Imatinib Mesylate-Induced Erythema Multiforme: Recurrence after Rechallenge with 200 mg/day Imatinib

Dear Editor:

Imatinib mesylate (Gleevec; Novartis AG, Basel, Switzerland), a selective tyrosine receptor kinase inhibitor, is increasingly used for treating chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia, and high-grade gastrointestinal stromal tumors (GISTs)¹. Several cases of cutaneous reactions after imatinib use have been reported¹. We report a case of EM after imatinib administration for the treatment of a GIST.

A 66-year-old woman was referred for pruritus from the department of oncology. She received a diagnosis of a GIST, for which she received adjuvant imatinib therapy after gastric wedge resection. She noticed a pruritic rash on her trunk after 5 weeks of 400 mg/day imatinib therapy. Physical examination revealed generalized variable-sized erythematous wheal-like patches with some targetoid lesions on the trunk, face, and extremities (Fig. 1). Immunoglobulin (Ig) G and IgM antibodies to the herpes simplex virus were not detected. A skin biopsy from the trunk revealed vacuolar degeneration, tagging of lymphocytes along the dermal-epidermal junction, and perivascular lymphocytic and some eosinophilic infiltrations in the upper dermis (Fig. 2A). Some dyskeratotic and necrotic keratinocytes were obvious in the epidermis (Fig. 2B); therefore, EM was diagnosed. As imatinib was the only medication administered to the patient, it was considered the most probable cause. Imatinib was discontinued, and oral steroid and antihistamine were prescribed. For 2 weeks, 30 mg/day steroid, tapered to 5 mg/day, was administered. One month after the discontinuation of imatinib therapy, the rash was fully cured. Imatinib treatment was restarted at a lower dose of 100 mg/day without steroids; no skin lesion developed for 2 months. However, when the dose was increased to 200 mg/day without oral steroids, a similar rash developed. The patient could continue imatinib therapy with a gradual dose escalation from 100 to 200 mg/day with concomitant 5 mg/day oral steroids. No additional skin lesions were detected during 5 months of follow-up.

Fig. 1. Clinical manifestations of the patient. (A) Generalized erythematous variable-sized wheal-like patches on the trunk. (B) Several lesions showing the typical targetoid appearance.

Fig. 2. Histopathological findings of the lesion. (A) Vacuolar degeneration, tagging of lymphocytes along the dermal-epidermal junction, and perivascular lymphocytic and a few eosinophilic infiltrations in the upper dermis (H&E, ×200). (B) Spongiosis and necrotic keratinocytes in the epidermis (H&E, ×400).

It is estimated that approximately 7%~21% of patients treated with imatinib experience variable degrees of skin eruptions². There are a few reports of imatinib-induced EM. Park et al.³ reviewed patients with cutaneous eruptions after imatinib therapy, and 2 of 10 patients (20%) had EM-like drug eruptions. The cutaneous adverse effects of imatinib are dose dependent and seemingly related to a pharmacological effect of the drug¹,². The most common skin reactions are maculopapular rashes¹,², and these are spontaneously relieved with a minimal dose of antihistamine or topical steroids. Several uncommon or severe reactions such as Stevens-Johnson syndrome have also been reported; however, they seem to be an idiosyncratic adverse reaction of hypersensitivity⁴. These reactions require the concomitant use of oral steroids, and immediate discontinuation of imatinib therapy is imperative⁴,⁵.

Here, we observed a case of imatinib-induced EM. We noted a dose-dependent relation; thus, we consider that imatinib-induced EM is related to a pharmacological effect of imatinib. The skin lesion subsided and did not recur only with the concomitant use of low-dose oral steroids. As imatinib is a very effective therapeutic agent and alternative treatment options are limited, recognition of adverse cutaneous reactions after imatinib therapy and the appropriate management required is helpful.