Researchers are aiming to better understand the molecular signaling pathways and the immune microenvironment of cutaneous T-cell lymphoma. The use of targeted or mechanism-based therapies may lead to better-understood combinations, higher response rates and better survival.
Cutaneous T-cell lymphoma (CTCL) lags behind others in terms of targeted treatment advances, but with better understanding of its molecular signaling pathways and the immune microenvironment, it could soon catch up, according to experts who presented at the 3rd Annual World Cutaneous Malignancies Congress (2014, San Francisco, Calif.).
“The hope in the CTCL field is that we are approaching an entry door of drug development based on advances in basic science research,” Pierluigi Porcu, M.D., associate professor of medicine at The Ohio State University, Columbus, Ohio, told attendees.
But in addition to the need for drug development, there are several fundamental issues that should be clarified, one pertaining to staging with the tumor-node-metastasis-blood (TNMB) system, he suggests.
“We have a single tool to assess and describe different things: mapping of sites of involvement, prognostic risk assessment at diagnosis, quantitative measurement of disease, and linking mycosis fungoides (MF) and Sézary syndrome (SS) as a stage transition of the same disease,” he says.
“Relatedness on a molecular level suggests that gene expression profiling overlaps, but the current staging system universally presents the evolution as fixed, and that is not true,” he indicates.
For example, while stage IB patients are considered to have early-stage disease, at 30 years their rate of stage progression is high. “We have a convoluted stage classification system,” he maintains.
More needs to be learned about the risk of stage progression in MF/SS and the effect of treatment on this risk, the prognostic factors beyond TNMB stage, the optimal way to describe the involvement of multiple sites, the treatment of large cell transformation, and the best time to initiate systemic therapy.
The overall management of CTCL across stages is complex. Different stages require different types of care; so multidisciplinary management is important. Chart: Pierluigi Porcu, M.D.NCCN guidelines recommend for stage IB, IIA and IIB disease both skin-directed and systemic treatments. Among the available systemic agents are romidepsin and vorinostat (histone deacetylase [HDAC] inhibitors), denileukin diftitox (a fusion protein), and bexarotene (a retinoid receptor activator). Pralatrexate (an antifolate), which is approved in peripheral T-cell lymphoma, and alemtuzumab (an IgG1 antibody), are used off label. Brentuximab vedotin (an antibody-drug conjugate) is expected to become FDA-approved. For patients with good performance status who progress on systemic therapies, allogeneic stem cell transplant can be beneficial.
“The overall management of CTCL across stages is complex (See chart). There is no unified standard of care or universal algorithm,” Dr. Porcu notes. “And since different stages require different types of care, multidisciplinary management is important. All patients with advanced stage disease also have skin lesions remaining in the early stage, and dermatologists should be involved in treating these lesions.”
Next: New Systemic Therapies: Beyond the old Paradigm
The conventional treatment paradigm for CTCL has not changed much, but investigational agents are encouraging and are being evaluated in a more evidence-based way, according to Steven M. Horwitz, M.D., associate attending on the Lymphoma Service at Memorial Sloan Kettering Cancer Center, New York.
“We are still giving mild systemic therapies sequentially, but we are getting better quality data now. We are beginning to look at progression-free and overall survival. And, on the horizon, we have targeted treatments that will be better understood,” he says.
The established treatment paradigm is exemplified by an underpowered trial from the 1980s, which showed that aggressive initial treatment was no better and more toxic than a conservative, sequential approach using skin-directed therapy and single-agents.
“We still use this paradigm,” he notes.
Thereafter, newer drugs became approved based on phase 2 studies.
“The bar was pretty low. Basically, a drug with activity and relative safety could get approved, without much data on survival or quality of life.”
Recently, the bar for drug approval in CTCL has been raised, and randomized studies are comparing investigational agents to standard therapies. One phase 3 trial is comparing the brentuximab vedotin (Adcetris, Seattle Genetics) (an anti-CD30 antibody plus monomethyl auristatin E) to methotrexate or bexarotene (Targretin, Valeant) in patients with relapsed CD30+ MF. In early studies, very high response rates have been observed, approximately 70% across the spectrum of CD30 expression. The most common side effects with this drug are peripheral neuropathy and fatigue.
Another phase 3 trial is comparing the anti-CCR4 antibody mogamulizumab (Poteligeo, Kyowa Hakko Kirin) to the HDAC inhibitor vorinostat (Zolinza, Merck), with progression-free survival as an endpoint. The CCR4 receptor is present in all stages of CTCL, and levels of expression levels increase with stage of disease. Mogamulizumab is engineered to have potent antibody-dependent cellular cytotoxicity activity and is reasonably well tolerated. In a recent study, 35% of CTCL patients responded, 14% being complete responses.
“We are not really changing the treatment paradigms yet, but we are doing better quality studies. We have several agents that appear reasonably active in CTCL, and they are being compared to standard therapies in randomized studies. In terms of level of evidence, this is a step up,” Dr. Horwitz says.
NEXT: Future Developments
Elaborating on these compounds, Dr. Horwitz described IPI-145 as a potent oral inhibitor of the PI3K gamma and delta isoforms that inhibits malignant B-cell and T-cell survival. The drug has interesting activity in T-cell lymphomas, producing response rates around 30% in CTCL and durable responses in some SS patients, he says.
Dr. Horwitz also was encouraged to see research on immune checkpoint inhibitors “trickling over into T-cell lymphomas.” This is based on the PD1 and PD-L1 expression observed primarily in SS and to some degree in MF, which down-regulates the antitumor CD8 T-cell response. A multicenter study will evaluate the anti-PD-1 agent pembrolizumab in refractory MF and SS.
Potential efficacy of selective HDAC inhibition
Anjali Mishra, Ph.D., assistant professor of dermatology at The Ohio State University Comprehensive Cancer Center, shared new insights about the pathogenesis of CTCL, focusing on interleukin (IL)-15 and how this could impact treatment. IL-15 is overexpressed in patients with CTCL, and IL-15 transgenic mice progress to a severe stage of the malignancy, she noted.
“IL-15 has long been known to stimulate the immune system. What was perplexing is that we found this growth factor to be responsible for cancer,” Dr. Mishra says.
Dr. Mishra and her colleagues showed that the IL-15 promotor gene causes its upregulation and signaling during oncogenic transformation, which contradicts the central dogma that methylation switches off a gene. “We found that T-cells had acquired epigenetic abnormalities in the IL-15 promotor that turns on IL-15 production. IL-15 goes out of the cell, binds to its own receptor, and causes upregulation of HDAC 1, 2, and 6. We think, therefore, that the right therapeutic approach in CTCL should be to target these HDACs specifically,” she suggests.
This occurs with the experimental and topical HDAC inhibitor, SHP-141, which inhibits the HDAC isoforms 1, 2, 3 and 6, according to Dr. Horwitz. He described SHP-141 as a “soft drug” that is active in the skin but then breaks down to an inactive metabolite, avoiding systemic effects. In a study presented at ASCO 2014, the drug was consistently more active than placebo at multiple sites and was well tolerated. SHP-141 is expected to enter phase 2 trials.
“The use of targeted or mechanism-based therapies such as these will, I hope, lead to better-understood combinations, higher response rates-especially complete responses-and better survival,” Dr. Horwitz says.
 Kaye FJ et al. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med 1989;321(26):1784-90
 Krathen M et al. Brentuximab Vedotin Demonstrates Significant Clinical Activity in Relapsed or Refractory Mycosis Fungoides with Variable CD30 Expression. ASH 2012. Abstract 797
 Ogura M. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol 2014;32:1157-63
 Horwitz SM et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory lymphoma. ASCO 2013. Abstract 8518
 Kim YH et al. A phase 1b study in cutaneous T-cell lymphoma (CTCL) with the novel topically applied skin-restricted histone deacteylase inhibitor (HDAC-i) SHP-141. ASCO 2014. Abstract 8525