Response to Pembrolizumab and Lenalidomide in Advanced Refractory Mycosis Fungoides

Primary cutaneous T-Cell lymphoma (CTCL) is a rare but heterogeneous group of extra-nodal lymphoproliferative disorders. Mycosis fungoides (MF) is the most common subset [1]. While prognosis in early-stage MF is excellent, patients who present with extensive skin involvement and/or nodal, visceral, or hematologic involvement with erythroderma >80%, commonly known as S ezary Syndrome (SS), have markedly worse survival [2]. Large cell-transformation of cutaneous disease or nodes and LDH have also been shown to be a poor prognostic markers [3,4]. While treatment of early-stage disease is comprised primarily of skin-directed therapies, advanced-stage disease requires the addition of systemic agents. Historically, this has included the use of retinoids or biologicals (interferon), chemotherapy, and radiation, with short duration of response and time to next treatment of less than 10 months [5]. Allogeneic stem cell transplantation has showed promise in delivering improvements in diseasefree survival, but it is associated with significant morbidity and mortality [6]. Thus, the recent focus has been in drug development for advanced disease, including HDAC inhibitors such as romidepsin, anti-CD30 antibodies like brentuximab vedotin, and the anti-CCR4 antibody mogamulizumab [7–11]. While responses to these drugs have been more durable [8], the need for novel combinations of agents remains. The role of immune-mediated therapy in the treatment of MF and CTCL is currently unclear. Progression from early to late-stage MF is characterized by loss of Th1 cytokine expression and antitumor immune response [12]. Lenalidomide is an immunomodulatory drug (IMiD) that upregulates the Th1 microenvironment and has been shown to have a modest 28% overall response rate (ORR) in a small phase II clinical trial of 22 patients with advanced, refractory mycosis fungoides/Sezary syndrome [13]. Notably, all were partial responses with median progression free survival of eight months and no grade 4 toxicities. Similarly, early trials with PD-1 inhibitors nivolumab and pembrolizumab as single agents in relapsed/ refractory disease have been promising. In a phase 1B trial of nivolumab in advanced, refractory hematologic malignancies, 13 patients with mycosis fungoides were treated with two PRs documented and median progression free survival of 10 weeks [14]. Single-agent pembrolizumab was evaluated in a phase 2 trial of 24 patients with advanced disease who failed a median of four prior lines of systemic therapy with ORR of 38% including one complete response. Responses were noted to be durable with 89% ongoing at 32 weeks [15]. IMiDs are hypothesized to act synergistically with PD-1 inhibition through several mechanisms. In addition to direct proapoptotic and antiangiogenic effects, IMiDs modify the tumor microenvironment by increasing inflammatory cytokines interferon-gamma and interleukin-2 [16–18]. In conjunction with downstream activation of the B7-CD28 costimulatory pathway, IMiDs functionally enhance cytotoxic T-cell and NK-cell activity [17,19]. When compared to pretreatment samples, biopsies from MF patients treated with lenalidomide demonstrate increased CD8þ expression [13]. To our knowledge, the combination of an IMiD with PD-1 inhibitor has not been previously reported in CTCL. Here we present a case of refractory MF with large cell transformation treated with pembrolizumab and lenalidomide inducing a near-complete response with minimal toxicity A 40-year-old male presented to MD Anderson Cancer Center in December 2015 with a life-long history of ichthyosis and a 3-year history of disseminated psoriasiform skin lesions. Biopsy of a scaly plaque in 2012 showed chronic dermatitis with psoriasiform epidermal changes. He had been treated for suspected psoriasis with oral methotrexate, cyclosporine, and ustekinumab without benefit. Repeat biopsy in 2015 showed atypical epidermotropic and dermal lymphoid infiltrates composed of small cerebriform cells consistent with mycosis fungoides. Upon initial presentation, he had advanced disease, and was unable to ambulate secondary to severe pain from denuded, ulcerated, and erythematous skin of the face, neck, torso, and limb covering 60% of the body surface area. Additional skin biopsies of tumorous lesions confirmed a CD3þ, CD4±, CD7 , CD8 , TCR-Beta T-cell