A Discussion About Treatment Options for PTCL Patients With Dr. David Christopher Fisher
Assistant Professor of Medicine at Harvard Medical School, Boston, Massachusetts
Can you describe peripheral T-cell lymphoma?
Peripheral T-cell lymphoma (PTCL) is a rare, aggressive lymphoma. T-cell lymphomas account for about 15 percent of all lymphomas. PTCL is a term sometimes used for a general category of T-cell lymphomas that includes other types, such as angioimmunoblastic lymphoma. PTCL noted as "not otherwise specified" excludes some of these other subtypes.
The cause of PTCL is unknown. Patients typically present with apparent lymph node enlargement or with internal symptoms such as a cough due to enlarged lymph nodes affecting an airway or from enlarged lymph nodes in the abdomen causing gastrointestinal symptoms, pain, or discomfort. An enlarged lymph node can be biopsied externally or by exploratory surgery. Biopsy—getting a piece of the malignant lymph node under a microscope—is usually the crux of a diagnosis.
What are the current treatment options for patients with a PTCL diagnosis?
The difficulty in treating this type of lymphoma is that there is not a standard T-cell-directed treatment available. Hopefully, we will get to that point, but that has been a challenge so far.
Most patients with PTCL are treated with chemotherapy based on cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), which has been the backbone for treating lymphomas for years. There is some evidence that it may be helpful to add etoposide to the CHOP regimen (called CHOEP).
Researchers are now looking at incorporating a new drug, brentuximab vedotin into the CHOP regimen. Brentuximab vedotin is made of a monoclonal antibody that binds to the protein CD30 on one end and a chemotherapy agent, a microtubule inhibitor, on the other end. CD30 is a protein on many, but not all, T-cell lymphomas. The antibody directs the chemotherapy right to the cancer cell so that a better interaction is achieved between the two. Brentuximab vedotin has shown good results in some T-cell lymphomas such as anaplastic lymphoma. The response rate from brentuximab vedotin for CD30-positive lymphomas is much higher than the rate achieved with any other chemotherapy. It is believed to be more effective because it is directly targeting the tumor with the antibody. This can potentially be very helpful for treating CD30-positive lymphomas.
For patients who are otherwise healthy and younger, physicians will often add an additional step using high-dose chemotherapy that requires a stem cell transplant. Usually, this is what we call an autologous stem cell transplant, which means that we use the patient's own stem cells for the transplant. This approach has become more common to increase the likelihood of curing patients with the first treatment.
Patients with relapsed disease, by definition, have disease that is more resistant to standard chemotherapy. There are other chemotherapy drugs, most commonly gemcitabine-based regimens, which can be used. We may be able to use a newer drug like brentuximab vedotin in that setting; however, relapsed disease is difficult to cure because the malignant lymphoma cells have some level of resistance to chemotherapy. A stem cell transplant using a donor, which is called an allogeneic stem cell transplant, may be considered. The advantage of using stem cells from a donor is that it gives the patient a new immune system that can attack the lymphoma. This type of transplant can often be pursued in patients who have recurrent disease.
Can you discuss the potential treatment options for patients in the future?
There are a few different approaches. One is determining if a drug can be added to the CHOP regimen during initial treatment to try to improve outcomes for patients with CD30-positive lymphoma. There is a trial that has been looking at replacing vincristine in the CHOP regimen with brentuximab vedotin. There are also trials investigating the addition of other drugs to CHOP that have activity in other T-cell lymphomas, including histone deacetylase (HDAC) inhibitors such as romidepsin and belinostat (which was approved in July 2014 for the treatment of PTCL). Whether these agents have activity and whether they improve initial outcomes over standard CHOP therapy is a question we hope to answer in clinical trials.
Any time a cancer cell is attacked in a different location or in a different manner, it opens up a new opportunity. Most chemotherapy agents work by damaging DNA. HDAC inhibitors, on the other hand, block a group of enzymes that are important in helping cells read the DNA and turn the message from the DNA into proteins that are important in cell growth. HDAC inhibitors were found to be effective in treating T-cell lymphomas and there are now three drugs in the HDAC class (belinostat, romidepsin, and vorinostat) approved for treatment of T-cell lymphomas or a subtype of T-cell lymphomas.
In B-cell lymphoma, there are a number of drugs in a class known as kinase inhibitors. These drugs work outside of the nucleus of the cell where the DNA is found, blocking enzymes important in cell growth and survival pathways that are active in cancer cells. These drugs may also have some activity in T-cell lymphomas. A trial was just completed with an aurora kinase inhibitor, and there are other kinase inhibitors that I think will be studied in T-cell lymphomas in the future.
There are two other areas of new drug development. One is a group of drugs known as checkpoint inhibitors. The immune system is designed to attack cancer cells, but sometimes it develops a tolerance to the cancer cells and no longer recognizes them as something to attack. There are certain proteins important in preventing the immune system from attacking cancer cells, including PD-1 (or programmed cell death protein-1), which is a target that can be blocked with a number of different monoclonal antibodies now being studied. These antibodies have shown activity in Hodgkin lymphoma and some B-cell lymphomas are now being studied in T-cell lymphomas.
The other area of interest is modified T-cells. Over the years, there have been a number of attempts to manipulate the immune system to attack lymphoma cells. Some T-cell lymphomas express proteins related to the Epstein-Barr virus (EBV). Modified T cells are now being programmed to attack EBV in at least the initial treatment of EBV-related T-cell lymphomas. This represents an interesting approach that we hope will be effective.
Can you discuss the importance of clinical trials, especially in regards to PTCL?
Clinical trials are critical to advancing research. These trials test new treatments, such as brentuximab vedotin or belinostat, and treatment combinations such as high-dose chemotherapy and stem cell transplant, to determine if they provide a benefit. We know there is room to improve treatment options and clinical trials are imperative in advancing research.
What would you tell a newly diagnosed PTCL patient?
I would tell them that while traditional treatment methods can potentially eradicate the disease they should investigate available clinical trials that might offer a better opportunity than standard chemotherapy alone. Patients can look clinical trial options online at www.clinicaltrials.gov. They can also go to the Lymphoma Research Foundation's web site where they have a helpline and clinical trials service. I think if a patient has a type of T-cell lymphoma that does not already have a standard treatment available a clinical trial is in his/her best interest.
It is helpful for patients to have some idea of what is involved in a clinical trial when discussing this option with their physician. Clinical trials usually involve a novel treatment approach, which patients should take the time to learn about. While there can sometimes be more testing, such as additional scans or biopsies in a clinical trial, in general patients are likely to receive state-of-the-art care so it is usually in their best interest.
How are you involved with the Lymphoma Research Foundation and why would you recommend that patients become involved with the organization?
The Lymphoma Research Foundation (LRF) has been very helpful in a number of ways LRF hosts patient education forums including their Ask the Doctor programs where physicians have the opportunity to talk with patients and present information about T-cell lymphomas. This is so important in educating patients and helping them manage their disease. The organization also supports physician meetings where lymphoma specialists meet to discuss ways of trying to improve treatment. In addition, LRF supports lymphoma research by providing grants, notably to young investigators who hopefully go on to advance research in the future.