Cutaneous T cell lymphomas (CTCLs) not only are largely incurable but also make patients miserable with itching, burning skin and unsightly lesions. Because CTCL can resemble various benign skin conditions, many patients are diagnosed at an advanced and difficult-to-treat stage. But ongoing clinical trials may offer patients with CTCL improved treatments and better quality of life.
“Most cancer patients have disease on the inside, but CTCL is a disease that patients wear every day,” said Madeleine Duvic, M.D., a professor in the Department of Dermatology at The University of Texas MD Anderson Cancer Center. “It’s also a disease with many clinical facets, and its diagnosis and treatment require collaboration among dermatologists, medical oncologists, and radiation oncologists.”
A difficult diagnosis
CTCL comprises a heterogeneous group of non-Hodgkin lymphomas categorized by clinical findings and T cell markers. The most common forms of CTCL are mycosis fungoides and its leukemic variant, Sézary syndrome; other forms include anaplastic large T cell lymphoma and subcutaneous panniculitis-like T cell lymphoma.
With early diagnosis and treatment, these diseases can be put into long-term remission and prevented from becoming incurable or uncontrollable. “Patients whose disease is caught and treated early can be in complete remission for years and never get worse,” Dr. Duvic said. “Unfortunately, just diagnosing CTCL is difficult, and it requires expertise in immunopathology and understanding of T cell markers.”
One of the main challenges in diagnosing CTCL is the cancer’s resemblance to other skin diseases. In many cases, lesions that appear to be benign may in fact be malignant. Mycosis fungoides, which usually starts as patches and plaques on unexposed areas, is often initially misdiagnosed as psoriasis or eczema, and patients often undergo multiple biopsies before the disease is correctly identified. Sézary syndrome, too, can be erythrodermic and often mistaken for psoriasis or eczema. This is problematic because many of the antipsoriatic agents used to treat psoriasis or eczema are very immunosuppressive and can exacerbate Sézary syndrome or promote opportunistic infections.
Therefore, Dr. Duvic said, CTCL should be suspected in patients whose lesions resemble psoriasis or eczema but do not respond to treatment or occur in sun-shielded regions of the skin. When CTCL is suspected, a biopsy of the involved sites—if 1 month has passed since treatment with topical steroids, which rid the skin of lymphocytes—should be performed to make the correct diagnosis. In addition, full skin examinations are essential to detecting mycosis fungoides when the disease is suspected, as it tends to develop on unexposed areas. Finally, flow cytometry of a blood sample can detect atypical T cells indicative of CTCL.
In other cases, lesions that appear to be malignant may in fact be benign. For example, the benign form of CD30-positive anaplastic large T cell lymphoma, lymphomatoid papulosis, appears as a solitary papule that usually resolves without intervention in 3–4 months. But the malignant form of the disease can be associated with Hodgkin disease, mycosis fungoides, or cutaneous anaplastic large T cell lymphoma. A solitary lesion resembling lymphomatoid papulosis typically is removed surgically for biopsy; however, the benign and malignant forms appear identical on biopsy. Therefore, the differential diagnosis is a clinical one, and aggressive cancer treatment is withheld unless further lesions appear to confirm malignancy.
The correct diagnosis of CTCL is essential to effectively treating the disease, as treatments vary according to the type and extent of the disease. For patients with mycosis fungoides or Sézary syndrome, treatment depends on the disease stage and consists of skin-directed therapy, including radiation therapy, with or without systemic therapy.
Treatment by disease characteristics
For patients with early-stage mycosis fungoides involving 10% or less of the body, the primary treatment is topical steroids, which have response rates of around 70%, with or without phototherapy. For patients with more than 10% skin involvement, topical steroids may be combined with more intensive phototherapy in the form of narrowband ultraviolet B radiation or with psoralen plus ultraviolet A radiation. Retinoids such as the vitamin A derivative bexarotene, which may be administered topically or orally, and/or topical chemotherapy with nitrogen mustard may also be used in these patients.
Patients with refractory mycosis fungoides involving more than 10% of the skin may require additional systemic therapy. Such patients may receive oral retinoids such as bexarotene or acitretin with or without interferon-alpha or interferon-gamma. Histone deacetylase (HDAC) inhibitors, such as oral vorinostat or intravenous romidepsin, may also be used to help manage refractory mycosis fungoides or anaplastic large T cell lymphoma. Although only about 30% of CTCL patients have even a partial response to HDAC inhibitors, these agents do reduce itching, a major issue in these patients.
First-line systemic therapy for Sézary syndrome, a disease characterized by Sézary T lymphocytes in the blood, includes photopheresis plus interferon or bexarotene. In photopheresis, T lymphocytes collected from the patient’s peripheral blood are exposed to a photosensitizing agent and then ultraviolet light to damage their DNA. Once reintroduced into the patient, the photochemically damaged abnormal cells are taken up by macrophages, which then trigger an immune response against the disease. Sézary syndrome patients may also receive sequential single-agent chemotherapy.
Combination chemotherapy, which is generally not used in patients with mycosis fungoides, may be used in those with Sézary syndrome or anaplastic large T cell lymphoma. “We usually don’t use combination chemotherapy for any type of CTCL unless patients have visceral or bulky nodal disease or single-agent therapy has failed,” Dr. Duvic said. “When CTCL patients get multiple chemotherapy agents, they get further and further along the pathway of immunosuppression, and they may die of opportunistic infections.”
Stem cell transplant is also an option for patients with Sézary syndrome. “We’ve found that if Sézary syndrome is diagnosed early enough, before patients’ immune systems are totally gone, you can treat them with electron-beam radiation to get rid of the lymphoma cells in the skin and then replace their bone marrow with allogeneic stem cells,” said Dr. Duvic, who estimates that about 50% of Sézary syndrome patients who undergo the procedure are cured.
The role of radiation therapy
Radiation therapy, a mainstay of CTCL treatment, can be used alone or in conjunction with other skin-directed therapies and/or systemic treatments. Electron-beam radiation is typically used. Unlike photons, which release their maximum energy several centimeters deep in the body and thus may expose internal organs to the radiation dose, electrons release most of their energy near the surface to treat the skin while avoiding damage to internal organs.
Whether radiation is given locally or bodywide in the form of total skin electron-beam therapy (TSEBT) depends on the extent of the disease. If the disease involves less than 40% of the skin, local radiation therapy typically is used; if 40% or more of the skin is involved, TSEBT may be used. Thus, TSEBT is often used for palliative therapy in Sézary syndrome patients whose disease extent precludes local radiation therapy.
“In general, patients with Sézary syndrome have very extensive disease, and a higher dose of TSEBT—usually 32 Gy—has to be used to give them relief,” said Bouthaina Dabaja, M.D., an associate professor in the Department of Radiation Oncology.
Likewise, a sizeable dose of radiation, 24–32 Gy in the form of TSEBT, is given to CTCL patients who will undergo stem cell transplantation. “When a patient is undergoing stem cell transplantation, we give radiation to reduce the burden of skin disease to as little as possible prior to the transplant,” Dr. Dabaja said. “This makes the donor stem cells’ job easier. Their major role is not necessarily to kill actual cancer cells as much as it is to prevent new cancer cells from forming.”
Although highly effective against CTCL, radiation therapy must be used judiciously because of its adverse effects. “Your skin never forgets the radiation that you get,” Dr. Dabaja said. “The more radiation a person receives, the more side effects he or she will experience. Eventually, the fat under the skin is depleted, and the skin becomes leathery and cannot heal after wounds, infections, or additional tumors.”
Therefore, Dr. Dabaja and others are working to increase the effectiveness of radiation therapy while reducing its side effects in CTCL patients. In a recent International Lymphoma Radiation Oncology Group study, the researchers showed that a high proportion of CD30-positive anaplastic large T cell lymphoma patients achieved complete remission regardless of the radiation dose. As a result of this and other studies, radiation doses for treating many types of CTCL have dropped dramatically. For example, at MD Anderson, 12 Gy is now the most common dose given to patients with mycosis fungoides, whereas patients with the disease once received 32–36 Gy. Similarly, Dr. Dabaja said, doses as low as 6 Gy can achieve complete remission in patients with cutaneous CD30-positive anaplastic large T cell lymphoma, a disease once commonly treated with 45 Gy.
The main takeaway from the recent studies, Dr. Dabaja said, is to always use the smallest radiation dose possible in CTCL patients. “If their disease responds to that dose, they’re done. Their disease is extremely sensitive to radiation; giving them a higher dose would only result in more toxicity with no benefit,” she said. “If their disease doesn’t respond to the lower dose, we can always give more.”
However, Dr. Dabaja also cautioned against giving additional radiation in the absence of an immediate response. “We can’t panic if we don’t see an immediate response,” she said. “And we can’t be afraid to ease the patient into the therapy by giving a lower dose at 4 Gy or 8 Gy and then watching and waiting. In 4–6 weeks, those lesions are likely going to heal.”
Just as research has led to changes in radiation therapy, several new systemic agents for the treatment of CTCL are already in or moving toward clinical trials, Dr. Duvic said.
Among these new agents, targeted antibodies represent one of the most exciting areas of development. For example, the humanized monoclonal antibody mogamulizumab, which targets the chemokine receptor CCR4 (a molecule that recruits T cells to the skin), has shown great promise for the treatment of Sézary syndrome. In a phase I/II trial, the agent elicited a response rate of 47% in Sézary syndrome patients, with some having a response that lasted years.
Brentuximab vedotin, a chimeric monoclonal antibody–drug conjugate that targets CD30, has also shown promise against CTCL. Dr. Duvic and her colleagues are investigating the agent, which is already approved for relapsed Hodgkin disease and relapsed anaplastic large T cell lymphoma, in patients with mycosis fungoides, lymphomatoid papulosis, and cutaneous anaplastic large T cell lymphoma. Among patients with high levels of CD30 on their T cells, Dr. Duvic said, the response rates have been in the range of 75%–80%. She and her colleagues recently published their experience with the agent in 48 patients with CD30-positive lymphoproliferative disorders or mycosis fungoides in the Journal of Clinical Oncology.
“We’re seeing some amazing responses with brentuximab vedotin—it melts away tumors, which is pretty impressive,” Dr. Duvic said. “And we’re finding that mogamulizumab gets rid of Sézary cells in the blood in just one or two doses. So we are definitely making progress with these types of agents.”
Another agent, E7777, has also shown promise against CTCL. A reformulation of denileukin diftitox (DAB389IL2) with improved purity, E7777 consists of a diphtheria toxin and an interleukin-2 receptor and targets interleukin-2–expressing cells. In its initial formulation, the agent elicited an overall response rate of 30% and complete response rate of 10% in CTCL patients. More recently, Dr. Duvic and her colleagues conducted a phase I dose-finding study that showed that E7777 had activity against persistent or recurrent CTCL at different dose levels and an acceptable toxicity profile. Dr. Duvic said that clinical trials of E7777 are on hold but are expected to resume once a lyophilized formulation of the agent becomes available.
“I think E7777 is one of the best drugs for patients with advanced disease characterized by tumors. It works very quickly for tumors—you can start to see them shrinking in a couple of days. And it’s much better tolerated than cytotoxic chemotherapy,” Dr. Duvic said.
New topical therapies are also gaining a foothold in the treatment of CTCL. The HDAC inhibitor vorinostat is now being tested as a cream. The oral formulation of vorinostat has multiple side effects, but these are greatly reduced with topical vorinostat. Another topical drug, resiquimod, is a dual toll-like receptor 7/8 agonist that has been found to induce a local immune response that may become systemic: in a phase I dosing study of the drug, researchers found that applying the agent to one lesion can clear lesions at other places on the skin. A larger trial of topical resiquimod is in the planning stages.
Other agents that are entering or already in clinical trials for CTCL patients include phosphoinositide 3–kinase inhibitors, microRNA (e.g., miR155) inhibitors, and ONC201, a compound that induces the tumor necrosis factor–related apoptosis-inducing ligand pathway. ONC201, which has been shown to have activity against several cancers, is given as a pill weekly or once every 3 weeks.
A major hurdle in developing new treatments for CTCL is an incomplete understanding of the genetic features that lead to the various types of the disease. In an effort to overcome this hurdle, Dr. Duvic and her colleagues conducted a multiplatform genomic analysis (genomic exon sequencing in parallel with RNA sequencing and single nucleotide polymorphism analysis) of 37 Sézary syndrome patients to identify new therapeutic targets in the disease. The study, which was reported in Nature Genetics in December 2015, yielded valuable insight into the genomic basis of Sézary syndrome.
“We found many driver mutations for Sézary syndrome. Most of them are in the T cell signaling pathway, which is what you might expect,” Dr. Duvic said. “In particular, we found that IL32, which had been known to be expressed in mycosis fungoides cells, was highly expressed in peripheral blood samples from patients with Sézary syndrome and was associated with a poor prognosis.”
The study has opened new avenues toward effective therapy for CTCL. Dr. Duvic said, “The ability to match the correct therapy to the correct patient is where we’d like to be with this disease.”
For more information, contact Dr. Bouthaina Dabaja at 713-563-2406 or Dr. Madeleine Duvic at 713-745-4615.
OncoLog, February 2016, Volume 61, Issue 2