Flexural cutaneous eruption due to palifermin (2007)

We have read with lot of interest the article by Keijzer et al (2007) regarding a case of palmar-plantar erytrodysesthesia (PPE) related to palifermin (Kepivance®), a recombinant human keratinocyte growth factor that plays an important role in stimulating proliferation of epithelial cells (auf demKeller et al, 2004). This new agent is approved for use in the prevention of oral mucositis caused by myelosuppressive treatment and stem cell transplantation. Its efficacy and safety have been evaluated in clinical trials, indicating that it is an effective and well tolerated agent, with common side effects being rash, pruritus and mouth and tongue disorders (auf demKeller et al, 2004; Meropol et al, 2003). Nevertheless, serious (Keijzer et al, 2007) or characteristic(Lane et al, 2007) cutaneous reactions due to palifermin have been reported, showing that palifermin induces cutaneous effects different from unspecific allergic rashes or mucous alterations, consistent with the pharmacological action of palifermin in epithelial cells. We report a case of a cutaneous reaction, presumably in response to palifermin and describe its clinical and unique histological features. A 57-year-old man with multiple myeloma was admitted to our institution to undergo autologous stem cell transplantation following conditioning therapy with melphalan 200 mg/m2. Four days before the introduction of melphalan he was administered palifermin intravenously (60 μg/kg body weight) for three consecutive days in order to decrease oral mucosal injury. Coinciding with the third dose of palifermin, the patient developed an intense macular erythematous eruption that affected skin fold areas (neck, axilla, groins and infra-mammary areas) in a symmetric fashion. (Fig 1A) This reaction was not pruritic and disappeared within 3 d of the suspension of palifermin combined with the administration of methylprednisolone (50 mg b.i.d.) and local application of a steroid cream. (A) Erythema located in the left axila. (B) Histological features includes large keratinocytes in the lower layers of the epidermis showing an elongated shape. Original magnification x90. Two punch biopsies were performed that showed mild superficial perivascular lymphocytic infiltrates, with large and elongated keratinocytes in the lower layers of the epidermis (Fig 1B). High proliferative activity was assessed by Ki67 immunostaining. Although the patient had been receiving other drugs before hospitalization, the cause was attributed to palifermin due to the coincidence in the introduction of this drug and the onset of the eruption. To our knowledge, only two clinical descriptions of cutaneous reactions due to palifermin have been reported before. Keijzer et al (2007) described a serious palmar-plantar erytrodysesthesia after the use of palifermin to support chemotherapy (carmustine, etoposide, cytarabine-low dosage and melphalan) and stem cell transplantation. They hypothesized that palifermin increases the susceptibility to cytarabine-induced PPE by increasing the number of basal keratinocytes as a possible explanation to the development of PPE when using low doses of cytarabine, as this adverse event is often seen after using high doses of the drug. Lane et al (2007) reported a flexural cutaneous reaction in a patient after using palifermin to support treatment for myeloma with melphalan and stem cell transplantation, the clinical features of which were comparable with the one exhibited by our patient (axillary rash that spontaneously resolved over 3 d). The authors consider this to be consistent with acanthosis nigricans although no biopsy was performed. As far as we know, this is the first time that a clinical description of a cutaneous reaction related to palifermin has been supported by histological analysis, whose most striking feature is the presence of large keratinocytes, suggesting a direct effect of palifermin in cell proliferation and differentiation, consistent with previous studies that showed these changes in a skin equivalent model system when treated with keratinocyte growth factor (KGF) (Andreadis et al, 2001). This action of KGF in epidermic epithelial cells could explain cutaneous reactions, such as increased risk of PPE or the development of a characteristic flexural erythematous reaction that resolves in few days, as a consequence of increased proliferation and de-differentiation of basal cell keratinocytes. From our point of view, the patient reported by Lane et al (2007) most probably represents a case of this characteristic cutaneous reaction due to palifermin, as acanthosis nigricans rarely develops suddenly and resolves in 3 d, no histological study was done and the clinical description was similar to that of our case. It is possible that these serious cutaneous reactions due to palifermin are isolated cases, but also new cutaneous reactions due to this drug could appear. Caution should be warranted when using this drug; as all we know, the skin is the outer envelope that not only covers, but also reveals, our inner state.