‘Explosion of genomic data’ should improve treatment of cutaneous T-cell lymphoma

NEW YORK — An increasing knowledge of the genomics underlying cutaneous T-cell lymphoma may soon lead to targeted therapies for this disease, according to a speaker at HemOnc Today Melanoma and Cutaneous Malignancies.

“There have been obstacles and issues regarding the definition of how to best approach patients with cutaneous T-cell lymphoma [CTCL],” Pierluigi Porcu, MD, professor in the division of hematology in the Cutaneous Lymphoma Program at The Ohio State University Comprehensive Cancer Center, said during his presentation. “Historically, there was strong institutional bias about the best treatment approaches, as this is a disease that was managed by experts, and really there was not a lot of focus on evidence base.”

Further, the dichotomy between medical oncology and dermatology has impeded understanding of the natural history of CTCL, Porcu said.

“Medical oncologists were seeing the patients with advanced-stage disease, and dermatologists were seeing patients with early-stage disease,” he said. “In the absence of an integrated multimodality program, it was impossible for anyone to have a full view of the progression of the disease.”

Large outcome studies have been published, but they remain from single institutions, Porcu added.

Five drugs have been approved over the past 10 years for CTCL, three of which are histone deacetylase inhibitors. The goal of treatment usually is to prevent patients from progressing to later-stage disease, as outcomes are substantially improved in patients with early-stage vs. late-stage disease.

A retrospective comparison of systemic therapies suggests time to next treatment is longest with interferon (8.7 months; 95% CI, 6-18) and bexarotene (7.3 months; 95% CI, 2.6-110.8).

Several papers have been published in the prior year evaluating the genomics of CTCL.

“There is an explosion of genomic data that is going to provide a lot of information on the mutation landscape of CTCL, and I would imagine over the next several years that is going to lead to the identification of targets for therapy,” Porcu said.

Some key targets have already been identified, Porcu said. These include activating mutations in T-cell receptor signaling pathways, mutations of immune checkpoint genes, mutations of epigenetic regulators, mutations of TNFR/NFB pathway and ZEB1 loss of function mutations and deletions.

CTLA-4–CD28 fusion is one example of an immune checkpoint genetic aberration that has been detected in a few patients, and anecdotal accounts showed harboring this mutation may lead to benefit with ipilimumab (Yervoy, Bristol-Myers Squibb).

“This is an interesting observation that needs to be pursued further,” Porcu said.

Key signaling mutations found in patients with CTCL also include RAS, MAPK, P3K and NF-B.

Studies have also shown a significant amount of loss of the gene ZEB1 in patients with CTCL, Porcu said. ZEB1 — located on chromosome 10p — may be deleted in upwards of 60% of patients with CTCL. Further, ZEB1 knock-out mouse models have developed CD4-mature T-cell lymphoma.

“This indicates the ZEB1 has a very important role in T-cell lymphoma genesis,” Porcu said.

Researchers have developed a model that shows interleukin-15 is important in the pathogenesis of CTCL. Porcu and colleagues observed several ZEB1 binding sites in the promoter region of human interluekin-15 gene, suggesting ZEB1 has a regularly function of interluekin-15, which had not been described before.

“We really think ZEB1 plays a key role in the upregulation of IL-15 in CTCL, and demethylating the promoter with a demethylating agent is a strategy that we are looking into,” Porcu said. – by Alexandra Todak

Reference :

Porcu P. Cutaneous T-cell lymphoma update. Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 18-19, 2016; New York.

Disclosure: Porcu reports a consultant role with Actelion and research funding from Actelion, Celgene, Cell Medica, Galderma, Innate Pharma, Kiowa, Miragen, Pharmacyclics and Tetralogic.