The Challenge of Treating Rare Skin Cancers: Mycosis Fungoides and Sezary Syndrome
In the realm of cancer treatment, advancements in therapy have greatly enhanced the effectiveness of anticancer drugs. In addition to cytotoxic drugs, targeted therapies and immune checkpoint inhibitors have emerged as fourth-generation anticancer drugs. However, the development of these treatments presents a parallel challenge to the prevalence of cancer itself: the treatment of rare diseases that affect only a small number of patients.
The Rarity of Mycosis Fungoides and Sezary Syndrome
Mycosis Fungoides (MF) and Sézary Syndrome (SS) are types of cutaneous T-cell lymphoma (CTCL) that specifically affect the skin. In the United States, approximately 70% of CTCL patients have mycosis fungoides, while only 1-3% suffer from Sézary syndrome. In Korea, mycosis fungoides, along with other skin cancers, accounts for 2.6% of all cancer cases, affecting about 100 people annually. While early-stage CTCL is usually asymptomatic, if left untreated, the skin lesions can progress rapidly and even metastasize to lymph nodes and internal organs, leading to aggressive lymphoma.
Sézary syndrome, although rare with a prevalence of 3%, presents more severe symptoms than mycosis fungoides. Patients with Sézary syndrome exhibit systemic erythema, enlarged lymph nodes, and the presence of malignant T lymphocytes called Sézary cells in their blood. While this disease is scarce in Korea, it carries a poor prognosis due to the aggressive nature of lymph node enlargement and liver and spleen invasion.
The Challenge of Diagnosis
Professor Seokjin Kim, a renowned hemato-oncology specialist at Samsung Hospital Seoul, explains that diagnosing mycosis fungoides can be challenging. The initial lesions may be asymptomatic, leading to frequent misdiagnoses of refractory contact dermatitis, atopic dermatitis, or psoriasis. Interestingly, mycosis fungoides gets its name from a French dermatologist who mistakenly believed it was a fungal disease with mushroom-like characteristics. However, it is actually a T-cell lymphoma that occurs in the skin, completely unrelated to fungal infections.
Despite its notoriety, the exact cause of mycosis fungoides remains unknown, making prevention methods elusive. It typically begins as variously shaped plaques that persist for several years. As malignant cells proliferate, the lesions become firm and progress to different forms, including plaques, nodules, erythroderma, or tumors. These skin manifestations can occur anywhere on the body, with a higher affinity for inconspicuous areas such as the breast, armpits, groin, and buttocks. Although studies have explored potential viral, bacterial, and environmental factors, no definitive causes have been identified.
The Importance of Early Detection and Treatment
Early detection is essential in effectively treating mycosis fungoides. Phototherapy and local treatments can yield positive outcomes when the disease is diagnosed promptly. However, a delayed diagnosis can lead to the need for chemotherapy or radiation treatment. Professor Kim emphasizes the significance of differentiating mycosis fungoides from common skin diseases through proper testing, as late-stage diagnosis significantly reduces the patient’s chances of survival. Unfortunately, late-stage treatments remain limited in Korea, with hematopoietic stem cell transplants being one of the few options, albeit with only a 30% success rate.
New Hope: Fortelgio
While treatment options have been scarce, a glimmer of hope has emerged for patients with mycosis fungoides and Sézary syndrome. The drug Fortelgio, which contains the active ingredient mogamulizumab, has shown promising results in addressing the unmet medical needs of these patients. Fortelgio is a humanized monoclonal antibody that targets CC chemokine receptor type 4 (CCR4), an antigen frequently expressed in malignant T-cell tumors. It enhances the body’s immune response, promoting anti-tumor effects in cells expressing CCR4.
Last year, Fortelgio gained approval from the Ministry of Food and Drug Safety in Korea, marking a significant advancement for patients in need. Although it is already approved and reimbursed in major countries such as the UK, Canada, France, Germany, the United States, and Japan, its reimbursement status in Korea is still pending. The drug has been recognized for its clinical utility and cost-effectiveness, passing validation at NICE in the UK and CADTH in Canada.
As we await the decision of the Serious Diseases (Cancer) Review Committee on reimbursement standards for Fortelgio, medical professionals urge patients to seek early diagnosis and appropriate treatment. While there is currently no known method for preventing mycosis fungoides, increasing awareness and understanding of this rare disease can contribute to earlier detection and improved outcomes.
The patient asks the care… Mycosis fungoides Sezary syndrome
The effectiveness of anticancer treatment is increasing with the advent of new treatments. Following cytotoxic anticancer drugs, targeted therapies have emerged, and immune checkpoint inhibitors and antibody drugs (ADCs), a fourth-generation anticancer drug, coexist in the current clinical treatment field. However, the development of such a treatment is unfortunately a story that parallels cancer with many patients. In the case of a rare disease with a small number of patients, it is not easy to find the disease and treat it.
① Skin cancer whose causes and prevention methods are also a mystery
‘Mycosis Fungoide (MF)’ and ‘Sézary Syndrome (SS)’ are types of cutaneous T-cell lymphoma (CTCL). CTCL refers to all T-cell lymphomas that occur in the skin. In the United States, approximately 70% of patients with CTCL have mycosis fungoides, and 1-3% are known as Sazari syndrome. According to data from the Central Cancer Registry in Korea, as of 2020, skin cancer including mycosis fungoides is 6,464 cases per year, accounting for 2.6% of all cancers, and is a rare disease that occurs in about 100 people a year in Korea. .
Early CTCL is usually asymptomatic (or slowly progressive), and most patients experience only skin symptoms without serious complications, but skin lesions can develop rapidly if the disease progresses over a long period of time. In addition, metastases to lymph nodes and internal organs can progress to aggressive lymphoma.
In particular, Sezary syndrome, which is rare with a specific gravity of about 3%, is a disease in which systemic erythema, enlarged lymph nodes, and malignant T lymphocytes, known as Sézary cells, are observed in the blood. It is very rare in Korea, but compared to mycosis fungoides, the prognosis is poor because of the aggressive course clinically due to enlarged lymph nodes and invasion of the liver and spleen.
Professor Seokjin Kim
Kim Seok-jin, professor of hemato-oncology at Samsung Hospital Seoul, said, “Mycosis fungoides is a rare non-Hodgkin’s lymphoma. The initial lesions may be asymptomatic, and some lesions resolve on their own, so you can think of them as eczema.” Even when symptoms do occur, many patients are often misdiagnosed with refractory contact dermatitis, atopic dermatitis, or psoriasis.”
In fact, mycosis fungoides was first diagnosed in the 1800s by a French dermatologist to mean a mushroom-like fungal disease. However, it is a T cell lymphoma that occurs in the skin which is completely different from mycosis, which is caused by a fungus.
Diagnosis is not easy, but the cause is unknown, so there is no proper prevention method. Mycosis fungoides develops plaques of various shapes and lasts for several years, and then, as malignant cells proliferate, the lesion becomes hard and progresses to various shapes of plaques, nodules, erythroderma, or tumors. It can occur anywhere on the skin, and round, arcuate, or atrophic lesions often occur in inconspicuous areas such as under the breast, armpit, groin and buttocks. Various viruses, bacteria, and environmental factors such as industrial chemicals and metals have been studied, but not proven. It is not known what causes it because the research ① that it is caused by genetic predisposition or radiation has not been supported.
If detected early, it can be adequately treated by phototherapy or local treatment, but if a long period of time passes without a proper diagnosis, it can deteriorate into a situation requiring chemotherapy or radiation treatment.
Professor Kim Seok-jin said, “Since the cause of the outbreaks has not been identified, there is no proper prevention method.” “There are patients who think about the possibility of other diseases and visit the hospital only when they think it is generalized dermatitis and they do not get better even after long treatment. So, the exact tissue Mycosis fungoides needs to be differentiated from common skin diseases through tests,” he said.
When the stage progresses due to failure to diagnose and treat early, that is, from stage 2B or above, the survival rate of patients drops sharply. Currently, there are not many late stage treatments in Korea. A hematopoietic stem cell transplant can be expected to improve, but is known to be only 30% effective.
‘Adcetri Inj (component brentuximab)’ as a drug is currently available for mycosis fungoides and Sezari syndrome, but it has been approved and benefits for some indications. Patients not included in the indication are in a situation where there is no suitable alternative drug. Amidst this, treatment was approved which would address unmet medical needs last year. ‘Forteligiio (ingredient: mogamulizumab)’ by Kyowa Kirin.
Fortelgio is a humanized monoclonal antibody that targets CC chemokine receptor type 4 (CCR4), which is frequently expressed in malignant T-cell tumor cells such as mycosis fungoides and Sezary syndrome. It is manufactured with a low fucose content through a powerful technology to enhance the ‘antibody cell-mediated cytotoxicity (ADCC)’ action, showing anti-tumor effects on malignant T cells expressing CCR4.
Fortelgio received product approval from the Ministry of Food and Drug Safety in September last year. It has been four years since it was approved by the US Food and Drug Administration (FDA) in 2018 as a treatment for incurable/recurrent mycosis fungoides or Sezary syndrome. At the time of FDA approval, it was listed as the first treatment for Sezari syndrome, and was also approved by the European Commission (EC) in the same year. Forteligiogio is in the process of being listed on the payroll in Korea.
In February, the Serious Diseases (Cancer) Review Committee, which is the first review portal for the reimbursement of anticancer drugs, did not set reimbursement standards, so we await the next meeting. It is already registered for reimbursement in major countries such as the UK, Canada, France, Germany, the United States, and Japan, and is being used by patients after passing validation of clinical utility and cost- effectiveness at NICE in the UK and CADTH in Canada.
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