Can high dose methotrexate be continued after severe hypersensitivity reaction?

Abstract

We read with great interest the report [1] describing a case of successful readministration of high-dose methotrexate (HD MTX) after a hypersensitivity reaction. We would like to support the conclusions with our own recent experience.A 16-year-old female was diagnosed with a localized osteoblastic osteosarcoma of the right humerus. She had no associated comorbidities and began treatment according to the Italian Sarcoma Group OS-2 (ISG/OS-2) protocol. She received a first course of HD MTX (12 g/m 2 in 4 hours) with normal drug clearance and good tolerance. The second course was complicated by moderately elevated transaminases and emesis. The patient underwent surgery and good histological response to neoadjuvant chemotherapy was documented.Fifteen minutes after completing the infusion of the third course of HD MTX the patient developed abdominal pain, emesis, emission of loose stools, and persistent hypotension. She received fluid resuscitation, two doses of hydrocortisone and two doses of im. adrenaline. After 1 hour, her blood pressure normalized and her clinical symptoms faded. Four hours after completing the infusion, the concentration of MTX in blood was 350 mmol/L; at the same time blood tests revealed altered coagulation and elevated liver enzymes (AST 2,905 U/L, ALT 2,594 U/L). Due to signs of rapid and severe organ damage, the patient was given high-dose calcium levofolinate and glucarpidase; 1 hour after such treatment her MTX level was 9.95 mmol/L and reached 0.43 mmol/L 32 hours later.Given the importance of HD MTX in the treatment of osteosarcoma, we decided to continue with its administration. The next course was given after premedication with methylprednisolone and chlorphenamine, and the timing of MTX infusion was extended to 6 hours, starting with 400 mg of MTX/m 2 /h and gradually increasing the infusion rate. The total dose was unchanged (12 g/m 2 ). The patient reported no symptoms or signs during or after the next two MTX infusions, apart from a moderate elevation in liver enzymes. The MTX levels measured in the blood 24 and 48 hours after starting the infusion did not differ substantially from those measured after the first two cycles.Compared with the case reported [1], our patient suffered more severe cardiovascular impairment and liver toxicity. Our experience supports the conclusion that it is not necessary to exclude methotrexate from the treatment plan after an even severe hypersensitivity reaction. This may be a crucial issue for osteosarcoma patients because methotrexate is essential to their treatment. Giving adequate premedication, prolonging the infusion time from 4 to 6 hours and increasing the infusion rate gradually seem to allow safe re-administration of HD MTX.

Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease

“…89,90 Methotrexate-induced pneumonitis (MIP) is an idiosyncratic hypersensitivity reaction that is significantly more common, with some case series reporting prevalence as high as 12%, although this is chiefly in the rheumatoid arthritis literature. 87,91,92 The prevalence of methotrexate hypersensitivity pneumonitis in patients with CD is more likely between 0.3 and 0.7%, 92 although a recent meta-analysis found that MTX use in rheumatologic and inflammatory bowel disease was not associated with an increased risk of adverse respiratory events (RR, 1.03; 95% CI, 0.9–1.17).…”