

Side Effects:

Headache, seizures, behavioral alterations, insomnia, tachycardia, tachypnea, N/V/D, transient diuresis

 

Supporting Evidence:

 

Case Report: Treatment

·        Bernini JC, Fort DW, Griener JC, Kane BJ, Chappell WB, Kamen BA. Aminophylline for methotrexate-induced neurotoxicity. Lancet. 1995 Mar 4;345(8949):544–7.

o       Six pediatric patients (3-16yo) with MTX (PO, IT, or continuous infusion) induced neurotoxicities (grade 3-4) treated with aminophylline 2.5 mg/kg.  Complete resolution of symptoms was noted within 30 mins of aminophylline infusion in 4/6 patients while 2/6 patients experienced no or partial resolution of symptoms.     

·        Peyriere H, Poiree M, Cociglio M, Margueritte G, Hansel S, Hillaire-Buys D. Reversal of neurologic disturbances related to high-dose methotrexate by aminophylline. Med Pediatr Oncol. 2001 Jun;36(6):662–4.

o       A 9yo male with IT and high dose MTX induced neurotoxicities treated with aminophylline 2.5 mg/kg x 1 dose.  Rapid but partial improvement of neurological symptoms was noted at the end of infusion. 

·        Jaksic W, Veljkovic D, Pozza C, Lewis I. Methotrexate-induced leukoencephalopathy reversed by aminophylline and high-dose folinic acid. Acta Haematol. 2004;111(4):230–2.

o       A 20yo female with IT MTX induced neurotoxicities treated with aminophylline 145 mg po daily x 7d and high dose folinic acid.  Gradual and progressive improvement of neurological symptoms was observed.  Future dosing was modified to decrease neurotoxicities. 

 

Case Reports: Prophylaxis

·        Inaba H, Khan RB, Laningham FH, Crews KR, Pui C-H, Daw NC. Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2008 Jan;19(1):178–84.

o        Two patients (14yo female and 12yo male) received aminophylline prophylaxis with high dose MTX as a result of neurotoxicities with previous treatments.  The male patient did not experience recurrent symptoms however the female patient presented with headache and treatment was subsequently discontinued. (Prophylaxis dosing strategy was not provided)

 

Bottom Line:

A limited number of case reports display possible efficacy of aminophylline in reversing methotrexate induced neurotoxicities.  However higher quality evidence is lacking therefore few conclusions can be made at this time. 

 

Amy Smith is a graduate of the College of Pharmacy at the University of Saskatchewan.  After completing a hospital residency program with the Regina Qu’Appelle Health Region, Amy began working with the Saskatchewan Cancer Agency in Saskatoon as a pediatric oncology pharmacist.  She is now attending the U of T post-baccalaureate PharmD program. During her time away from work, Amy enjoys traveling, volunteering and participating in a various athletics including powerlifting and running. Amy is a member of CAPhO's Communication Committee. 

 

References:

1. Bernini JC, Fort DW, Griener JC, Kane BJ, Chappell WB, Kamen BA. Aminophylline for methotrexate-induced neurotoxicity. Lancet. 1995 Mar 4;345(8949):544–7.

2. Peyriere H, Poiree M, Cociglio M, Margueritte G, Hansel S, Hillaire-Buys D. Reversal of neurologic disturbances related to high-dose methotrexate by aminophylline. Med Pediatr Oncol. 2001 Jun;36(6):662–4.

3. Lexi-Comp Online (accessed August 4, 2014)

4. CPS Online (accessed August 4, 2014)

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