Periocular Cutaneous Anaplastic Large Cell Lymphoma Clearance with Brentuximab Vedotin

aBenjamin H. Kaffenberger, MD; aFrancisca Kartono Winardi, DO; aJulie Frederickson, DO; bPierluigi Porcu, MD; aHenry K. Wong, MD, PhD
Departments of aDermatology and bHematology, Ohio State University College of Medicine and James Cancer Hospital, Columbus, Ohio

The treatment options for primary cutaneous anaplastic large cell lymphoma are numerous, including excision, external beam radiation, methotrexate, and chemotherapy. In patients with recalcitrant tumors, alternative options may be necessary. The authors report a 60-year-old man with a 6cm primary cutaneous anaplastic large cell lymphoma located on the right cheek, near the eye. After failing four months of methotrexate, and due to concern for ocular radiation toxicity, the patient started brentuximab vedotin, an anti-CD30 antibody-drug conjugate. With two cycles of brentuximab vedotin, he had a complete response that was histologically confirmed. Six months after a total of four cycles, he remains clear. He experienced no side effects other than a mild infusion reaction. Brentuximab vedotin may be an effective option for primary cutaneous anaplastic large cell lymphoma in patients with large tumors in cosmetically sensitive areas, those who have not responded to conventional therapy, or those who have contraindications to radiation therapy. Optimal dosing for primary cutaneous anaplastic large cell lymphoma and long-term outcomes are not currently known.
(J Clin Aesthet Dermatol. 2013;6(8):29–31.)

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a subtype of cutaneous T-cell lymphoma (CTCL) histologically characterized by large, highly atypical CD30+ T-cells that clinically presents as a solitary tumor. The authors report a case of a large pcALCL arising on the face with periorbital extension. The size and periorbital location were relative contraindications to radiation therapy and surgery. Oral weekly methotrexate was initiated, but the tumor enlarged in size and the growth extended near the eye despite generally adequate doses. After brief treatment with brentuximab vedotin, the tumor resolved completely.

A 60-year-old man presented with a large tumor over his right cheek with periorbital extension (Figure 1A). The tumor had been present for about four years, and the patient estimated that it was 6mm and stable until the preceding 10 months when the size rapidly increased. A biopsy of the tumor revealed a CD30+ lymphoproliferative disorder and he was referred to the authors’ institution for evaluation. Prior to his presentation, he had received an injection of intramuscular triamcinolone, which resulted in a decrease in tumor edema. On his initial physical examination, he was found to have a 6x4cm well demarcated, smooth, lobulated, erythematous tumor. A repeat biopsy (Figure 2A-2C) showed a dense lymphocytic infiltrate present throughout the papillary and reticular dermis, with mild lymphocytic epidermotropism and minimal spongiosis. The majority of lymphocytes were CD4+ (Figure 2B) and CD30+ (Figure 2C), with loss of CD5 expression. The CD4:CD8 ratio was increased, anaplastic lymphoma kinase 1 (ALK1) was negative, and monoclonality was positive by T-cell receptor gene rearrangement studies. The histological data supported a diagnosis of pcALCL.

A positron emission tomography (PET)/computed tomography scan (CT), quantitative immunoglobulin panel, B2-microglobulin, peripheral blood T-cell receptor  gene rearrangement study, peripheral blood flow cytometry, complete blood count, and metabolic panels were unremarkable. A bone marrow biopsy was not performed since preliminary studies did not show evidence of systemic involvement.

Initially, the patient was started on 15mg of weekly oral methotrexate, and subsequently titrated to 50mg weekly with continued tumor progression over four months (Figure 1B). Adjacent satellite tumors greater than 1cm developed that were in close proximity to his eye. The patient declined radiation therapy out of concern for ocular toxicity, and the tumor was too large for an excision. Consequently, the decision was made to use brentuximab vedotin.

Although this use of brentuximab was off label, his insurance company approved the treatment based on the large and periocular nature of the tumor. He underwent dosing at 1.8mg/kg dosed every 21 days, which is the approved dose and schedule for the treatment of refractory Hodgkin’s lymphoma and systemic ALCL.[1,2] After the second infusion, the patient noted complete clinical clearance of the lesion with only residual xanthomatous discoloration (Figure 1C). A biopsy was taken at that time, which confirmed resolution of the dense lymphocytic infiltrate with residual foamy histiocytes and xanthogranulomatous changes (Figure 2D). The patient underwent two additional cycles thereafter and is currently disease free and off treatment 14 months after starting brentuximab (Figure 1C and 1D). He did not have any side effects other than an infusion reaction with his second infusion, which resolved after intravenous treatment with 20mg of dexamethasone and 25mg of diphenhydramine.

PcALCL is a CD30+ CTCL that demands distinction from its nodal counterpart with a less favorable prognosis. Five-year disease-specific survival rates range from 77 to 93 percent in pcALCL.[3] Risk factors for worse prognosis may include involvement of the leg and more extensive disease based on a proposed tumor node metastasis staging system.[3] Because the disease is rare, prognostic variables have not been prospectively validated. Some have suggested that a null cell phenotype and extensive regional disease or involvement of the head and neck are poor prognostic indicators.[4,5] The most frequent treatments for pcALCL are surgical excision and external beam radiation therapy.[6] Based on the size and location, neither was feasible for the patient described in this case. A subset of pcALCL may spontaneously regress,[4,6] but as the tumor in this case enlarged and approached the eye, a second-line treatment was chosen. Pralatrexate was considered, which can be effective in up to 46 percent of patients with CTCL who were previously treated with methotrexate.[7] However, this study only had one patient with pcALCL, leaving the efficacy unclear. For that reason, the authors chose brentuximab vedotin.

Brentuximab vedotin (SGN-35) is an antibody drug conjugate (ADC) that contains anti-CD30 Fab’ domains linked to the antimitotic agent monomethyl auristatin E (MMAE). The initial results in other CD30+ malignancies have been promising with an 86 percent overall response rate and 57 percent complete response rate in patients with systemic ALCL and 75 and 34 percent, respectively, for patients with relapsed or refractory Hodgkin’s lymphoma.[1,2] Its predecessor (SGN-30), which lacked the conjugated MMAE, demonstrated a complete response of pcALCL in 6 of 11 patients,[8] but was significantly less active in systemic ALCL and HL.

Brentuximab vedotin is dosed as a 30-minute infusion every three weeks at a dose of 1.8mg/kg.[1,2] Since this patient was treated, a registration trial in pcALCL has begun accruing. A recently published case report of the use of brentuximab vedotin in pcALCL also used 1.8mg/kg, but for only three cycles. That patient achieved a complete remission with three months of disease-free follow-up.[9] The authors chose to treat their patient with four cycles of brentuximab, based on the principle of giving two additional cycles of therapy after documentation of complete response. In Hodgkin’s lymphoma and ALCL, brentuximab is given up to 16 cycles,[1,2] but in pcALCL, it is likely that a shorter duration of therapy is sufficient. The optimal treatment duration in pcALCL will be determined by ongoing clinical trials.

The previously published case did not develop any xanthomatous changes based on a published clinical image.[9] The authors suspect that the xanthogranulomatous changes in their case relate to the rapid destruction of the tumor and infiltration of tumor-associated macrophages. It is possible that these changes would not be seen in the treatment of smaller tumors.

Common side effects of brentuximab vedotin include sensory peripheral neuropathy, nausea, fatigue, neutropenia, diarrhea, pyrexia, and thrombocytopenia. Despite these side effects, there were no deaths in the Phase 2 trials for Hodgkin’s lymphoma or systemic ALCL that were determined to be drug related.[1,2] The most common reason for discontinuation of therapy was peripheral sensory neuropathy, which developed in about 40 percent of patients in both Phase 2 trials and almost always improved after drug discontinuation or dose reduction.[1,2] Typically, neuropathy does not develop until a mean of 12 to 13 weeks of therapy and much later for grade 3 to 4 toxicity. Both trials gave maximum of 16 cycles of treatment and are still accruing data for long-term follow-up, which could indicate that other serious or late side effects may still exist. One case of progressive multifocal leukoencephalopathy with immune reconstitution inflammatory syndrome was recently described in a patient with pcALCL treated with brentuximab.[10] This developed after the second cycle of therapy and was histologically confirmed. Therefore, the drug may pose a significant risk in a disease with low mortality, so patients should be appropriately selected.

The case described herein illustrates how brentuximab vedotin, a newly approved anti-CD30 agent for relapsed Hodgkin’s lymphoma and systemic ALCL, may be highly effective for selected patients with pcALCL. Patients should be made aware that many questions remain on how many cycles are adequate, how persistent the response will be, and whether the benefit of this medication outweighs the risks.

1.     Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–2189.
2.     Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–2196.
3.     Benner MF, Willemze R. Applicability and prognostic value of the new TNM classification system in 135 patients with primary cutaneous anaplastic large cell lymphoma. Arch Dermatol. 2009;145(12):1399–1404.
4.     Liu HL, Hoppe RT, Kohler S, et al. CD30+ cutaneous lymphoproliferative disorders: the stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol. 2003;49(6):1049–1058.
5.     Yu JB, Blitzblau RC, Decker RH, et al. Analysis of primary CD30+ cutaneous lymphoproliferative disease and survival from the surveillance, epidemiology, and end results database. J Clin Oncol. 2008,26(9):1483–1488.
6.     Kempf W, Pfaltz K, Vermeer MH, et al. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood. 2011;118(15): 4024–4035.
7.     Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2012;119(18):4115–4122.
8.     Duvic M, Reddy S a, Pinter-Brown L, et al. A phase II study of SGN-30 in cutaneous anaplastic large cell lymphoma and related lymphoproliferative disorders. Clin Cancer Res. 2009;15(19):6217–6224.
9.     Desai A, Telang GH, Olszewski AJ. Remission of primary cutaneous anaplastic large cell lymphoma after a brief course of brentuximab vedotin. [Published Online ahead of print October 21, 2012]. Ann Hematol. 2012. Accessed on October 28, 2012.
10.     von Geldern G, Pardo CA, Calabresi PA, Newsome SD. PML-IRIS in a patient treated with brentuximab. Neurology. 2012;79(20):2075–2077.

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