CD30-positive anaplastic large-cell lymphoma associated with mycosis fungoides after treatment with dupilumab

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphomas (CTCLs), representing about 40% of cases [1]. Primary cutaneous anaplastic large-cell lymphoma (pcALCL) is a CD30-positive CTCL [1]. Dupilumab, an interleukin 4/13 blocking monoclonal antibody, is a safe and effective treatment for moderate-to-severe atopic dermatitis (AD) [2]. Its efficacy against cutaneous lymphomas is controversial, and patients may experience worsening [3, 4] or improvement [5]. Here, we report a patient with MF, who responded to dupilumab, but later developed an ALCL. A 55-year-old male patient with a long history of AD since the age of four presented to our clinic in October 2019 due to exacerbation with generalized lichenified, excoriated lesions (figure 1A) that were refractory to topical treatments. His Dermatology Life Quality Index (DLQI) was 22/30 with severe pruritus. He had inactive hepatitis B and C infection and type 2 diabetes. A first (2019) skin biopsy showed a hyperplastic, acanthotic, papillomatous epidermis, parakeratotic stratum corneum and spongiosis, compatible with AD. Because of the co-morbidities and the low toxicity, we decided to introduce dupilumab, however, a new biopsy was taken on the first day of treatment. This second routine biopsy (2019), taken from the most infiltrated lesion, revealed atypical lymphocytic infiltrates within the dermis and epidermotropism with a CD3+, CD4+ (90%), CD7(100%) immunophenotype, consistent with MF (Annexe 1supplementary figure 1). High-throughput sequencing of the TCR beta (HTSTCRB) gene revealed the same dominant T-cell clone in two different skin biopsies. When we received the results and called the patient back to switch therapy, we observed a quick response with a significant reduction of pruritus and improved DLQI after a month. Almost complete remission was obtained after four months of treatment (figure 1B). After six months of dupilumab, the patient presented with painful reddish nodules on both palms, ulceration on the right side (figure 1C), and severe pain. A skin biopsy showed focal ischaemic necrosis in the epidermis, a dermal lymphocytic infiltrate with moderate density and large and medium lymphocytes and atypical nuclei, and discreet epidermotropism. An immunophenotypic study showed that the lymphocytic infiltrate was made of large-sized CD4+, CD30+ lymphocytes (>70%) (Annexe 1supplementary figure 1) and a minority of CD8+ lymphocytes, and granzyme B was expressed in 10% of cells. Anaplastic lymphoma kinase (Alk) was negative. HTS-TCRB revealed the same T-cell clone, which was found in the two previous biopsies. The LDH level was not elevated and systemic involvement was excluded by PET scan. After withdrawal of dupilumab, radiotherapy led to complete remission (figure 1D). However, the initial AD lesions rapidly recurred with superinfections necessitating systemic antibiotics. Considering the ALCL associated with MF, in complete remission, we decided to re-introduce dupilumab. The patient has now been free of AD and lymphoma lesions for six months. However, during the follow-up after one year, the patient developed new tumoural lesions on his neck, leading to treatment cessation. Co-existence of pcALCL and MF has previously been reported [6, 7]. Solitary ulcerated nodules, without signs of lymphomatoid papulosis, new appearance of the lesions on previously uninvolved skin, and predominance (>75%) or large clusters of CD30+ blastic cells favour the diagnosis of pcALCL [8, 9]. However, large cell transformation of the MF cannot be fully ruled out because of the discrete epidermotropism and a reddish infiltration surrounding the nodules. Importantly, our patient was treated with dupilumab before the nodules appeared. The role of dupilumab regarding this evolution is unclear. Dupilumab is used as treatment for AD as it inhibits the Th2 pathway [2]. On the other hand, blocking the IL-4/13 pathway exerts a negative effect on tumour cell growth [10]. This case highlights the phenotypic plasticity of cutaneous lymphomas. Although the association between mycosis fungoides and pcALCL is known, it remains to be elucidated whether dupilumab plays a role in the development of pcALCL. The two episodes of almost complete response point to a potent effect of dupilumab in certain cases of MF. However, because of the tumours and based on the contradictory findings from the literature, it should probably rather be used as an effective add-on treatment. Close follow-up of these patients is mandatory.