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.
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