Case report on hypersensitivity to methotrexate infusion in a pediatric acute lymphoblastic leukaemia patient

Manjusha Sajith , Atmaram Pawar , Vibha Bafna and Sandip Bartakke.

Atmaram Pawar, Department of Clinical Pharmacy, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune, Maharashtra, India.

Email: p_atmaram@rediffmail.com

Abstract Methotrexate is extensively used in the treatment of various malignancies and autoimmune conditions. Methotrexate is associated with several toxicities, while hypersensitivity reactions to methotrexate are unusual, but have been reported in adult cancer patients. Hereby, we detail the case of a child with acute lymphoblastic leukaemia who developed a hypersensitivity reaction to high-dose methotrexate infusion (HDMTX) during the fourth cycle of HDMTX. The child was rechallenged with another brand of methotrexate; she started complaining of itching on trunk within 5 min of infusion. Few studies have reported that desensitization has been helpful in children with hypersensitivity reactions allowing the continuation of HDMTX. However, it was decided to omit parenteral methotrexate for this child. Cranial radiotherapy was given for CNS prophylaxis. In conclusion, unexpected hypersensitivity with methotrexate should be kept in mind during the treatment especially with high-dose infusion.

Case report A seven years nine month old girl with a body surface area of 0.79 m2 was diagnosed with pre B cell ALL and had no history of any hypersensitivity reactions. She was treated with BFM-based treatment protocol4 which includes four courses of HDMTX. Patient was hydrated for 48-h before HDMTX infusion with intravenous dextrose 0.45%, normal saline and 40 meq NaHCO3/liter, at the rate of 125 ml/m2 /hour until the urine pH was 6.5. In each HDMTX course, MTX infusion was given at a dose of 3 g/m2 in 500 mL 0.9% normal saline for 24 h. After 42 h of HDMTX infusion, folinic acid was administered to the child for every 6 h until the serum MTX level was below 0.2 mmol/L. Antiemetic prophylaxis Ondansetron was also given. 

The patient completed three cycles of high-dose MTX (HDMTX) infusion with no side effects. During the fourth course of HDMTX infusion, she developed acute chest pain, breathlessness, intense abdominal pain and vomiting immediately after receiving HDMTX. Simultaneously, her extremities were cold and clammy, there was a marked decrease in Spo2 (70%), despite the administration of 6 liters per minute of oxygen with a facemask, the systolic blood pressure was 80 mmHg, diastolic blood pressure was not recordable, with tachycardia (180 bpm), centralperipheral cyanosis and prolonged CRT(>4 s). MTX infusion was stopped, and she was initiated with 0.9% normal saline, intravenous hydrocortisone 100 mg, intravenous pheniramine maleate 5 mg and oxygen. The child responded quickly and her vital parameters were stabilized. Taking into consideration, the severity of the anaphylactic reaction, the infusion was not restarted. All her vitals were monitored every 4 h till the next day. MTX was assumed for an anaphylactic reaction. 

Other medications administered prior to the HSR included ondansetron and dexamethasone. Both of them had been repeatedly administered to the patient before and after the hypersensitivity reaction without any adverse effect. In spite of the administration of the same brand of MTX in the previous cycles, an adverse drug reaction (ADR) was observed in the fourth cycle. Later the child was rechallenged with another brand of MTX in a much-diluted form which is 15 mg in 100 mL normal saline for 1 h slowly under close monitoring, also apparently showed the similar ADR. 

The child started complaining of itching on the trunk, and on examination, there were several crops of papular eruptions surrounded by a zone of erythema within 5 min of HDMTX infusion (Figure 1). HDMTX was stopped, and the hydrocortisone and diphenhydramine intravenously started for hypersensitivity reaction, and she improved over the next 2 h. 

To confirm if the ADR was actually caused due to the drug, we used (1) Causality assessment scales; wherein the most widely known scales are WHO scale and Naranjo scale,5 (2) Severity assessment scale, known as Hartwig’s severity scale.6 The scoring of Naranjo scale was 10 (9 definite ADR) and the ADR’s severity assessment by Hartwig et al. was moderate level 3.

J Oncol Pharm Practice 2020, Vol. 26(2) 462–464