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Imatinib induced severe skin reactions and neutropenia in a patient with gastrointestinal stromal tumor
© Hwang et al; licensee BioMed Central Ltd. 2010
Received: 8 December 2009
Accepted: 18 August 2010
Published: 18 August 2010
Imatinib mesylate has been used for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST). The current recommended dose of imatinib is 400 mg/day that is increased to 800 mg/day in cases with disease progression. However, imatinib can be associated with diverse adverse events, which has limited its use. We report a case of severe adverse skin reactions with neutropenic fever during imatinib treatment in a patient with GIST.
A 71-year-old man was admitted with a one month history of epigastric pain and a palpable mass in the right upper quadrant. An abdominal CT scan revealed a 20 × 19 cm intraabdominal mass with tumor invasion into the peritoneum. Needle biopsy was performed and the results showed spindle shaped tumor cells that were positive for c-KIT. The patient was diagnosed with unresectable GIST. Imatinib 400 mg/day was started. The patient tolerated the first eight weeks of treatment. However, about three months later, the patient developed a grade 4 febrile neutropenia and a grade 3 exfoliative skin rash. The patient recovered from this serious adverse events after discontinuation of imatinib with supportive care. However, the skin lesions recurred whenever the patient received imatinib over 100 mg/day. Therefore, imatinib 100 mg/day was maintained. Despite the low dose imatinib, follow up CT showed a marked partial response without grade 3 or 4 toxicities.
The recommended dose of imatinib for the treatment of GIST is 400 mg/day but patients at risk for adverse drug reaction may benefit from lower doses. Individualized treatment is needed for such patients, and we may also try sunitinib as a alternative drug.
Imatinib mesylate is a selective tyrosine kinase inhibitor. It has become the gold standard treatment for unresectable or metastatic gastrointestinal stromal tumors (GIST). It has inhibitory activity against, BCR-ABL, c-KIT, and PDGFR [1, 2]. The most common adverse events associated with imatinib include edema that is most frequently periorbital, nausea, diarrhea, muscle cramps, fatigue, skin rash, headache, and abdominal pain. Imatinib induced grade 3-4 neutropenia and skin rash may occur in as many as 7.1% and 3.8% of GIST patients, respectively [3, 4]. The toxicities are generally mild or moderate and of grade 1 or 2 severity (NCI-CTC). Rarely, serious gastrointestinal or intraabdominal hemorrhage can occur in patients with large, bulky tumors [2, 3]. Most cutaneous reactions are mild, however, severe reactions such as exfoliative dermatitis, toxic epidermal necrolysis and Stevens Johnson syndrome can also occur . Sunitinib has demonstrated efficacy in treating patients with GIST who have experienced disease progression on or intolerance to imatinib . However, due to the effectiveness of imatinib, imatinib may need to be used again in some patients despite a history of severe reactions. We report a case of severe adverse skin reactions with neutropenic fever during imatinib treatment.
The cutaneous findings were compatible with the diagnosis of an exfoliative dermatitis due to imatinib. The patient was managed with hydration and parenteral injections of a third generation cephalosporin as well as granulocyte colony stimulating factor. For the skin lesion management, systemic steroids (oral prednisone 30 mg/day) with topical steroid and emollient cream were provided. The patient recovered from the febrile neutropenia, and the eosinophil count normalized subsequently. The results of blood culture was negative and there were no infection foci. The skin lesions gradually improved with a reduction of the extension and severity of the erythema and scales. Further dermatological treatment was continued and one month later the rashes completely resolved with hyperpigmented areas remaining.
Gastrointestinal stromal tumors (GIST) are a subtype of sarcomas that have a unique natural history. Imatinib mesylate, a selective tyrosine kinase inhibitor, has become the gold standard for the treatment of unresectable or metastatic GIST .
Skin rashes are a well recognized side effect of imatinib treatment. In most cases, the lesions are mild, self limiting, and easily managed with anti-histamines or topical steroids, whereas a short course of oral steroids can be used to treat more severe cases . Grade 3 or 4 skin rashes may occur in 3.8% of patients. In some patients, severe rashes can develop with desquamative components, including a report of Steven-Johnson syndrome [8–10]. In such cases, immediate discontinuation of therapy and systemic steroids are indicated. Severe skin lesions that were resistant to supportive measures have been the most frequent cause for permanent discontinuation of imatinib therapy. However, the frequency of this event is small (<1% of all patients) .
Standard management of drug induced skin rashes usually includes discontinuation of the suspected drug and avoidance of further exposure to this drug in the future. However, due to the effectiveness of imatinib, most oncologists try to maintain or reinitiate treatment with imatinib. To overcome severe skin reactions, several methods such as temporary discontinuation of imatinib treatment, once weekly dosing, a lower daily dose with or without a short course of an oral corticosteroid, and gradual dose escalation, have been reported [11–13, 9, 14].
In this case, febrile neutropenia resolved as soon as treatment was initiated and the skin rashes resolved gradually over one month. We started the imatinib again, but we could not increase the dose above 100 mg/day due to recurrence of the lesions. However, even with the low dose of imatinib, 100 mg/day, follow up CT demonstrated a decreased tumor mass. We could also try sunitinib which had demonstrated efficacy in treating patients with GIST who have experienced disease progression on or intolerance to imatinib . However, the patient had good tumor response to imatinib, therefore we tried to maintain the imatinib.
Several studies have reported a dose related skin toxicity of imatinib, indicating a pharmacological effect of imatinib. This case can also mainly be related to the pharmacological effect of imatinib, but the delayed type hypersensitivity might be involved in some aspects like other skin rashes considering eosinophilia and pruritus [15–17]. The cause of the skin rashes is unclear. However, the platelet derived growth factor receptor is found abundantly in keratinocytes, and its inhibition by imatinib may play a role in the occurrence of this reaction . Other investigators have proposed that certain skin reactions may result from an inhibition of KIT, found in basal cells [7, 14, 18]. However, it is unclear why these severe skin rashes develop in only a minority of patients.
Recently, Demetri et al. suggested that imatinib trough levels at steady state were associated with a clinical benefit . According to this report, patients with an imatinib trough concentration, below 1,100 ng/ml, showed a shorter time to progression (11.3 months) and lower rate of clinical benefit. In our case, the trough concentration at steady state was 331 ng/ml. It remains to be seen whether the tumor will progress earlier or maintain a partial response. However, to date, the patient has showed a good tumor response over 14 months. The current recommended daily dose of imatinib is 400 mg, however, patients at risk for adverse drug reactions may benefit from lower doses. Individualized treatment is needed for such patients, and we may also try sunitinib as a alternative drug.
In conclusion, we describe a patient with an intraabdominal GIST that had a good tumor response, although we could not increase the dose of imatinib above 100 mg/day due to severe adverse skin reactions.
Written informed consent was obtained from the patient for publication of this case report and any accompanying clinical images, including the image of the face.
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