Download Highlights from the T-Cell Lymphoma Forum

Seventh Annual T-Cell Lymphoma Forum
January 29-31, 2015
The seventh annual T-Cell Lymphoma Forum was held in San Francisco at the end of
January. This annual scientific meeting provides a forum for researchers, scientists and
clinicians from around the world to come together to share updates and latest findings
related to the biology of T-cell lymphoma as well as information about treatment options
using existing therapies along with new therapies on the horizon.
Although the meeting covers all T-cell lymphomas, there were several presentations
specific to cutaneous T-cell lymphoma and posters presented by experts in the field.
Drs. Pierluigi Porcu, Youn Kim, Madeleine Duvic, Christiane Querfeld and Miles Prince
were among the cutaneous lymphoma presenters.
The major take-away from this meeting was research to understand the molecular basis
of T-cell lymphomas is ongoing and is essential to help ensure that new drugs and other
therapies being developed specifically target the different types of T-cell lymphomas.
Synopsis of Cutaneous T-Cell Lymphoma Presentations
Biology of Cutaneous Lymphoma
Understanding the molecular pathogenesis of Sézary syndrome
There continues to be discussion among the clinical community in cutaneous lymphoma
whether or not Sézary syndrome (SS) and mycosis fungoides are different stages of the
same primary cutaneous T-cell lymphoma or distinct diseases with similar cellular
tissue, immune system response and genetic features. Although significant advances
are now being made in mapping the underlying cell biology of CTCL, the molecular
development of Sézary syndrome is still poorly understood. In order to learn more about
the overlap between MF and SS, as well as their distinct differences, additional studies
are needed. Requirements for these new studies should include multi-institutional
collaborations, the adoption of standardized approaches in patient selection and
longitudinally-acquired samples from the same patients to detect changes in the
mutational biology.
Rare subtypes of T-cell lymphoma
Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a very rare but
aggressive form of T-cell lymphoma. Despite the very low incidence of these
lymphomas, they are important to study because their extremely aggressive clinical
course typically responds poorly to chemotherapy-based treatments. The effectiveness
of newer therapies on these disorders is not well studied and long-term remissions have
been achieved with stem cell transplantation. Additional studies to understand the
biology of these rare subtypes are needed including international collaborative efforts to
learn how to improve outcomes for these patients worldwide. Some responses have
been seen using brentuximab vedotin and other non-chemotherapy agents.
Microenvironment of CTCL
Many factors contribute to the microenvironment of the cells that form cutaneous
lymphoma. Researchers currently do not understand what stimulates the cancerous
cells. Work is being done to understand the program death (PD-1) pathway in restoring
the immune response to cancer cells. The normal immune system recognizes cancer
cells and can mount an active anti-cancer cell response. One way the cancer cells can
evade this normal immune response is to inhibit these cancer-fighting T-cells,
deactivating them which allows the cancer cells to proliferate. By finding ways to
reactivate this specific pathway with new therapies, the immune system might be
restored and become active again in targeting the cancer cells and eliminating them.
New Treatment Therapies in Cutaneous Lymphoma
Therapeutic immune system approaches in CTCL
A new drug that supports the immune system in doing its job to kill the cancerous
cutaneous lymphoma cells (pembrolizumab) focuses on blocking the expression of PD1 and PD-L1 (program death) pathways that may play a significant role in blocking the
growth of MF/SS cancer cells. Two cases of patients with relapsed MF were treated
with this new targeted therapy in clinical trial and responded to the treatment. Phase II
clinical trials are currently recruiting for this study at Stanford University Cancer Institute
and the University of Pennsylvania.
Comparative study chemotherapy vs biologics in MF/SS
Numerous systemic treatment options exist for patients with mycosis fungoides and
Sézary syndrome but no large comparative studies of the treatments have been
published. In order to study the effectiveness of treatments, specifically the timing of
treatment regimens, a retrospective analysis of data from the Peter MacCallum Cancer
Centre in Australia was performed. The study reviewed 198 MF/SS patients undergoing
systemic therapies, comparing chemotherapy regimens with interferon and histone
deacetylase inhibitor therapies (HDACi - romidepsin and vorinostat are examples of the
HDACi therapies). It showed that all the chemotherapy regimens assessed had very
modest effectiveness when compared directly with interferon and HDACi therapies.
Additionally, the non-chemotherapy regimens had a greater time lapse before the next
treatment was required. The recommendation is that chemotherapy use be restricted
until other options are exhausted.
Brentuximab Vedotin (brand name Adcetris) in combination with other therapy
Promising activity has been seen in a variety of T-cell lymphomas that express CD30
proteins on the cells. Multiple studies are in progress testing brentuximab vedotin in
combination with different types of biologic and immune therapies as well as in
combination with radiation therapy. The challenge in testing these combinations will be
to minimize toxicity to the patient while optimizing the therapeutic benefit. A number of
these trials are currently being undertaken in several cancer centers. Information on
specific clinical trials for cutaneous lymphoma can be found on www.clinicaltrials.gov or
by asking your treatment team about options that may be available at their center.
Treatment review for CTCL
Several therapies are approved for the treatment of mycosis fungoides and Sézary
syndrome, although skin-directed therapies for early disease are still limited and options
to treat advanced stage or large-cell transformation successfully remain challenging.
New topical approaches currently in the development pipeline (i.e. topical resiquimod
and vorinostat) may offer new options for treating early stage disease. Combination
therapies along with new targeted therapies that treat the cancer cells with less toxicity
are showing some promise. Because the malignant cells that cause cutaneous
lymphoma are not uniform in structure (being somewhat unique to each person), future
therapies need to target a variety of cell markers and pathways in order to improve
overall survival. There is still a huge unmet need for safer, more effective and affordable
agents for CTCL patients based on understanding individual molecular makeup. As
identifying patient’s specific disease information becomes possible, we will be able to
have better therapeutic outcomes.
New agents in the pipeline for CTCL:
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SGX301 (synthetic hypericin) is a first-in-class potent photosensitizer
which utilizes safe visible light for activation. Phase 2 clinical trial.
SHP141 topical histone deacetylase inhibitor. Phase 2 clinical trial.
Topical resiquimod. Phase 1 clinical trial.
Topical sirolimus (rapamycin) in the treatment of early stage CTCL.
E777 (improved purity denileukin diftitox). Phase 1 clinical trial.
Topical Stat and JAK signaling pathway inhibitors in the wings.
Electron beam - lower dose as palliative therapy.
IPH4102 a first-in-class anti-KIR3DL2 antibody granted Orphan Drug
Designation in Europe for the treatment of CTCL and has shown potent
anti-cancer cell properties in early non-human models. A Phase 1 trial is in
development.
Diagnostic Updates in Cutaneous Lymphoma
High throughput T-cell receptor sequencing
Diagnosis of early stage cutaneous T-cell lymphoma is challenging due to skin lesions
containing a mixture of both benign and malignant T-cells. High throughput T-cell
receptor sequencing is a new method for identifying both the total malignant T-cells in a
biopsy sample as well as the breadth of diversity of cell types. This type of diagnostic
testing for cutaneous T-cell lymphoma can provide important quantitative data about the
number of benign versus malignant cells, extent of disease and disease response to
treatment.
Cutaneous Lymphoma International Consortium (CLIC) Study
The goal of the CLIC is large-scale scientific collaboration to study cutaneous
lymphoma worldwide. The initial study undertaken by CLIC evaluated prognostic
parameters in advanced stage MF/SS in a retrospective fashion. The pilot study
demonstrated the intrinsic flaws of a retrospective analysis and the need for a
prospective study. A collaborative, world-wide prospective study is currently being
developed to capture an unprecedented large-scale collection of data, employing welldefined criteria with the hope that it may enable the building of a prognostic index model
to augment the current clinical staging system.
In Summary
The T-Cell Lymphoma Forum provided an ideal venue for the exchange of clinical and
research information. While progress in the development of new and effective therapies
for T-cell lymphomas may seem slow, great strides are being made in gaining a better
understanding of what is happening at the molecular level that will, in turn, lead to better
and more targeted therapies resulting in longer remissions and less treatment toxicity
for patients.