The Elodia Kehm Chair of Hematology
Professor of Medicine
Rush University Medical Center/Rush University
Can you briefly describe follicular lymphoma?
Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL). It accounts for about 22 percent of all NHL types. It is the most common indolent lymphoma, meaning that it is generally slow-growing. It is also generally not curable.
How is FL typically treated?
FL really has no standard of care. There are many different approaches to treating a patient with FL.
I make a decision as to whether or not, and how, I will treat a patient by first looking at the patient’s tumor burden. If a patient has low tumor burden and is newly diagnosed, this patient may not need treatment. I use what is called the “watch and wait” approach, which means the patient will visit every few months, be examined, have blood work, and maybe get a computer axial tomography (CAT) scan once every six months or once a year. Only when the tumor burden becomes large, or when the patient becomes symptomatic, would we consider treatment.
A lot of patients do not like the idea that they have a cancer and we just watch and wait. So, this is where the role of single-agent rituximab (Rituxan), a monoclonal antibody, has been introduced. There are many clinical trials looking at monotherapy with rituximab in patients with low tumor burden. A recent study presented at the American Society of Hematology Annual Meeting last year by Dr. Ardeshna looked at patients with low tumor burden FL. Dr. Ardeshna randomized patients to observation (“watch and wait”) alone, single-agent rituximab for 4 weeks, or single-agent rituximab for 4 weeks followed by maintenance rituximab therapy every few months for 2 years. He concluded that patients who received rituximab for 4 weeks and then maintenance had a delay to when they first needed chemotherapy compared with the other 2 groups.
I think many of us still do not treat newly diagnosed patients with rituximab if they have low tumor burden. Dr. Ardeshna was trying to demonstrate that if you use rituximab, you can delay chemotherapy for a year or so. But, with “watch and wait,” most patients don’t need treatment for about 3 years. Even when you do, sometimes these patients can eventually be treated with rituximab monotherapy. So my point is, why treat patients if they really don’t need it? However, if the patient wants treatment, then rituximab monotherapy is certainly something to consider.
Patients are considered to have a high tumor burden when they have fevers, night sweats, weight loss, or an enlarged spleen, or if their lymph nodes appear very large on a CAT scan. For the patient who presents with newly diagnosed FL and a high tumor burden, the classic approach is chemoimmunotherapy, in which chemotherapy drugs are combined with rituximab.
There are many different chemotherapy drugs used: R-CVP, which is rituximab plus cyclophosphamide, vincristine, and prednisone; R-CHOP, which adds doxorubicin to R-CVP; and bendamustine (Treanda) combined with rituximab.
Radioimmunotherapy (RIT) is a very important treatment for follicular and other indolent non-Hodgkin lymphoma. There are two RIT drugs currently approved for follicular lymphoma (FL): ibritumomab tiuxetan (Zevalin) and tositumomab (Bexxar). Ibritumomab tiuxetan has recently been approved as consolidation after chemotherapy in the front-line treatment of patients with FL. The efficacy of ibritumomab tiuxetan was reported in the First-line Indolent Trial (FIT) by Dr. Morschhauser in 2008. The patients who received consolidative RIT had a prolonged progression-free survival. Both drugs are also approved for relapsed FL and, when used earlier rather than later in the relapsed setting, many patients have had very durable remissions for years. RIT remains an underutilized modality of treatment. It is one of the most effective therapies for indolent and follicular NHL.
What are the current main areas of research for FL?
We are continuing to improve the survival rate of patients with FL because of some of the new agents that are available. We are trying to approach it as a chronic disease rather than a cancer that keeps coming back all the time.
The main areas of research today involve looking at novel biomarkers for predicting a patient’s outcome or prognosis. Gene expression profiling is being looked at not only on the tumor cell but in the microenvironment to see what in the genes, or the cells in the environment, cause a cancer cell to grow. It appears that if you have a lot of T cells, for example, your prognosis is better than if you have a lot of monocytes or macrophages. Those are just a couple examples of biomarkers. Researchers are also looking at lymphocyte counts in patients with FL, which may also be a prognostic indicator.
There are many disrupted enzymatic pathways in the cells of patients with FL. We’re trying to look at pathways that make the tumor cell survive. New agents are being developed to inhibit some of these abnormal pathways; these agents enter a tumor cell through what we call the B-cell receptor on the cell surface. Some examples include Bruton’s tyrosine kinase inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, and many others.
Immunomodulatory drugs like lenalidomide (Revlimid) are being studied in FL. We know that lenalidomide has a lot of activity in mantle cell and diffuse large B-cell lymphoma in the relapsed setting, and now it’s being studied in FL, as front-line treatment, maintenance therapy, and in the relapsed setting.
There is another class of agents called mammalian target of rapamycin (mTOR) inhibitors, which include drugs called temsirolimus (Torisel) and everolimus (Afinitor). Temsirolimus has demonstrated efficacy in the relapsed setting of FL.
I anticipate that these novel agents will be studied in the relapsed setting of FL, show some efficacy, and then be combined with known agents such as rituximab. We are actually trying to use less chemotherapy and more novel agents, including oral agents and less toxic drugs, in combination.
Do you talk to patients about enrolling in clinical trials?
Always. If we do not get more patients in clinical trials, we are never going to make the necessary advances in treatment. For example, we know that maintenance therapy after chemoimmunotherapy for front-line treatment of FL keeps patients in remission longer. There are currently clinical trials investigating if there is a drug in addition to rituximab that could be added to rituximab maintenance to keep patients in remission even longer. Maybe we should combine rituximab with lenalidomide, and maybe that will keep patients in remission longer?
A new front-line clinical trial includes lenalidomide, bendamustine, and bortezomib (Velcade). This group is also studying different combinations of bendamustine with rituximab, such as bendamustine with bortezomib and rituximab. They are also looking at different maintenance regimens.
A small phase II trial was performed investigating lenalidomide and rituximab as front-line treatment for FL and has reported 100 percent overall response, with a complete response of 70 percent to 80 percent. The patients had poor prognosis and high tumor burdens, and were treated with an immunomodulatory drug and a monoclonal antibody with no chemotherapy drug in the regimen. These are impressive results. The trial is being expanded to include up to a 100 patients.
We have made a lot of strides in treatment advances, and clinical trials are how we make those strides. We need to get more than the current 3 percent of all cancer patients participating in clinical trials in the United States.
What is on the horizon for FL research and treatment?
There is a very active community of researchers consisting of PhDs and physician scientists who are developing all kinds of ideas for determining how the FL cell grows–for example, how do the proteins in the environment around that tumor cell aid in the tumor’s growth? Many new clinical research projects looking at FL and its basic science are being proposed to the Lymphoma Research Foundation (LRF). LRF has a Scientific Advisory Board which reviews these applications of new and exciting research grant proposals for not only FL but mantle cell lymphoma, diffuse large B-cell lymphoma, and others.
How are you involved with LRF and would you recommend a patient become involved with them?
LRF is one of the most patient-oriented organizations that I know, and it is on the cutting-edge of funding for research in lymphomas. I have been involved with LRF for years. The Scientific Advisory Board consists of the top lymphoma doctors in the country and internationally, and a great deal of time is donated to helping research progress and helping patients understand their disease.
I think that it is a wonderful organization. When I see 600 patients coming to a national meeting and being able to go into a breakout session with top-notch lymphoma experts from around the country and the world talking to them about their disease, it is gratifying to see the kind of networking that’s done and what the organization offers to patients. I have loved doing patient programs every year in Chicago, and I’ve gone around the country and participated in many patient programs. I’ve also chaired one of their national programs in California.
Is there anything else you would like to add?
I think that it is so important for physicians to talk to their patients about all of these issues and to determine the patient’s tumor burden. There is no standard of care for FL. I think that physicians need to understand that this is a very heterogeneous disease and that there are many different approaches to the treatment of newly diagnosed and relapsed patients. There is certainly a role for stem cell transplant in patients who are young and have relapsed. I also think that every patient with FL should go to a major medical center, with a very large lymphoma program, for a second opinion.
Updated: September 20, 2012