Int J Hematol DOI 10.1007/s12185-012-1167-x

LETTER TO THE EDITOR

Injection site reaction after subcutaneous administration of bortezomib in Japanese patients with multiple myeloma Tomohiko Kamimura • Toshihiro Miyamoto Shuichiro Takashima • Noriko Yokota • Yong Chong • Yoshikiyo Ito • Koichi Akashi

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Received: 10 July 2012 / Revised: 24 August 2012 / Accepted: 27 August 2012 Ó The Japanese Society of Hematology 2012

The proteasome inhibitor bortezomib (Bor) is important in the management of multiple myeloma (MM). However, when administered intravenously, its efficacy can be limited by significant exacerbation of peripheral neuropathy (PN) [1]. Recently, Moreau reported that the response rate in patients treated with subcutaneous Bor (sBor) was nearly equal to that in patients treated with intravenous Bor (ivBor), although the incidence and severity of PN in patients treated with sBor was lower than those in patients treated with ivBor [2–4]. The most common injection site reaction was erythema, however, only four patients (3 %) developed an injection site reaction of grade 3 or more, necessitating a reduction in Bor dose in two (1 %) patients [3]. The injection site reactions in the other two patients treated with sBor were severe, although detailed information regarding the clinical courses following these reactions was not provided [3]. According to a classification of skin symptoms, Bor is classified as an irritant, as it causes extravasation of cytotoxic agents [5]. Further studies that focus on injection site reaction of sBor, particularly in Japanese patients, are required. The present study retrospectively analyzed injection site reactions in 19 Japanese patients with newly diagnosed (n = 9) or relapsed (n = 10) MM, and who were treated T. Kamimura
Y. Chong
Y. Ito Department of Hematology, Harasanshin Hospital, Fukuoka, Japan T. Miyamoto (&)
S. Takashima
K. Akashi Department of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan e-mail: [email protected] N. Yokota Department of Nursing, Harasanshin Hospital, Fukuoka, Japan

with sBor at a concentration of 2.5 mg/ml (3.0 mg Bor reconstituted with 1.2 ml normal saline), as described previously [3], between April 2011 and June 2012. We injected bortezomib to eight different sites in the right and left abdomen, upper and lower quadrant, or right and left thigh, proximal and distal sites of each patient in turn, as described previously [3]. These patients were treated with weekly BD (Bor 1.3 mg/m2 on day 1, 8, 15, 22, and dexamethasone 20 mg on day 1–2, 8–9, 15–14 and 22–23) [6], twice-weekly VCD (Bor 1.3 mg/m2 on days 1, 4, 8 and 11, cyclophosphamide 500 mg/m2 on days 1 and 8, and dexamethasone 20 mg on days 1–2, 4–5, 8–9 and 11–12) or once-weekly VCD (Bor 1.3 mg/m2, cyclophosphamide 300 mg/m2, and dexamethasone 40 mg on days 1, 8, 15 and 22) [7]. Tolerability of subcutaneous administration at the local injection site was systematically from 2 to 4 h after each injection and observed every day during the first cycle. After the second cycle, patients documented their own injection site reactions in a detailed diary between visits. Medical records were used to evaluate injection site reactions for every course. Reactions were graded according to National Cancer Institute Common Toxicity Criteria version 4.0. The treatment protocol for sBor was approved by the Institutional Review Board of Harasanshin Hospital on September 2011. Of the 10 patients in whom relapse occured, seven patients had been previously treated with ivBor and four had undergone autologous peripheral blood stem cell transplantation before sBor treatment. The median age of all patients was 65 years (range 49–85 years). The median dose of sBor was 11.5 mg/m2 (range 5.2–36.8 mg/m2). Twelve patients (63 %) developed injection site reactions, including eight (42 %) with grade 1 reactions and four (21 %) with grade 2 reactions. These reactions manifested as skin erythema and occurred after the first injection in

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T. Kamimura et al.

Fig. 1 A 62-year old patient with an injection site reaction of grade 2. a Skin erythema and phlebitis of the left thigh with itching 2 days after sBor. Due to moderate itching, external steroid therapy was

administered on the day. b Phlebitis and itching disappeared and skin erythema significantly decreased on the day after administration of external steroid therapy

most cases. The median duration of these reactions was 5 days (range 3–23 days). External steroid therapy (hydrocortisone butyrate) was administered because of moderate itching in one patient (62 years old) who developed a grade 2 injection site reaction with erythema and phlebitis (Fig. 1a). Itching and phlebitis around the local injection site quickly disappeared on the day after administration of external steroid therapy, and skin erythema also decreased significantly thereafter (Fig. 1b). In the other 11 patients, injection site reactions spontaneously disappeared within a couple of days. Recently, Obeid et al. [8] reported a case of severe injection site reaction as a complication of the first subcutaneous administration of Bor. In this study, a small boillike lesion developed at the injection site, gradually increasing in size and becoming tender. In addition, high fever developed. The cutaneous lesion, a skin biopsy of which showed separation of the epidermis and stratum corneum, ischemic keratinocytes, and lymphocytic infiltration of the dermis, had enlarged during antibiotic therapy, eventually involving most of the abdominal wall. Interestingly, significant improvement in the form of reduced fever and regression of the skin lesion was observed only after systemic administration of methylprednisolone (dosage not specified). In the cases described here, no severe Bor-induced cutaneous lesions developed, and no systemic steroid treatment was required. However, the rapid effectiveness of external steroid therapy was demonstrated in one patient. Recently, Pour et al. [9] reported that systemic corticosteroids were useful in the treatment of ivBor-associated systemic rash, while maintenance treatment with antihistamine alone was not effective. The clinical courses of these patients who developed ivBor-associated skin rash or injection site reactions after treatment with sBor suggested that the development of skin

lesions after administration of Bor was mediated by an immune response to Bor. This study focused on injection site reactions after sBor treatment. To our knowledge, this is the first study to show that sBor caused only mild injection site reactions in Japanese patients, and that early treatment with external steroids provided effective relief. This study would include the contents, which are suggestive for physicians about injection site reaction caused by sBor. A large prospective study is required to further assess the safety and efficacy of sBor treatment in Japanese patients with MM.

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