Transient response to nivolumab and relapse after infliximab in a patient with primary cutaneous CD8‐positive aggressive epidermotropic cytotoxic T‐cell lymphoma
Authors: F. Toussaint, M. Erdmann, E. Grosch, S. Schliep, G. Schuler, R. Dummer, L. Heinzerling
Journal: British Journal of Dermatology (2020)

Dear Editor, Primary cutaneous CD8+ aggressive epidermotropic T-cell lymphoma (CD8+ AECTCL) is a very rare subtype of cutaneous T-cell lymphoma. The frequency is less than 1% of all primary cutaneous lymphomas and prognosis is poor, with a 5-year disease-specific survival rate of 31%.1 Because of the rarity of this entity, there are no evidence-based treatment options. We report the case of a 70-year-old female patient who presented with a red plaque with central ulceration on the left shin rapidly developing in 2 weeks. Skin biopsy revealed atypical lymphoid cells in the epidermis and dermis with atypical mitoses (Figure 1a). Immunohistochemical stains showed reactivity with CD3, CD8 (Figure 1b), TIA-1 and programmed cell death 1 ligand 1, with weak reactivity for programmed cell death protein 1 (PD-1) expression. CD2, CD4, CD20, CD30 and CD56 were negative. Cranial magnetic resonance imaging (MRI) and computed tomography (CT) scan of neck, thorax and abdomen showed no evidence of metastases. Bone marrow biopsy revealed no infiltration with lymphoma cells, and blood count was normal. Primary cutaneous CD8+ aggressive epidermotropic T-cell lymphoma was diagnosed. Chemotherapy with cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone (CHOEP) every 21 days was started. After six cycles of chemotherapy the plaque was clearly regressive, and consolidating radiotherapy of the left lower leg was started. Still on radiotherapy, the patient developed disseminated, well demarcated erythematous patches and plaques, many with necrotic ulcerations, involving all extremities and trunk (Figure 1c), and ulceration on the hard palate. Cranial MRI, CT scan and fluorescence-activated cell sorting analysis ruled out extracutaneous manifestation. Photochemotherapy with psoralen plus ultraviolet A and treatment with topical corticosteroids class IV were initiated without significant improvement. Due to progression, therapy was changed to an anti-PD-1 antibody. After five infusions of nivolumab (2 mg kg–1) the patient experienced near complete remission of all lesions (Figure 1d). Only a singular new erythematous plaque with no ulceration appeared on the trunk during treatment. An additional skin biopsy was performed, which showed similar findings to the initial diagnostic specimen. After seven infusions of nivolumab she developed autoimmune diarrhoea grade 2 (Common Terminology Criteria for Adverse Events). Therapy was paused and treatment with prednisolone at 1 mg kg–1 orally was started and slowly tapered. Owing to persistent symptoms, one infusion with a tumour necrosis factor (TNF)-α inhibitor (infliximab) 5 mg kg–1 was applied. Diarrhoea improved and nivolumab was restarted 1 month after cessation. However, in the following 3 months, new disseminated erythematous and ulcerated plaques appeared and the patient developed a painful massive swelling in the preauricular region. MRI showed a mass in the parotid lodge infiltrating the masseter muscle. Treatment was switched to total body irradiation. However, the patient's condition deteriorated rapidly and she died from sepsis 14 months after diagnosis. Checkpoint inhibitors play an increasing role in the treatment of patients with solid and haematological malignancies. More recent studies evaluated the safety and efficacy of anti-PD-1 antibodies in patients with cutaneous T-cell lymphomas, including a phase Ib study for nivolumab that included 13 cases of mycosis fungoides and five cases of peripheral T-cell lymphoma. The objective response rate in that study was 15% among patients with mycosis fungoides and 40% among patients with peripheral T-cell lymphoma with no further specification of the subtype.2 A phase II study of 24 patients with pretreated mycosis fungoides and Sézary syndrome showed an overall response rate of 38%.3 To our knowledge, there are no descriptions of treatment of CD8+ AECTCL with anti-PD-1 antibody. Reported treatment regimens in cases of CD8+ AECTCL consist of polychemotherapies with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). However, results are disappointing, with limited success and often rapid recurrence.4 So far the most promising results were achieved with allogeneic hematopoietic stem cell transplantation with a possible curative option,5, 6 which was not possible in our patient owing to rapid progression after multiagent chemotherapy, age and comorbidity. Our patient initially responded surprisingly well to therapy with anti-PD-1 antibody. However, after a short duration of nearly complete remission she required immunosuppressive medication including TNF-α inhibitor in steroid-refractory immune-related diarrhoea. Subsequently, the disease recurred with rapid progression and she finally died, 14 months after diagnosis of CD8+ AECTCL, due to sepsis. There is ongoing discussion of whether treatment with TNF-α inhibitors could induce progress of cutaneous lymphoma.7 Also in our case, it is not excluded that disease progression was accelerated by anti-TNF-α treatment. In conclusion, anti-PD-1 antibodies present a potential treatment option for CD8+ AECTCL, an entity with otherwise few options. open access funding enabled and organized by Projekt DEAL. Frédéric Toussaint: Conceptualization (lead); Visualization (lead); Writing-original draft (lead). Michael Erdmann: Resources (equal); Writing-review & editing (equal). Ella Grosch: Resources (equal); Writing-review & editing (equal). Stefan Schliep: Resources (equal); Writing-review & editing (equal). Gerold Schuler: Writing-review & editing (equal). Reinhard Dummer: Writing-review & editing (equal). Lucie Heinzerling: Supervision (lead); Writing-review & editing (equal).