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Cutaneous T-cell Lymphoma (CTCL) is a rare group of extra-nodal non-Hodgkin lymphomas, arising primarily in the skin and comprising roughly 75 percent of the primary cutaneous lymphomas. Many genetic and immunologic abnormalities occur in the tumorigenesis of this group of skin diseases, manifesting clinically as a heterogenous group of skin lesions that can be difficult for dermatologists to diagnose. Roughly 50 percent of CTCL is mycosis fungoides, which classically arises in the sun-protected areas, such as the lower trunk, and can evolve from a macular/patch stage into plaque stage and ultimately tumor stage in older patients with an average age of onset ranging from 55 to 60 years. Further, it seems to have a predilection for male sex and has an incidence of approximately 0.5 per 100,000, occasionally occurring in the juvenile population, especially as a hypopigmented variant in African Americans.

The early stages of mycosis fungoides are typically indolent, with the later and more advanced stages (beginning typically with tumor stage IIB) showing compromised survival. The erythrodermic and leukemic counterpart to mycosis fungoides, which is thought to arise from a different subset of malignant clones, known as Sezary Syndrome, also portends a poor prognosis.

Clinical diagnosis is difficult even for experienced dermatologists both in academics and in community private practices for several reasons. Just like the notorious eruption of secondary syphilis, mycosis fungoides has been called a “great mimicker,” as in its early stages it can appear like psoriasiform or eczematous benign disease. In many instances, patients will have been treated topically or even with systemic agents, such as TNF-a inhibitors, that can render serial biopsies of these lesions spuriously unrepresentative of the true pathology. Further, because the initial stages of mycosis fungoides are usually indolent without quick progression, biopsies obtained early in the course of the disease may not show observable numbers of characteristic atypical lymphocytes. To complicate the matter, atypical lymphocytes can be seen in non-malignant lymphocytic processes such as lymphomatoid drug reactions.

All of these factors can make this process very frustrating for both patients and dermatologists, especially as many of these patients have likely been treated empirically by a nondermatologic provider at some point prior to presentation to the dermatology clinic. Ideally, the dermatologist will synthesize the clinical, histological, and immunophenotypic data to provide an accurate diagnosis of CTCL. This can be supplemented with T-cell receptor gene rearrangement studies.1-4The delay in diagnosis has been reported in one study as a mean of 55 months,5 with some studies showing average ranges from four to six years.6-8

The prognosis for mycosis fungoides has been shown to be similar in age, sex, and race-matched controls. In one study of 309 patients, it has been described as having a 96 percent 10-year survival rate for the limited patch and plaque stage, followed by 83 percent for the generalized patch and plaque stages. Tumor stage, however, even without nodal involvement, was shown to have a forty-three percent ten-year survival rate.4

The only treatment that has been shown to be curative is allogeneic hematopoietic stem cell transplantation once mycosis fungoides advances into late stage disease. The therapeutic ladder starts with topical agents, such as corticosteroids, retinoids, and nitrogen mustard, with or without a variety of phototherapeutic agents for early disease stages. These phototherapies include narrow-band UVB light treatments or UVA light with sensitizing psoralen agents (PUVA), which can be stepped up to modalities such as extracorporeal photopheresis.9 Radiotherapy is also usually indicated somewhere along the spectrum of IA to IIA, depending on the clinical presentation (e.g., solitary patch versus thick, generalized plaques) and can include single, focused, local radiation therapy to total skin electron beam radiotherapy. All of the above modalities depend upon the treatment facility and what they have available.

The standard of care in many communities, depending upon availability and access, is referral once diagnosed to a dedicated CTCL clinic, which may be at an academic center, as treatments such as extracorporeal photopheresis are not available nor practical in most single specialty dermatology private practices. Systemic treatment for mycosis fungoides is indicated when the lesions are tumors, or stage IIB, usually beginning with an oral retinoid such as bexarotene. Systemic therapy can be stepped up a treatment ladder all the way to highly toxic multi-chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). Other options include histone de-acetylase inhibitors, immune modulators (e.g., denileukin difitox), and interferon. 4 Here arises the second half of the challenge dermatologists face regarding mycosis fungoides, which is how to treat.

Response to systemic therapies varies and is associated with worsening treatment response as the disease progresses. By the time toxic chemotherapy regimens such as CHOP are employed, the patient has usually failed other systemic agents, is beyond the reach of topical and phototherapeutic options, and already has nodal and/or visceral involvement. Response to six-cycle administration of CHOP, especially when combined with other treatments, has been shown to be effective and elicit responses; however, they are usually short-lived. At higher disease stages, risks of medication toxicity must be weighed against their treatment response benefit. Novel therapies with more specific targeting and less robust side effects, as well as more adequate and durable treatment responses, are thus needed.

For many diseases in dermatology, biologic therapies, such as the monoclonal antibodies, have enabled more specific targeting and less robust side effects, as well as more adequate and durable treatment responses. But what exactly would be targeted in MF that has not responded to other systemic agents, let alone Sezary Syndrome? As MF is thought to arise from effector CD4+ memory T-cells, which become skin-homing and epidermotropic, clonal, and malignant, losing their Th1 phenotype in favor of Th2 phenotype, this is one area of interest. As Th2 cells predominate in the infiltrate, their cytokine and interleukin profile, particularly Il-4, 5, and 10, blunt an antitumor Th1 response. CD8+ cytotoxic T-cells are depleted proportionally with malignant progression. As the neoplastic cells predominate locally and Th2 phenotype is overexpressed, cell surface antigens such as C-C Chemokine Receptor 4 (CCR4) is overexpressed. These moieties provide tumorigenic properties to cells but also provide potential targeting for new antibody therapies.10-12

CCR4, expressed on Th2 cells and functional regulatory T-cells, has known ligands macrophage-activated chemokine and thymus-and-activation-regulated chemokine. CCR4 is demonstrated in approximately 40 percent of patients with CTCL and peripheral T-cell lymphoma. The interaction between CCR4 and its ligands may be involved in malignant T-cell trafficking and distant organ involvement and, in certain T-cell neoplasms (e.g., adult T-cell leukemia/lymphoma), the extent of expression of CCR4 by malignant T-cells is related to the degree of skin involvement.10,11 Prior to targeting of the CCR4, several antibody options existed for treatment of CTCL. For example, alemtuzumab, a humanized IgG1 kappa monoclonal antibody against CD52, which is expressed by most B and T lymphocytes, previously showed substantial remissions in patients with Sezary Syndrome. However, high-dose treatment can lead to immune suppression, cytopenias, and significant opportunistic infections. Brentuximab, an anti-CD30 monoclonal antibody conjugated to monoethyl auristatin E, a cytotoxic anti-tubulin agent, represents one of the newer agents for advanced stage MF, SS, and primary CD30+ lymphoproliferative disorders.12

A more recent development is mogamulizumab, a defucosylated antibody, meaning a fucose carbohydrate group is removed and the antibody is rendered much more effective in eliciting an antibody-dependent cytotoxic cellular response. It does so by two mechanisms. The first is binding of the CCR4 receptor on the functional regulatory T-cells, which prohibits inhibition of cytotoxic T-cells. In doing so, they allow the second arm of their proposed mechanism to be carried out, which is binding the CCR4 of malignant T-cells, with the Fc antibody portion then being joined with the Fc receptor of an effector cell. This effector cell subsequently releases intracellular perforins, granzymes, and TNF granules, leading to lysis of the neoplastic T-cells.11-13

In 2009, a Phase 1/Phase 2 clinical trial in the US assessed the safety and efficacy of mogamulizumab. Forty-one patients were enrolled; 22 had MF, and 19 had Sezary Syndrome. All subjects were 18 or older, with histologically confirmed CTCL. Additionally, they previously failed one or more systemic therapies (that had not been administered in at least four weeks) and had adequate renal and hepatic function. Of these patients, 26 had stage IV disease.14 In the Phase 1 dose-escalation phase, although there have been reports of hepatitis B reactivation and toxic epidermal necrolysis associated with mogamulizumab,15,16 no dose-limiting toxicity was reached, nor was a maximum dose reached. Patients were escalated on doses of 0.1mg/kg IV infusion weekly for four weeks to 0.3mg/kg and finally 1mg/kg in the same manner, with a two-week break in between.

In the Phase 2 preliminary efficacy determination phase, patients were dosed with 1.0mg/kg according to the same schedule for the course followed by infusion every two weeks until disease progression. Because of the relatively long clinical course of CTCL, controlled clinical trials have typically used response rates, rather than time-based end points, to evaluate the potential benefit of novel therapies. The overall response rate was 36.8 percent: 47.1 percent in Sezary Syndrome and 28.6 percent in MF. Eighteen of 19 (94.7 percent) patients with B1-staging blood involvement had a response in blood, including 11 complete responses. Overall response rate comprised complete response, partial response, and stable disease. The medication was well-tolerated with no grade four or five symptoms. The majority of symptoms were pyrexia, chills, nausea, vomiting, skin eruption, infusion reaction, headache, and fatigue. No life-threatening infections were reported. This clinical trial was completed in 2012; these promising results led to Phase 3.14

The MAVORIC trial included 372 patients with histologically confirmed stage IB to IVB MF or Sezary Syndrome who failed one or more systemic therapies. It was designed to assess the primary endpoint of progression-free survival between mogamulizumab and the histone-deacetylase inhibitor vorinostat. Patients were evenly randomized to 1.0mg/ kg of mogamulizumab weekly for the first four-week cycle and then every two weeks, or vorinostat at 400mg daily. Independent review showed progression free survival was 6.7 months versus 3.8 months. The overall response rate (ORR) was 28 percent with mogamulizumab versus 4.8 percent with vorinostat (p<0.0001). Mogamulizumab also improved ORR in patients with stage III disease at 22.7 percent versus 0 and stage IV disease at 36 percent versus 3.1 percent. Among patients assigned to vorinostat who crossed over to mogamulizumab, the ORR was 30.1 percent. Numbers reported in the study boasted double the effect of mogamulizumab versus vorinostat; results generated by independent reviewers still show tremendous efficacy in the mogamulizumab treatment for advanced stage MF/Sezary Syndrome and superiority in outcomes. As a result of the MAVORIC trial, the FDA approved mogamulizumab in 2018 for the treatment of MF/ Sezary Syndrome who failed one or more systemic therapies.17

There is no ideal treatment for advanced MF or Sezary Syndrome, as the available therapies for progressed disease have significant toxicity with variable treatment response. The only known cure is allogeneic hematopoietic stem cell transplant, which is typically a treatment for young patients and has limited data. There are few options for an older population of patients. Disconcerting is the morbidity reflected in these patients, who suffer dysesthesia, discomfort, internal pain, unbearable pruritus, as well as stigma and embarrassment from the physical appearance that can accompany advanced disease, especially generalized tumor stage and ichthyotic and erythrodermic Sezary Syndrome. This is the opinion of patients treated and interviewed who trudged a four- to six-year average duration of time from symptom onset to diagnosis with little relief. There has historically been a paucity of relatively safe options because of the intricate cytologic, immunologic, and histologic changes that manifest themselves clinically as described. Fortunately, we practice in an age when these intricacies may be used as targets, and medications such as mogamulizumab have been shown to benefit patients with advanced stage disease with a more favorable side effect profile. There is promise for future targeted therapy development. More durable responses are desired, and cell-cycle/checkpoint inhibitors are now being investigated. Treatment for CTCL is now headed in a direction of safer alternatives to the traditional toxic chemotherapy regimens when topical, phototherapeutic, and radiation therapies fail altogether.

The authors have no conflicts of interest to report.

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2. Willemze R, Hodak E, Zinzani PL, Specht L, Ladetto M. Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 29 (2018): iv30–iv40.

3. Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors.” Blood 116.5 (2010): 767-771.

4. Wellinze, R. Mycosis Fungoides. Jean Bolognia et al. Dermatology. 2019-2034 vols. Elsevier, 2018.

5. Amorim GM, Neimeyer-Corbellini JP, Quintella DC, Cuzzi T, Ramos-e-Silva M. Clinical and epidemiological profile of patients with early stage mycosis fungoides. Anais Brasileiros de Dermatologia 93.4 (2018): 546-552.

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7. Skov AG, Gniadecki R. Delay in the histopathological diagnosis of mycosis fungoides. Acta Dermato-Venereologica 95 (n.d.): 472-475.

8. van Doorn R, Van Haselen CW, van Voorst Vader PC, Geerts ML, Heule F, de Rie M, et al. Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients. Archives of Dermatology 136 (2000): 504-510.

9. Trautinger, F. Phototherapy of mycosis fungoides. Photodermatology, Photoimmunology, & Photomedicine 27.2 (2011): 68-74.

10. Pease, J. CCR4 Chemokine Receptor. XPharm: The Comprehensive Pharmacology Reference. 2007. 1-8.

11. Ohyama, Y, et al. Induction of molecular remission by using anti-cc-chemokine receptor 4 (anti-ccr4) antibodies for adult T-cell leukemia: a risk of opportunistic infection after treatment with anti-ccr4 antibodies. Annals of Hematology 93 (2013): 169-171.

12. Welborn M, Duvic M. Antibody-based therapies for Cutaneous T-Cell Lymphoma. American Journal of Clinical Dermatology 20.1 (2018): 115-122.

13. Duvic M et al. Mogamulizumab for the treatment of cutaneousT-cell lymphoma: recent advances and clinical potential. Therapeutic Advances in Hematology 7.3 (2016): 171-174.

14. Duvic M, et al. Phase 1/2 study of mogamulizumab, a defucosylated anti-ccr4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood 125 (2015): 1883-1889.

15. Nakno N et al. Reactivation of hepatitis B virus in a patient with adult T-cell leukemia-lymphoma receiving the anti-cc chemokine receptor 4 . Hepatology Research 44 (2013): 354-357.

16. Shiratori S et al. Late onset toxic epidermolysis induced by mogamulizumab, an atni-cc chemokine receptor 4 antibody for the treatment of adult t-cell leukaemia/lymphoma. Hematological Oncology 35 (2015): 138-140.

17. Kim Y et al. 459 anti-ccr4 monoclonal antibody, mogamulizumab (moga), demonstrates superior efficacy compared to vorinostat (vor) in patients with previously treated cutaneous t-cell lymphoma (ctcl): results of the phase 3 MAVORIC study.” Journal of Investigative Dermatology 138 (2018).

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