A 63-year-old man presented with back pain in April 2011. A computed tomography (CT) scan revealed enlargement of his retroperitoneal lymph nodes. The patient underwent excisional biopsy and was diagnosed with malignant lymphoma. He was heavily pretreated: with cyclophosphamide, doxorubicin, vincristine, and prednisolone (3 cycles); ifosfamide, methotrexate, etoposide, and prednisolone plus L-asparaginase (1 cycle); rituximab with dose-modified cyclophosphamide, vincristine, doxorubicin, methotrexate/etoposide, ifosfamide, and cytarabine (1 cycle); and gemcitabine with dexamethasone (1 cycle). During treatment, new skin lesions developed at multiple sites, including the face, trunk, arms, and legs, with a skin biopsy revealing malignant lymphoma. The patient was subsequently treated with 5 cycles of bortezomib in combination with dexamethasone, and 4 cycles of pralatrexate (20 mg once a week, every 4 weeks). However, the disease still progressed.

Despite the extensive treatment, the disease proved refractory to most chemotherapeutic agents. The skin lesions initially manifested as multiple papules and nodules, which gradually developed into ulcerative lesions (Fig. 1A, B). Since brentuximab vedotin was available at the time, we analyzed the skin biopsy performed in January 2012 to evaluate CD30-positivity. The skin biopsy demonstrated the tumor to be an ENKL positive for CD3 (Fig. 2A), CD30 (Fig. 2B), and Epstein-Barr virus in situ hybridization (Fig. 2C). Informed, written consent was obtained prior to treatment with single-agent brentuximab vedotin. In December 2013, treatment commenced and the patient received a 1.8 mg/kg dose of single-agent brentuximab vedotin, administered intravenously every 3 weeks. From December 2013 to March 2014, the patient received 4 cycles of single-agent brentuximab vedotin treatment. After 4 cycles, all of the skin lesions had cleared, and a [18F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan showed CR of the disease (Fig. 1C, D). The patient developed grade 2 toxicity dyspnea with no other significant adverse events. Treatment was stopped for 3 months due to the dyspnea and relapse was observed in May 2014.

ENKL is usually derived from NK cells or, in rare instances, from cytotoxic T-cells. NK/T-cell lymphomas are typically positive for CD2, CD56, and cytoplasmic CD3 [5]. CD30-positivity is known to be associated with Hodgkin's lymphoma, but it is also detected in ALCL, some T- and B-cell lymphomas, and embryonal cell carcinomas [6]. In a study of patients with ENKL, 36.4% were CD30-positive, exhibiting reduced event free survival and overall survival compared to those without CD30 expression [7]. For patients with refractory ENKL, benefits may be anticipated with L-asparaginase-based combination chemotherapy, but it is not an established therapy [8].

A recent phase 2 clinical trial by Horwitz et al proved that single-agent brentuximab vedotin could be a viable therapeutic option for relapsed and refractory peripheral T-cell lymphoma [4]. However, there has been no study or clinical trial, to date, evaluating the use of single-agent brentuximab vedotin in ENKL. We report a case where single-agent brentuximab vedotin induced CR that was long lasting in a patient with refractory CD30-positive ENKL. The only toxicity of brentuximab vedotin treatment in this patient was dyspnea of grade 2, with other studies having also reported manageable toxicities. Among the most common adverse events were dose-related sensory peripheral neuropathy, nausea, neutropenia, diarrhea, and pyrexia, with lung toxicity occurring very rarely [9].

In conclusion, we suggest that single-agent brentuximab vedotin could be a viable treatment option for refractory CD30-positive ENKL without causing significant toxicity, even in heavily pretreated patients. However, since this case report is the first to show CR in CD30-positive ENKL with brentuximab vedotin, further studies will be required to confirm these results and establish a dosing schedule. This report implies that brentuximab vedotin could be effective in treating CD30-positive non-Hodgkin lymphoma other than ALCL and peripheral T-cell lymphoma.