By Annette M. Boyle

BIRMINGHAM, MI — After decades on the sidelines, research in cutaneous T-cell lymphoma (CTCL) has exploded in recent years, bringing patients with this rare disease new opportunities for treatment.

Increasingly, research is focusing on the “prognostic indicators, how does the disease develop, what distinguishes the variants of the disease and what makes one person’s an indolent disease and another’s life threatening,” said Susan Thornton, chief executive officer of the Cutaneous Lymphoma Foundation.

For the majority of patients with mycosis fungoides, which accounts for about 70% of all CTCL, the disease has a favorable prognosis; it will either never progress or will develop very slowly. About one-third of patients, however, will eventually develop tumor lesions and experience involvement of the blood, lymph nodes, bone marrow or visceral organs. For them, the outlook deteriorates sharply.

More than 50% of mycosis fungoides patients with Stage 3 or 4 disease die of the disease, and median survival is only five years, according to the National Cancer Institute.

A growing number of researchers are working to identify the “telltale signs that a person’s disease is taking a turn for the worse,” Thornton told U.S. Medicine.

Inflammation appears to be one of the critical markers, according to a study recently published in Seminars in Immunopathology. A global team of researchers, including Erik Langhoff, MD, of the James J. Peters VAMC, Bronx, NY, found that the “transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation.” 1

As inflammation increases, malignant T cells stage a “hostile takeover” of the environment, suppressing cellular immunity and responses that limit tumor growth. At the same time, changes wrought by the malignant T cells promote angiogenesis, lymph-angiogenesis, tissue remodeling and tumor development by exploiting “benign immune cells and stromal cells to produce pro-tumorigenic growth and survival factors,” the authors wrote.

The researchers suggested that the ability of the malignant T cells to transform their environment may derive from a combination of exogenous factors, such as infection, and genetic mutations. S. aureus seems to trip dysregulation of the Jak/Stat pathway and lead to malignant inflammation in CTCL, for instance. For veterans, there is a presumptive link to Agent Orange exposure in CTCL development.

A number of other studies are looking at the impact of various mutations, particularly as they offer targets for new therapies. One study published in the Cutaneous Lymphoma Foundation’s Forum 2017 newsletter found that aberrant DNA methylation prevents proper function of ZEB1, leading to overproduction of IL-15 gene and activation of three oncogenic pathways, HDAC1, HDAC2 and miR-21. “These observations have important treatment implications because drugs that decrease DNA methylation may be able to restore ZEB1’s physiologic repression of IL-15, thus interrupting this cancer signaling loop,” noted the authors. 2

A number of immunotherapies are currently in clinical trial. Pembrolizumab inhibits the programmed death-1 (PD-1) pathway and has shown promise in a Phase 2 trial in which 38% of those treated saw a 50% or greater improvement in their disease, according to another review by Steven Horwitz, MD, and Alison Moskowitz, MD, both of Sloan Kettering Cancer Center in New York and Youn Kim, MD, of Stanford Cancer Center in Palo Alto, CA. Based on the results in the trial, national guidelines now include pembrolizumab as a treatment option for CTCL.3

Brentuximab vedotin, which combines an antibody that targets CD30-positive tumor cells and chemotherapy, has also seen positive results in clinical trials. A Phase 3 study found it had 650% the response rate of either methotrexate or bexarotene, two standard therapies, earning it a recommendation as a new treatment option in national guidelines, said Horwitz and colleagues.

Another new agent, mogamulizumab, binds to the CCR4 protein on tumor and immune cells. A Phase 2 study found that 37% of participants who received mogamulizumab had at least 50% reduction in their lymphoma and a Phase 3 trial is now comparing its effectiveness to vorinostat. Another new drug currently in trials binds to the protein KIR3DL2, as is a combination therapy that uses both low dose skin radiation and an immune enhancer, according to the research review.

“There is also very interesting research on a topical photosensitizing agent, synthetic hypericin, and fluorescent light, instead of the UVA or UVB light that has been used in CTCL therapy,” Thornton told U.S. Medicine.

Patients with advanced disease might be particularly interested in a topical naloxone treatment now in Phase 3 clinical trial. “The itch is a horrific side effect of the disease. It feels like you have ants crawling from the inside out. It’s unlike anything topical, and the only relief comes from scratching until the skin bleeds,” Thornton said. Until recently, no therapy has relieved the itch unless the disease begins to recede.

CTCL therapy often starts with topical treatments including steroids, retinoids, mechlorethamine, carmustine, electron beam radiation and light therapy with UV-B or UV-A light boosted by psoralen. Topical treatments may be combined with interferon. Systemic therapies include interferon, oral retinoids, monoclonal antibodies and methotrexate. Other treatment options are surgical excision of patches or plaques followed by single dose radiation, extracorporeal photophoresis and cord blood and bone marrow transplantations.

Thornton attributed the recent proliferation of cutaneous lymphoma research to the Orphan Drug Act and increasing support for drug development in rare diseases. All in all, she said, “It’s a pretty exciting time for CTCL research.”

  1. Krejsgaard T Lindahl LM, Mongan NP, Wasik MA, Litvinov IV, Iversen L, Langhaff E, Woetmann A, Odum N. Malignant inflammation in cutaneous T-cell lymphoma—a hostile takeover. Semin Immunopathol. 2017. 39:269-282.
  2. Porc P, Mishra A. Epigenetics & biology of cutaneous T-cell lymphomas. Cutaneous Lymphoma Foundation Forum 2017, Issue 1.
  3. Horwitz S, Kim Y, Moskowitz A. Modernizing immunotherapy for cutaneous T-cell lymphoma. Cutaneous Lymphoma Foundation Forum 2017, Issue 1.