Abstract:

Methotrexate is a chemotherapeutic and anti-inflammatory agent used in cancers, hematologic and rheumatologic diseases, binding to Dihydrofolate Reductase (DHFR) as a competitive inhibitor, modulating inflammation by inhibition of transmethylation reactions.^1,2 Life threatening hypersensitivity reactions (HSRs) have been reported with methotrexate.^3,4,5 Alternative treatments result in suboptimal outcomes/ death due to cancer progression. Drug desensitization enables patients to continue treatment, preventing anaphylaxis by inducing a temporary tolerance.³ We report a case of a child with Acute B-cell Lymphoblastic Leukemia who successfully tolerated methotrexate desensitization, and subsequently weaned to a weekly oral challenge. He is now taking weekly methotrexate without any reactions.

Introduction:

Methotrexate is a chemotherapeutic and anti-inflammatory agent used in various cancers, hematologic and rheumatologic diseases. It binds to Dihydrofolate Reductase (DHFR) as a competitive inhibitor to kill cancer cells, and can modulate inflammation by the promotion of adenosine release and inhibition of transmethylation reactions. It disrupts the synthesis of purines, resulting in cell-cycle arrest in the S phase, with ensuing apoptosis.^1,2 Several studies have reported hypersensitivity reactions (HSRs) and anaphylactoid reactions during chemotherapy with methotrexate. In patients with HSRs to methotrexate, alternative treatments may result in suboptimal outcomes or death due to cancer progression. In these cases, it is recommended that patients undergo drug desensitization to continue treatment and prevent anaphylaxis. ^3,4,5 Drug desensitization induces a temporary tolerance in patients that would otherwise experience allergic reactions to a substance.⁶ We report a case of a child with Acute B-cell Lymphoblastic Leukemia who successfully tolerated intravenous (IV) and oral desensitization to methotrexate after premedication. Subsequently, this patient tolerated an oral challenge, and is now taking weekly methotrexate orally without any reactions.

Methods: Retrospective Electronic Medical Record (EMR) chart review and literature review.

Clinical Case:

A 5-year-old male was diagnosed with Acute B-cell Lymphoblastic Leukemia. The patient was treated with methotrexate and peg-asparaginase according to the chemotherapy protocol AAALL0932 (peg-asparaginase, vincristine, dexrazoxane, doxorubicin, intrathecal methotrexate, and dexamethasone). 4 months into the protocol, during intravenous methotrexate infusion, the patient immediately developed hives and respiratory distress with oxygen desaturations. Patient was treated with IV diphenhydramine and supplemental oxygen, and symptoms resolved. Same symptoms occurred during the next methotrexate infusion 2 weeks later, treated in the same way.

The Oncology team felt it was necessary for the patient to continue methotrexate. Following an allergy consultation, it was recommended that the patient should undergo an intravenous (IV) methotrexate desensitization procedure. Skin testing was not done because the oncologist preferred the patient to stay on the methotrexate schedule as much as possible, and their diagnostic value is controversial.⁴ If skin testing were to be done, methotrexate would have to be held for 4 weeks.

A 12-step IV desensitization protocol was adopted, premedication with antihistamines and corticosteroids (Table 1). The patient was eventually transitioned to an 8-step oral desensitization protocol (Table 2), with a total cumulative dose of 15.75mg (based on patient’s surface area). With each subsequent oral desensitization procedure, early steps of the protocol were removed but maintaining the total cumulative dose of 15.75mg. The final in-office drug challenge was a single full dose of methotrexate 15.75mg with observation, which was well tolerated by the patient. The patient continued a weekly dose of methotrexate 15.75 orally at home, without any systemic reactions.

Results:

As a result of the desensitization procedure and oral challenges, our patient was able to: (1) tolerate a much-needed chemotherapy; (2) transition to home with parent-managed therapy, and a better quality of life; (3) reduce cost of therapy, because of not needing inpatient monitoring.

Discussion:

Severe HSRs to methotrexate are rare, and may include urticaria, angioedema, rash, abdominal pain, bronchospasm, dyspnea, and hypotension, reported in <1% of HSRs to methotrexate.³ Our case was suspected to be a Type 1 immediate hypersensitivity reaction (IgE vs non IgE) based on the clinical history of repeated immediate reactions. Desensitization is a procedure inducing temporary drug tolerance for patients who previously experienced anaphylactic reactions to a medication. The procedure achieves temporary immunologic tolerance by gradually administering increasing doses of a drug until the final cumulative therapeutic dose is reached.⁶ Gradual dose escalation is done to allow safe administration of treatment. The exact mechanism of tolerance is unknown. A drug challenge is

We report a successful pediatric methotrexate desensitization and oral challenge protocol. This protocol can be useful as a guide for future desensitizations and oral challenges in patients who absolutely need methotrexate as part of their chemotherapy or treatment plan.

Conflict of Interest Statement: The author has no conflicts of interest to report.

Acknowledgment:

I would like to show my sincerest appreciation to ALEAH MCKENNEY (Undergraduate Student, Xavier University of Louisiana), for her valuable assistance in data collection and writing of the initial abstract.

References: