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Two Drugs Attack Attractive Targets in CTCL

Fuerst, Mark

doi: 10.1097/01.COT.0000466393.31783.4a
Figure. C

Figure. C

SAN FRANCISCO—Drugs now in development show promise in attacking two attractive targets of cutaneous T-cell lymphoma (CTCL), a rare and indolent type of Non-Hodgkin lymphoma, according to presentations at the American Academy of Dermatology Annual Meeting here.



CTCL, characterized by clonal proliferation and accumulation of skin-homing helper/memory T cells, has two major forms: mycosis fungoides (MF) and Sézary syndrome (SS).

“There is a very short list of FDA-approved systemic agents for CTCL, with limited duration of response. We have to plan therapy by sequencing them correctly. T-cell lymphoma is a very heterogeneous disease, so we need tailored, personalized medicine,” said Youn H. Kim, MD, Director of the Multidisciplinary Cutaneous Lymphoma Program at Stanford Cancer Institute & School of Medicine.

“We need better therapies and more options, such as brentuximab vedotin and mogamulizumab, both of which are now in Phase III clinical trials for CTCL. To develop rational combination strategies, we need multiple targets/pathways and complementary targets, and we need to know how to optimize efficacy without additive toxicities.

Targets for therapy in CTCL include tumor cell surface molecules, microenvironment immune mechanisms, and tumor proliferation, metabolism, survival, and progression mechanisms.

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Targeting CD30

“CD30 is an attractive target because CD30 expression is increased in proliferative or malignant lymphocytes, which leads to good tumor selectivity. CD30 engagement leads to activation of the NFkB pathway, which makes it a good target to promote apoptosis,” Kim explained.

The anti-CD30 agent brentuximab was approved in 2011 for use in Hodgkin lymphoma after autologous stem cell transplant has failed and in systemic anaplastic large cell lymphoma after multi-agent chemotherapy failure. MF and SS have variable CD30 expression in neoplastic cells. Transformed MF has more frequent, greater CD30 expression (30 to 50 percent) compared with that in non-transformed MF (zero to 15 percent), she said, noting that the majority of MF patients have the non-transformed type of the disease.

“Brentuximab has shown significant clinical activity in refractory/advanced MF/SS, with an overall response rate of 70 percent, which is significantly greater than the 35 percent response rate in other recently FDA-approved agents,” Kim continued. “With brentuximab, responses are seen across all stages and compartments, with encouraging duration of clinical benefit.”

Clinical responses are observed in all CD30 groups, but the reliability and depth of response correlates with CD30 expression—“The drug works quickly, within six to seven weeks. At six months, 90 percent of patients are still responding.”

There is no significant correlation of pre-treatment tissue microenvironment factors: “An abundance of tumor-associated macrophages with significant co-expression of CD30 may contribute towards an additional mechanism of action of brentuximab,” she added. “Further studies of biomarkers and effects on the microenvironment are warranted, which may help optimize management strategies.”

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Primary Toxicity

The primary toxicity is peripheral neuropathy, which unfortunately is not always reversible: “Don't use brentuximab for 16 cycles as you would for patients with Hodgkin lymphoma,” Kim said. “Use it only until you see disease response, and then stop: Oncologists need to know how to use new drugs and when to stop them. We don't want to induce permanent neuropathy. Many oncologists use systemic therapy for stage 1 disease patients. The patients need individualized care.”

She added: “The best scenario is a multidisciplinary approach, with dermatologists partnering with oncologists. If a patient has a new skin eruption, it could be a skin reaction, not necessarily progressive disease.”

Brentuximab is included in the 2015 NCCN practice guidelines for treatment of primary cutaneous CD30-positive T-cell lymphoproliferative disorders. “NCCN guidelines can be used to help patients get insurance approval of brentuximab since we use a lot of off-target drugs in CTCL,” Kim explained.

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Rational Combinations, Sequential Strategies

But because responses with brentuximab are not durable, researchers are considering rational combinations or sequential strategies. Good partners with brentuximab include immunotherapy, including tumor-specific monoclonal antibodies, cytokine therapy, immune-modulating agents or antibodies, adoptive T-cell transfer, vaccine-based approaches, and allogeneic hematopoietic stem cell transplant (allo-HSCT).

In summary, Kim said: “CD30 is a good tumor selective target that is expressed in the majority of CTCL cases. There are variable expression levels, and in some cases this is detectable only by multispectral imaging. It is a potent anti-CD30 antibody drug conjugant with promising clinical activity in refractory or advanced stage CTCL. Multiple mechanisms of action exist and need further investigation to establish effects on the tumor versus the microenvironment. We must consider toxicities, including peripheral neuropathy, for appropriate risk/benefit assessment.

“Immune checkpoint blockade with inhibitors of PD-1 and PD-L1 can restore the cytotoxic CD8 T cell response, providing augmented anti-tumor activity and clinical efficacy,” she continued, noting there is encouraging clinical activity in an MF/CTCL Phase II study using the anti-PD-1 monoclonal antibody MK-3745 (pembrolizumab).

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‘Ultimate Cellular Immune Therapy’

Harnessing the graft-versus-lymphoma effect in alloHSCT is the ultimate cellular immune therapy, Kim noted. A new approach in donor cell transplant non-myeloablative regimen is total lymphoid irradiation and antithymocyte globulin “protective conditioning,” which enables donor cell engraftment and reduces acute graft-versus-host disease (GVHD) to two to five percent compared with the usual 20 to 65 percent in current therapy. The one-year transplant-related mortality is also reduced to three percent compared with the standard 20 to 30 percent.

“New, improved technology is allowing us to help identify ideal targets, and to modify agents to be more safe and effective,” Kim said. “We have more approved treatment options, with more in the pipeline, including improved tumor-selective therapies. We are learning to partner with the immune microenvironment. We can cure patients with alloHSCT more safely, and provide lasting anti-tumor effects.”



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Targeting CCR4 to Treat CTCL

Although new treatments have become available, few target tumor cells specifically, and may weaken the host immunity. Specific target therapies for CTCL are urgently needed, said another speaker, Madeleine Duvic, MD, Professor of Cancer Research and Deputy Chairman of the Department of Dermatology at the University of Texas MD Anderson Cancer Center.

She noted that frontline therapy for CTCL includes oral methotrexate, CHOP chemotherapy, the histone deacetylase inhibitor (HDAC) romidepsin, alemtuzumab, combined immunotherapy-photopheresis, oral bexarotene and/or alpha interferon, topical steroids, and antibiotics.

For second-line therapy, available agents include romidepsin or another HDAC inhibitor vorinostat; targeted antibody therapy with brentuximab; zanolimumab, a monoclonal antibody to CD4+ T-cells; alemtuzumab, a monoclonal antibody to CD52 on mature lymphocytes; mogamulizumab, a monoclonal antibody to CCR4; or total body skin electron beam (TBSEB) therapy and non-ablative allogeneic SCT.

Duvic reviewed therapy with mogamulizumab, which inhibits CCR4-chemokine receptor expression on helper T cells and T-regulatory cells. Mogamulizumab is the first glyco-engineered humanized monoclonal and first approved for HTLV-1-positive adult T-cell lymphoma.

Studies show that about one-third of patients respond to the drug, she said. Overall response rates are about 47 percent in SS patients, 29 percent in MF patients, and 37 percent in those with combined MF/SS.

“Mogamulizimab depletes malignant T memory SS cells and T-regulatory cells rapidly,” Duvic said, adding that flow cytometry can aid diagnose of SS and monitor responses in the blood to CCR4 therapy.

Kim added that clinical responses with mogamulizimab are most impressive in the skin and blood compartments in CTCL. “Infections are absent with chronic therapy, and there is no need for antimicrobial prophylaxis.”

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In the question-and-answer session, Kim suggested using a risk-stratification approach: “For high-risk patients, who have a shortened life expectancy, you may need to gamble about inducing toxicity. Think about going to transplant. If you don't get to transplant in a reasonable time, the disease becomes refractory.”

Duvic noted that half of SS patients go on to transplant: “Transplanted patients need treatment with immunosuppressive agents that are not too powerful, or they develop GVHD and relapse within a few weeks. Be careful sending patients with large cell transformation to transplant.”



The moderator of the session at which Kim and Duvic spoke, Alain Rook, MD, Professor of Dermatology at the University of Pennsylvania, advised: “If you give donor lymphocyte infusions, do not follow immediately with brentuximab or other immunosuppressive agents or you will inhibit the patient's effector T cells that develop from the DLI.”

In an interview afterwards, he added: “Any young CTCL patient who presents with advanced disease who does not respond quickly to treatment, think of transplant. Patients with advanced disease or large cell transformation SS, layer on an immune potent agent, such as pegylated interferon or interferon-gamma, along with bexarotene and skin therapy with PUVA or TBSEB.”



Some patients go into durable remission—Rook says he is following many—“but if a patient does not do so within six to 12 months, they should be screened for transplant. Use TBSEB, Campath, and romidepsin as a bridge to transplant. If a patient has a large cell transformation in nodes, use brentuximab. If the patient is in good physical condition, use CHOP or hyperCVAD. For pure SS without tumors of enlarged nodes, use Campath [alemtuzumab].”

Some patients go into durable remission, but if a patient does not do so within six to 12 months, they should be screened for transplant. Use TBSEB and romidepsin as a bridge to transplant. If a patient has a large cell node on the skin, use brentuximab. If the patient is younger, use CHOP or hyperCVAD. For pure SS, use Campath [alemtuzumab].”

His message to oncologists: “Select rational therapies to get the patient clear for transplant—Ideally, you send a patient to transplant with the least amount of disease.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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