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Stefan K. Barta, MD, MS, discusses the CTCL subtype mycosis fungoides, common adverse effects, and optimal treatment approaches.
The management of adverse effects (AEs) and multidisciplinary approaches are critical in driving long-term remissions and maintaining treatment adherence for patients with myosis fungoides (MF), a cutaneous T-cell lymphoma (CTCL) subtype, according to Stefan K. Barta, MD, MS.1,2
In an interview with OncLive®, Barta discussed MF and similar CTCLs like Sezary syndrome (SS), specifically highlighting how working in tandem with other health care professionals like dermatologists and radiation oncologists is crucial for medical oncologists to ensure the best treatment for patients. Barta also overviewed the several approved treatment options for MF such as mogamulizumab-kpkc (Poteligeo), which patients are best suited for given treatments, and important general safety considerations for MF.
Barta is the director of the T-cell lymphoma program, executive officer of the AIDS Malignancy Consortium, and associate professor of medicine at the University of Pennsylvania Medicine in Philadelphia.
Barta: MF is the largest subgroup of CTCLs. About 50% to 60% of all CTCLs constitute MF and its counterpart, SS. The 2 are often mentioned together, so you often hear MF/SS. The way they're differentiated is mainly by 2 features that in SS, we have significantly more blood involvement. These are Sezary cells we measure in the blood, and if they're more than 1000, that gives us a B2 classification—that is how you move from MF to SS, in addition to also fulfilling other criteria. The main criteria for that is erythroderma, which means that the entire skin is usually inflamed and red.
We have other cutaneous lymphomas and cutaneous B-cell lymphomas, which we're not focusing on, that are a little more common. These include primary cutaneous marginal cell lymphoma and follicular central lymphoma. Another condition that can mimic MF is called lymphomatoid papulosis, which is a lymphoproliferative disease.
The way we differentiate MF and SS from other skin diseases is by the clinical appearance. Patients often present with an itchy or pruritic rash that can often look like other skin conditions, particularly eczema or atopic dermatitis, and it often takes a long time to get the diagnosis right.
Several biopsies are often needed, which is the next point of how we confirm a diagnosis. [MF and SS] do need a skin biopsy, and often, because features can be difficult to distinguish, even for the dermatopathologist, several biopsies are needed. On the biopsies, we do see specific features. We see infiltration of the epidermis with these abnormal T-cells. They're usually CD4-positive, [which] is a marker that tells us how the T-cells look and how we can tell them apart. We also often send off T-cell receptor rearrangement to see whether these cells are clonal or not. Additionally, we see whether there is loss of certain features, such as loss of CD7 for example. There is a score that has been developed with points and based on the clinical and pathological appearance. For example, the rash often prefers areas that are not commonly exposed to sun, like an old-fashioned bathing suit trunk, [in terms of] distribution [of the rash] ,and then for the features on biopsy that usually make up then the diagnosis in patients with MF. In SS, we commonly find significant blood involvement.
Whenever I speak to my patients about their diagnosis, what I say is that this is a multi-compartment disease. The compartments that are affected are the skin, but it can also be the blood, lymph nodes, and even internal organs such as the liver or lung. Based on that, we do approach each compartment slightly differently, and at different stages of the disease, it becomes more important to treat 1 compartment than another, and that's where a multidisciplinary input comes in. For example, in early-stage MF, that's usually just limited to the skin.
Skin-directed therapies are important, and they can be topical creams or ointments. It could also be light therapy, and [these therapies] get directed by the dermatologist. It could also include radiation. For example, for lesions that just don't respond to certain therapies, we need to get a fast response or if they're larger lesions or tumors, this is where the radiation oncologist comes in. For therapies that treat not only the skin but also have effect on other parts of the body, like the blood and lymph nodes, this is usually where the medical oncologist comes in. Even at times when systemic therapies are given, the skin therapy and dermatology involvement is still extremely important. Specifically, some therapies can cause rashes. It's always very important that all 3 disciplines talk to each other, although 1 may take the lead at any given time depending on stage of the disease.
Initially, staging is important to assess how much of every compartment is affected, and we use something called the TNMB staging. T stands for tumor, but it means the skin. We assess the skin by how much body surface is involved. We also assess how thick, for example, the skin involvement is. We [could possibly observe] patches that are flat, plaques that are much more thickened, and tumors.
The nodal assessment (“N”) and assessment of internal organs (“M”) is usually done by imaging. Oftentimes we use PET scans of the whole body, but sometimes [we] also [perform] CAT scans. Sometimes we need to do biopsies to confirm whether the nodes are just enlarged because they react to inflammation that happens in the skin or if there's involvement by the lymphoma itself. For blood involvement (“B”), we [evaluate] the peripheral blood by flow cytometry to see if we can quantify.
[Following the initial staging,] we always restage and do the same assessment again when patients get therapies to assess response to therapy or if we feel the patient’s disease is not responding as well to therapy. [Indicators of poor responses to therapies could be] that the lesions get worse, the itching gets worse, there's a new tumor, we find a lymph node that is now abnormal on the exam, or blood flow cytometry shows an increased involvement with Sezary cells.
I focus mainly on the intravenous therapies that we are in charge of as oncologists. Often, the initial systemic treatments can be oral therapies such as vitamin A derivatives like bexarotene or isotretinoin. Methotrexate is another drug that is given orally. Interferons are something we use to stimulate the immune system, and they're given subcutaneously. These are treatment options we often start off with, but later, they may not be enough or control the disease as much, [then when we refer to] intravenous therapies, of which we have several.
One concept I always try to discuss with a patient is: unfortunately, [MF] is a disease that we usually cannot cure with standard therapies, although stem cell transplant can cure MF/SS in some patient, however, we can manage. So MF/SS it's a manageable and a very treatable disease. We don't want to give patients intensive therapy that while they may have a quick response, these often do not last that long and come at the price of increased AEs or toxicity. [Thus,] usually we try to use single agent, meaning 1 agent at a time.
The response rates of each agent are unfortunately not 100%. [Thus,] not everybody responds to each therapy. We try to pick the best therapy based on the patient's history, the physical exam, and [other factors], because treatments work differently in different compartments and patients also have preferences. For example, a drug like mogamulizumab works best in patients who have blood involvement, and it works very well for SS, where there's a lot of blood involvement. [Mogamulizumab] helps most patients control blood involvement and often even get rid of it for a time, putting patients in a remission in the blood. [Mogamulizumab] does not work as well in the skin as in the blood, but it still can work relatively well and similarly well in the lymph node. We prefer it for patients who have blood involvement, but there are circumstances where we give it even to patients who don't have a lot or any blood involvement, just because it's a well-tolerated therapy that does not suppress the immune system.
It's very important to keep the immune system healthy because a lot of patients with CTCLs or other lymphomas get infections, and we don't want to weaken the immune system further. Sometimes we add on therapies that we feel are synergistic without adding a lot of AEs. Often, interferons or retinoids [are combined with] radiation or photopheresis, which is another therapy that is stimulating the immune system to help fight the lymphoma. [Additionally, we can tweak photopheresis], for example, to help increase the response in the skin or in the lymph nodes.
We have other drugs that can work well. Brentuximab vedotin [Adcetris] is an antibody-drug conjugate that targets a protein that we find on many of the MF cells called CD30. Although, the tests we have to determine whether CD30 is present are not that great, and expression of that protein at different sites of skin disease in a patient can be different, [thus] we even use it in patients who have very little CD30 expression or even no CD30 expression on a biopsy, and we do see responses.
We [also] have the HDAC inhibitors. [HDAC inhibitors] are a whole class of drugs that are called epigenetic therapies that modulate the way the DNA is read in the cancer cells and activate tumor suppressor genes to help control the cancer. There's an IV formulation [HDAC inhibitors], romidepsin [Istodax], and an oral formulation that's called vorinostat [Zolinza], that are approved for MF/SS. Pralatrexate, which is a chemotherapy, we give it at low doses so it's well tolerated. These are the FDA-approved agents, but we have others available that we use that work in other T-cell lymphomas. Ultimately, chemotherapy is always an option; sometimes we use single agent chemotherapy drugs like gemcitabine or liposomal doxorubicin. [Considering all these options,] we are usually able to manage the disease and control the symptoms [of MF].
The main treatment that causes a rash is mogamulizumab, and it even has a name, it's called mogamulizumab-associated rash [MAR]. MAR usually occurs in about 30 to 40% of patients who get the single agent, and if we combine it with other drugs that stimulate the immune system, [this rate] may be a little higher. When patients get a rash, it's actually not necessarily a bad thing, since it might indicate a good immune system that helps fight the disease. It seems there is data suggesting that responses to the drug are better in patients who develop the rash, but it can be difficult to tell rash and MF/SS apart, because on physical exam, [rashes and new lesions] can often look the same.
There are some features [to look for]; for example, rashes occurring in the head and neck that seem to be a particular location for MAR, and it can sometimes appear nodular. MAR can be photosensitive; it can look like granulomas. Usually, a biopsy is required, and in that biopsy, we then see mainly an increased ratio of CD8 to CD4 cells.
[T-cell receptor arrangements] are like a barcode for the cutaneous lymphoma, and if we see that the T-cells that are in the rash don't have that barcode, then we are fairly confident that this is MAR. There can be a little bit of the disease still left, which makes [diagnosing the rash] somewhat more complicated, and in general it takes a discussion with the dermatologist and a biopsy to be certain. Usually, the [mogamulizumab-associated] rash is manageable with topical steroids, treatment interruptions, spacing out the treatment, and maybe in some cases, adding on other drugs, like methotrexate, to help control the rash. The rash also is usually not itchy. Itchiness or pruritus is a common feature in MF, and [MAR] is often not itchy.
Most therapies that we have available result in a reduction of the disease burden, meaning [reductions in] how much of the skin is involved, how angry the skin is, how bad the itching is. [However,] in most patients, we are not able to get them into a complete response. The effectiveness of single-agent therapies is something we still have to work on.
Biomarkers for response is something [else] that would be important. For example, if we have blood involvement, we know mogamulizumab works better, or if we have strong CD30 expression, we can assume that brentuximab [Adcetris], for example, works better.
If we have agents that have less AEs, we can combine drugs where we don't feel AEs increase, but we do get improved efficacy. [We are looking for treatments] that work together synergistically, that help each other, where 1 plus 1 isn't 2, but it's 4. These are combinations we need to work on. I'm glad to see, though, that there have been several [drug] approvals for this rare disease in the last few years, and there are studies going on with new agents that target new targets. Hopefully, we'll continue to make progress even within the next 5 to 10 years.
