Successful Use of Brentuximab Vedotin for Treatment of CD30-positive Primary Cutaneous Extranodal Natural Killer/T-Cell Lymphoma

A 75-year-old Chinese man with a history of diabetes mellitus presented with multiple tender dermal violaceous ulcerative nodules over his extremities, which have increased in size and extent since their appearance 3 months ago (Figure 1). He reported a history of weight loss without fever or nasal symptoms. Histology from skin punch biopsies taken from his left arm and left thigh showed sheet-like infiltrate of medium-to-large atypical lymphoid cells. Immunohistochemistry (IHC) revealed positive staining with cytoplasmic CD3, CD2, CD56, CD30 and granzyme B. IHC staining for CD30 was variably weakly positive in a minority of the atypical lymphoid cells, ranging from less than 5% positivity in the left thigh specimen and 10-20% weak positivity in the left arm specimen, where atypical lymphoid cells appear larger. Ki-67 proliferation fraction was 90%. There was widespread nuclear positivity for Epstein-Barr virus-encoded small RNAs (EBER). IHC staining was negative for CD10, CD79a, CD 123 and TCL1 (Figures 2 and 3). A Positron Emission Tomography and Computed Tomography (PETCT) showed multiple enhancing and hypermetabolic nodular skin lesions with no involvement of lymph nodes and other organs (Figure 4). He was diagnosed with high-risk, advanced stage primary cutaneous extranodal natural killer/T-cell lymphoma, nasal type (ENKTL-NT). He received upfront treatment with Brentuximab vedotin (BV) in addition to chemotherapy (Table 1) which resulted in complete response.


Discussion
Extranodal natural killer/T-cell lymphoma (ENKTL) is deadly with an aggressive course. Primary cutaneous ENKTL describes disease that initially manifests in the skin. L-asparaginase-based chemotherapy with high-dose radiation therapy forms the basis of treatment in early disease and may be curative 1 . However, prognosis in advanced disease is invariably poor and developments in treatment have been impeded by the rarity of this disease. Asparaginase-based chemotherapy followed by consolidation with autologous transplantation may be used in advanced stages but treatment outcomes remain extremely poor 1 .
BV is a CD30-targeted antibody-drug conjugate that delivers vedotin (monomethyl auristatin E), a cytotoxic agent, to CD30-expressing cells 2 . CD30 has been identified as a therapeutic target due to its relative overexpression in specific tumour types and limited expression on normal cells 3 . CD30 expression is commonly associated with Hodgkin's lymphoma and anaplastic large cell lymphoma, but may also be seen in certain T-and B-cell lymphomas 4  In theory, the level of CD30 expression should influence the efficacy of BV, considering that CD30 is the molecular target of the drug. Interestingly, CD30 expression in our patient showed only weak positivity, with levels ranging from 5-20% from both specimens. A recent study by Jagadeesh et al in 2022 -which examined the response to BV by CD30 expression in Non-Hodgkin Lymphoma -showed that response to BV was observed in patients with all levels of CD30 expression 9 . The same study found no significant differences in overall response between patients with CD30 expression ≥10% or <10% 9 . The authors concluded that CD30 expression does not predict clinical response to BV and elucidating a meaningful threshold level of CD30 expression remains challenging. These findings were also demonstrated by Jacobsen et al in 2015, where the study found no statistical correlation between response to BV therapy and level of CD30 expression in patients with relapsed/ refractory diffuse large B-cell lymphoma 10 .
A number of hypotheses have been proposed to account for observable clinical response to BV independent of the degree of CD30 expression. These include an intra-and inter-tumoral heterogeneity of CD30 expression, the dynamic nature of CD30 expression on tumour cells and alternative modes of action of BV; such as through direct cytotoxicity thought to be enhanced by the bystander effect, immunogenic cell death and antibody-dependent cellular phagocytosis 9 .
We describe complete response using BV upfront in addition to conventional chemotherapy in our patient with primary cutaneous ENKTL-NT. Repeat PET-CT 5 months following diagnosis demonstrated resolution of all cutaneous nodules (Figure 4). At the time of writing (2 months after his interval PET-CT), our patient remains in remission. There are few reports of successful treatment of primary cutaneous ENKTL with BV upfront, as opposed to salvage therapy.

Conclusion
We add to the growing body of evidence of successful use of BV in CD30-positive ENKTL, with emphasis on primary cutaneous disease. Upfront BV could be efficacious in CD30-positive ENKTL.