TO THE EDITOR: Anaphylactic reaction to methotrexate (MTX) due to hypersensitivity to the drug is rare but can be fatal [1]; thus, prompt and adequate management is critical, particularly in cases of primary central nervous system lymphoma (PCNSL) in which MTX is a key therapeutic agent [2]. We herein report the first case of a successful 12-step desensitization to high-dose methotrexate (HD-MTX) in a patient with PCNSL who had recurrent episodes of anaphylaxis to HD-MTX.

A 49-year-old man with intermittent headache was diagnosed with PCNSL via stereotactic surgical biopsy of lesions in the left frontal lobe. The patient had no previous history of hypersensitivity or allergic reactions to any drugs or foods. We initially planned a total of 6 cycles of chemotherapy—4 cycles of HD-MTX (3.5 g/m²) followed by 2 cycles of high-dose cytarabine (HD-AraC) (3 g/m²) combined with HD-MTX. In the first cycle, intravenous (IV) HD-MTX infusion is usually given to patients over 2 hours on the first day; however, when the patient had received approximately 1.5 g of MTX after 30 minutes from starting the infusion, urticarial rashes with pruritus suddenly developed at the face, neck, and anterior chest area (Fig. 1). Throat tightness soon followed with a decrease in oxygen saturation level to 92% as measured via pulse oximetry, which prompted immediate cessation of HD-MTX infusion.

After administration of 4 mg IV chlorpheniramine and 100 mg hydrocortisone, the symptoms gradually improved without the need for epinephrine injection. On the following day, the same dose of HD-MTX was administered again but with premedication of IV chlorpheniramine and hydrocortisone. Nevertheless, identical symptoms and signs of hypersensitivity were immediately evident, and HD-MTX infusion was again halted. After the second episode of anaphylaxis, the serum level of creatinine was elevated from 0.91 mg/dL to 1.72 mg/dL. Moreover, serum level of MTX was markedly elevated at 2.74 µmol/L at 48 hours after the first infusion, which necessitated a rescue regimen using high-dose leucovorin. Once renal function was normalized, HD-MTX was re-administered in the second cycle according to the desensitization protocol following the instruction of the Allergy Department of our institution. The total dose of MTX was lowered from 7.0 g to 3.5 g.

During desensitization, the patient's vital signs were closely monitored via pulse oximetry and electric monitors, and resuscitation equipment and medications were prepared at the bedside. A total of 20 mg of dexamethasone was administered as premedication at 12, 6, and 1 hour before starting desensitization, and 4 mg chlorpheniramine and 20 mg famotidine were also administered 1 hour before. After premedication, the dose of MTX was gradually increased in 12 steps using three serially diluted solutions—solution A: 1:100 dilution; solution B: 1:10 dilution; solution C: final concentration (no dilution). Each step took 15 minutes except for the final step, which lasted for 6 hours, and the infusion rates were generally doubled every step. Details of the desensitization protocol are summarized in Table 1. No hypersensitivity reaction during and after infusion was noted.

Leucovorin rescue therapy was started 24 hours after the completion of MTX infusion and was administered every 6 hours until the serum level of MTX reached below 0.1 µmol/L. The full MTX dose (7 g) was administered in the third cycle, and while the doses in each solution were increased, other schemes of infusion remained the same as previous cycles. Three additional cycles of HD-MTX were successfully administered following this protocol, and partial remission was achieved after the fourth cycle of desensitized HD-MTX. After six cycles of chemotherapy, the size of the frontal lesion was further decreased (Fig. 2). Subsequently, the patient received high-dose conditioning chemotherapy with thiotepa, busulfan, and cyclophosphamide followed by autologous stem cell transplantation (ASCT). The patient achieved complete response (CR) of PCNSL and did not experience recurrence for 9 months after the ASCT.

Anaphylaxis is a fatal hypersensitivity reaction that does not necessarily need prior exposure or sensitization [3,4]. In our case, the patient with PCNSL experienced recurrent episodes of anaphylaxis to HD-MTX, which has been rarely reported in patients with PCNSL. Although we did not perform either skin test for MTX hypersensitivity or blood test to measure the serum level of tryptase, this was defined as an anaphylaxis because the hypersensitivity reaction occurred immediately after the first exposure to HD-MTX.

PCNSL is a rare subtype of B-cell lymphoma that generally presents with an aggressive natural course and unsatisfactory outcomes [5]. MTX became the most widely used single agent for patients with PCNSL because it was shown to markedly improve the survival outcomes [2,5]. Therefore, even in the case of anaphylaxis, desensitizing the patient to MTX seems a more favorable course of treatment rather than switching to an alternative chemotherapy agent. Because the infusion time of MTX is prolonged as the concentration is lowered during the desensitization process, potential risks of relatively high toxicities and low anti-neoplastic effect should not be overlooked when considering desensitization [6].

Several reports have suggested various protocols of MTX desensitization (Table 2). Davis et al. [7] started the infusion with 0.2 mg/mL of MTX and approximately doubled the dose every hour until it reached 12 mg/mL. The dose was then increased to 18.05 mg/mL, which was infused for 4 hours. MacGinnitie et al. [8] applied a three-week step-up protocol in which the starting dose was increased by 10-fold every week for three weeks. Bouchireb et al. [9] progressively increased the MTX dose that started at 1:1,000 and 1:100 dilution of the planned dose infused for 90 minutes to 1:10 dilution infused for 6 hours and the remaining dose for 18 hours. In our case, rapid drug desensitization (RDD) protocol was used, which is a more recently established protocol developed at Brigham and Women's Hospital (Boston, MA, USA). RDD is considered the safest and most effective protocol thus far based on several hundred cases [10]. Concurrently, RDD is very efficient in that it takes a shorter infusion time than other protocols.

In summary, a patient with anaphylaxis to HD-MTX was safely and successfully desensitized without any toxicity or additional hypersensitivity event. The patient finally achieved CR after receiving the planned chemotherapy followed by ASCT. Collectively, our results show that the RDD protocol is a safe and effective treatment option for PCNSL patients with anaphylaxis to HD-MTX.

No potential conflicts of interest relevant to this article were reported.

Hypersensitivity skin reaction after methotrexate infusion. After 30 minutes of methotrexate infusion, urticarial rashes developed in the face, neck, and anterior chest area.

MRI changes in the lymphoma lesion during chemotherapy. Prior to receiving chemotherapy, the size of the frontal lesion was approximately 4.1 cm with perilesional edema and midline shifting to the right side (A). After the fourth cycle of chemotherapy, partial remission was achieved, with decrease in tumor size to approximately 2.1 cm with perilesional edema as well as disappearance of midline shifting (B). After the sixth cycle of chemotherapy, the tumor further decreased to 1.8 cm with perilesional edema (C). After undergoing ASCT, the patient achieved CR (D).

Table 1 Rapid intravenous desensitization to 7 g of methotrexate in a patient with CNS lymphoma.

Table 2 Reported cases of MTX desensitization.