Treatment of Recurrent or Relapsed Follicular Lymphoma
Medically reviewed by Dr. C.H. Weaver M.D. (08/2018)
Patients with follicular lymphoma that has progressed after initial treatment have what is referred to as relapsed or recurrent disease. These patients have a low chance for cure with standard treatment options. Relapsed follicular lymphomas occur predominantly in elderly persons. Treatment plans are currently directed at prolonging life with minimal side effects.
However, patients who have achieved a remission of their cancer prior to relapse are still highly responsive to treatments. These patients may survive for many years with repeated treatment. Clinical studies have documented that approximately 70-80% of patients respond to a first re-treatment, and they may survive three to five years. Additional re-treatments are typically associated with a lower chance for survival and shorter remissions.
For younger patients with either relapsed or recurrent disease, aggressive treatment with stem cell transplantation can result in prolonged disease-free survivals and possibly even cure of the disease.
About this Follicular Lymphoma Treatment Information
The following is a general overview of treatment for relapsed follicular lymphoma. Cancer treatment may consist of surgery, radiation, chemotherapy, targeted therapy, or a combination of these treatment techniques. Combining two or more of these treatment techniques—called multi-modality care—has become an important approach for increasing a patient’s chance of cure and prolonging survival.
In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment.
Circumstances unique to each patient’s situation influence which treatment or treatments are utilized. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
Types of Follicular Lymphoma
Follicular lymphomas are classified according to two systems, the Revised European American Lymphoma (REAL) system and the International Working Formulation (IWF). The following are types of follicular Non-Hodgkin lymphoma (NHL); they are treated similarly (see table 1).
Table 1 Types of Follicular NHL according to two classification systems, REAL and IWF
Chemotherapy for Relapsed Follicular Lymphoma
Single-agent chemotherapy: Clinical trials have shown that Fludara® (fludarabine) appears to be an effective single drug for the treatment of progressive or relapsed follicular lymphoma. Other chemotherapy drugs that may be used to treat follicular lymphoma include:
- Cladribine® (2-chlorodeoxyadenosine)
- doxorubicin (Adriamycin®)
- mitoxantrone (Novantrone®).
Combinations of chemotherapy: Several multi-drug chemotherapy regimens can produce anticancer responses in patients with relapsed follicular lymphoma. Some of the combinations commonly used include the following:
- CHOP: cyclophosphamide, doxorubicin, Oncovin®, and prednisone
- CVP: cyclophosphamide, Oncovin®, and prednisone
- C(M)OPP: cyclophosphamide, Oncovin®, procarbazine, and prednisone
- FN: Fludara® and Novantrone®, with or without dexamethasone
Chemotherapy is commonly combined with the targeted therapy, Rituxan.
Targeted Therapy for Relapsed Follicular Lymphoma
A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. The addition of targeted therapy to conventional chemotherapy may offer the advantage of increasing the intensity of treatment delivered to the cancer and improving outcomes without increasing treatment-related side effects.
Conventional cancer treatments, such as chemotherapy and radiation therapy, cannot distinguish between cancer cells and healthy cells. Consequently, healthy cells are commonly damaged in the process of treating the cancer, which results in side effects. Chemotherapy damages rapidly dividing cells, a hallmark trait of cancer cells. In the process, healthy cells that are also rapidly dividing, such as blood cells and the cells lining the mouth and GI tract, are also damaged. Radiation therapy kills some healthy cells that are in the path of the radiation or near the cancer being treated. Newer radiation therapy techniques can reduce, but not eliminate this damage. Treatment-related damage to healthy cells leads to complications of treatment, or side effects. These side effects may be severe, reducing a patient’s quality of life, compromising their ability to receive their full, prescribed treatment, and sometimes, limiting their chance for an optimal outcome from treatment.
Rituxan is a type of targeted therapy called a monoclonal antibody that binds to proteins on the surface of B-lymphocytes, which are the cells that are cancerous in follicular lymphoma. This binding stimulates the immune system to attack and kill the cancer cells. A benefit of Rituxan therapy is that healthy cells are not targeted, limiting side effects. Rituxan has become standard treatment for patients with follicular lymphoma. Rituxan administered alone results in remissions in some patients with relapsed follicular lymphoma, and combining Rituxan with chemotherapy increases remissions.
The initial clinical trial that evaluated Rituxan in the treatment of follicular lymphoma demonstrated that the drug is well tolerated and did not cause significant side effects. This clinical trial involved patients with low-grade or follicular NHL who had failed previous treatments with chemotherapy, radiation therapy, or bone marrow transplantation. Approximately half of patients responded to four weeks of treatment with Rituxan. 
Re-treatment with Rituxan: Additional research has shown that 40% of patients respond to re-treatment with Rituxan and these second responses appear to be longer than the patients’ initial responses. Importantly, side effects were no different than from the first treatment. 
Longer duration of treatment: Patients with recurrent disease who were treated with eight weeks of Rituxan survived approximately two-times longer than patients treated for four weeks (23 months versus 13 months). Approximately 46% of patients responded to treatment. 
Chemotherapy plus Rituxan: The addition of Rituxan to chemotherapy improves response rates, but also increases side effects.
Fludara, either alone or in combination with other chemotherapy drugs may be the optimal type of chemotherapy to combine with Rituxan.
Patients with relapsed disease have been shown to respond to the chemotherapy drug Fludara plus Rituxan just as well as patients who have newly diagnosed follicular lymphoma. In a clinical trial that evaluated Fludara plus Rituxan in the treatment of patients with both stages of disease, 90% responded to treatment and 80% experienced complete anticancer responses.7
The combination of Rituxan and combination chemotherapy with Fludara produces more anticancer responses than combination chemotherapy alone; 83% of patients have been shown to experience a complete anticancer response with the combination, compared to 58% of patients who received only the chemotherapy drugs.6
Zevalin (90Yttrium-2b8 ibritumomab tiuxetan)
Zevalin is comprised of the targeted therapy, Rituxan, with a radioactive material (Yttrium 90) attached. This combination takes advantage of the anticancer effect of Rituxan while the radioactive material emits radiation that can directly destroy the cancer cells.
The Food and Drug Administration (FDA) has approved Zevalin, in combination with Rituxan, for the treatment of patients with low-grade NHL that has stopped responding to standard therapies.
Zevalin is an effective treatment for patients who have stopped responding to Rituxan. When Zevalin was administered to 57 patients with relapsed or refractory low-grade, intermediate-grade or mantle cell NHL who no longer respond to Rituxan, 15% had a complete anticancer response to treatment and 59% had a partial response. The anticancer responses lasted approximately 9 months. 
Bexxar® (tositumomab and Iodine 131)
Bexxar is similar to Zevalin in that it is comprised of a monoclonal antibody (tositumomab) that is attached to a radioactive material (iodine 131). Bexxar is FDA-approved for the treatment of a very specific group of patients with follicular NHL; they must have disease that is:
- Refractory to Rituxan
- Relapsed following chemotherapy
Clinical trials have shown that Bexxar produces anticancer responses in the treatment of patients with relapsed follicular NHL regardless of whether they have received Rituxan.
Bexxar for patient who have stopped responding to Rituxan: The clinical trial that led to the approval of Bexxar demonstrated that 68% of patients responded to treatment and the anticancer response lasted approximately 16 months. Most of the patients in this study (88%) had stopped responding to Rituxan.
A study published in 2005 showed similar results; 65% of patients responded to Bexxar and 35% had a complete response to treatment. More than half of the patients in this clinical trial did not respond to Rituxan and more than half were resistant to chemotherapy. 
Bexxar for patients who have not received Rituxan: Four additional clinical studies have shown that more than half (56%) of patients who have not received Rituxan also respond to Bexxar treatment. These patients had recurred or relapsed after chemotherapy and experienced an anticancer response to Bexxar that lasted for 12 to 18 months. Nearly one-third of the patients experienced a complete anticancer response and most of these continued in complete remission for four and a half years or more after treatment. 
Retreatment with Bexxar: Patients who have already received Bexxar may still benefit from retreatment. Clinical trial results indicate that over half of patients retreated with Bexxar experienced a complete or partial disappearance of their cancer. 
High-Dose Chemotherapy with Stem Cell Transplantation:
A Potentially Curative Treatment for Younger Patients
High-doses of chemotherapy are more effective at killing cancer cells than lower doses. However, high-dose therapy destroys many other cells in the body. A dangerous side effect of administering high-dose therapy is damage to the cells in the bone marrow that develop into mature blood cell, called stem cells.
Without functioning stem cells in the bone marrow, the body cannot produce red blood cells, white blood cells or platelets, which leaves patients vulnerable to infection and bleeding, and unable to supply adequate oxygen to their tissues.
However, bone marrow function can be restored after high-dose therapy by replacing the damaged stem cells with healthy ones. This is a procedure known as a stem cell transplant.
There are two possible sources of stem cells for transplantation; they may be collected from the patient prior to undergoing high-dose therapy or they may be collected from a donor. A stem cell transplant that utilizes the patient’s own cells is called an autologous stem cell transplant. When the stem cells are from a donor the procedure is called an allogeneic stem cell transplant.
Longer survival with ASCT: Results of a large clinical trial have demonstrated that patients with relapsed follicular lymphoma who respond to chemotherapy survived longer; these patients were five-times more likely to be cancer-free six years after treatment with high-dose chemotherapy and ASCT compared to continued conventional chemotherapy (see table 2). 
Table 2 High-dose chemotherapy with ASCT vs. conventional chemotherapy
Allogeneic stem cell transplantation: An allogeneic transplant utilizes stem cells from a carefully selected donor and is associated with higher risk because of the possibility that the donor cells may be incompatible.
Results of a study that compared outcomes between patients who underwent autologous versus allogeneic stem cell transplantation indicate that the two procedures appear to be equally effective after five years, despite higher rate of relapse among patients undergoing autologous transplant and more treatment-related deaths among patients who underwent allogeneic transplant (see table 3). 
Table 3 Outcomes of allogeneic and autologous transplantation
Three clinical trials have shown that approximately 60-80% of younger patients with relapsed follicular lymphoma survive when treated with allogeneic stem cell transplant:
- In the treatment of a group of patients who were 44 years of age, on average, 78% survived more than two years after treatment with an allogeneic stem cell transplant. At 2.3 years after treatment, there were no relapses among the 22 patients involved in this study. 
- A clinical trial conducted at a cancer center in France has demonstrated that in the treatment of patients under the age of 50, nearly 70% survived more than three years. Only two out of the 16 patients involved in this study experienced a relapse of their cancer. The researchers estimated that more than half patients would survive for two years or more without cancer. 
- In a trial that involved patients between the ages of 20 and 53 with relapsed or refractory disease, nearly 60% survived five years or more. One quarter of the patients involved in this trial died of treatment-related causes. 
Strategies to Improve Treatment of Relapsed Follicular Lymphoma
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of relapsed follicular lymphoma will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of relapsed follicular lymphoma include the following:
Advances in Targeted Therapy
Scientists continue to develop multi-drug chemotherapy treatment regimens that incorporate new or additional anticancer therapies. The addition of Rituxan to chemotherapy is an area of active investigation.
Cladribine plus Rituxan: Cladribine alone has been shown to produce anticancer responses in 58% of patients with relapsed follicular lymphoma. However, patients experienced significant side effects, including prolonged low blood cell counts.  The combination of Rituxan and cladribine appears to be associated with fewer side effects. 
Pentostatin plus Rituxan: Pentostatin (Nipent®) is a drug that is in the same class as Fludara, which has been proven effective in the treatment of patients with follicular lymphoma. The combination of Rituxan and pentostatin produced anticancer responses in 77% of patients with relapsed, low-grade NHL, including follicular lymphoma.  This combination was associated with limited side effects and may be an alternative to Fludara/Rituxan.
Rituxan plus Zevalin: Results of a clinical trial have shown administering Zevalin and Rituxan produces more anticancer responses, increases the likelihood that the cancer will disappear completely, and increases the time before cancer progresses compared to Rituxan alone (see table4 ). The 162 patients involved in this clinical trial had lymphoma that recurred following therapy, and the majority had stopped responding to further chemotherapy. 
Table 4 Addition of Zevalin to Rituxan significantly increases anticancer responses
Improving Outcomes of Autologous Stem Cell Transplantation
Rituxan and ASCT: The addition of Rituxan to treatment is integral to improving the results of autologous stem cell transplants for patients with follicular lymphoma.
Research indicates that the addition of Rituxan to the chemotherapy that patients undergo before stem cell collection increases the chance of collecting a stem cell sample that is free of cancer cells. In a clinical trial involving patients with follicular lymphoma, cancer-free stem cell samples were collected in 93% of patients treated with chemotherapy plus Rituxan compared to 40% for patients who only underwent chemotherapy alone before their stem cells were collected. 
Bexxar and ASCT: Researchers from the Fred Hutchinson Cancer Center have reported that high-dose therapy with Bexxar may be a better alternative to high-dose chemotherapy before autologous stem cell transplantation. This study compared the outcomes of 125 patients treated with high-dose Bexxar with ASCT to outcomes of a similar group of 98 patients who were treated with high-dose chemotherapy with ASCT, with or without radiation. Results indicate that the patients treated with Bexxar lived longer and were cancer-free for longer than those who underwent regular high-dose chemotherapy and stem cell transplant (see table).
Table High-dose Bexxar versus high-dose chemotherapy and transplant
Adding Immunotherapy to Rituxan
Immunotherapies are substances that stimulate the body’s immune system to destroy foreign substances, such as infection and cancer. Interleukins are substances that are produced by the body’s immune system that stimulate the immune system to attack cancer cells.
Rituxan plus interleukin-12 (IL-12): Researchers at the Mayo Clinic have reported that the combination of Rituxan and IL-12 may produce promising results in the treatment of patients with relapsed follicular lymphoma.  Researchers from the Dana Farber Cancer Center and Harvard Medical School have reported that more than half of patients treated with the combination have anticancer responses. These researchers also reported that patients who had an anticancer response or stable disease survived 13 months before their disease progressed. 
New Developments in Chemotherapy
Velcade® (bortezomib) is a chemotherapy drug that is FDA-approved for the treatment of patients with multiple myeloma. Velcade appears to produce anticancer responses in the treatment of patients with some types of NHL.  Research with this drug continues, and future clinical trials may evaluate Velcade in the treatment of patients with follicular lymphoma. Allogeneic Stem Cell Transplant for Older Patients
In an attempt to decrease the risk of treatment-related mortality with allogeneic stem cell transplant—which involves transplanting stem cells from a donor—doctors have administered high-dose chemotherapy regimens that are less aggressive. There is evidence that this approach may allow older patient to better tolerate treatment and be able to undergo transplantation. A reduced-intensity regimen that contained fludarabine followed by allogeneic stem cell transplantation appears to be an effective treatment for older patients with a low incidence of treatment-related complications. When this approach was used in the treatment of a group of patients who were, on average, 51 years of age, 84% of patients survived two years or more. 
While reducing the intensity of the high-dose regimen that precedes allogeneic stem cell transplants may be effective therapy for older patients with relapsed follicular lymphoma, this approach has not been proven superior to regular high-dose chemotherapy in the treatment of younger individuals.
 McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. Journal of Clinical Oncology. 1998;16 2825-2833.)
 Davis TA, Grillo-Lopez AJ, White CA, et al. Rituximab anti-CD20 monoclonal antibody therapy in Non-Hodgkin lymphoma: safety and efficacy of re-treatment. Journal of Clinical Oncology. 2000;18:3135-3143.
 Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004;103:4416-4423.
 Garcia-Conde J, Conde E, Sierra J, et al. Rituximab (IDEC-C2B8) and CVP chemotherapy in follicular or low-grade B-cell lymphoma after relapse: results after 6 months of follow-up. Proceedings from the 36th Annual Meeting of the American Society of Clinical Oncology. 2000;19:Abstract #96.
 Witzig TE, Finn IW, Gordon, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular Non-Hodgkin lymphoma. Journal of Clinical Oncology. 2002;20:3262-3269.
 Horning S, Younes S, Jain V, et al. Efficacy and Safety of Tositumomab and Iodine-131 Tositumomab (Bexxar) in B-Cell Lymphoma, Progressive After Rituximab. Journal of Clinical Oncology. 2005; 23: 712-719.
 Coleman M, Kaminski MS, Knox SJ, Zelenetz AD, et al. The BEXXAR Therapeutic Regimen (Tositumomab and Iodine I 131 Tositumomab) Produced Durable Complete Remissions in Heavily Pretreated Patients with Non-Hodgkin s Lymphoma (NHL), Rituximab-Relapsed/Refractory Disease, and Rituximab-Naive Disease. Proc Am Soc Hem, Blood. 2003; 102(11):29a, Abstract #89
 Kaminski M, Radford J, Gregory S, et al. Re-Treatment With I-131 Tositumomab in Patients With Non-Hodgkin Lymphoma Who Had Previously Responded to I-131 Tositumomab. Journal of Clinical Oncology. 2005. Early on-line publication. DOI: 10.1200/JCO.2005.01.0892
 Schouten HC, Quan W, Kvalay S, et al. High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin Lymphoma: Results From the Randomized European CUP Trial. Journal of Clinical Oncology. 2003;21:3918-3927.
 Toze CL, Barnett MJ, Connors JM, et al. Long-term disease-free survival of patients with advanced follicular lymphoma after allogeneic bone marrow marrow transplantation. British Journal of Haematology.2004;127:311-321.
 Ogura, M, Morishima Y, Kobayashi Y, et al. Durable response but prolonged cytopenia after cladribine treatment in relapsed patients with indolent Non-Hodgkin lymphomas: results of a Japanese study. International Journal of Hematology. 2004;80:267-277.
 Robak T, Smolewski P, Urbanska-Rys H, et al. Rituximab followed by cladribine in the treatment of heavily pretreated patients with indolent lymphoid malignancies. Leukemia Lymphoma. 2004;45:937-944.
 Drapkin R, Di Bella NJ, Faragher DC, et al. Results of a phase II multicenter trial of pentostatin and rituximab in patients with low grade B-cell Non-Hodgkin lymphoma: an effective and minimally toxic regimen. Clinical Lymphoma. 2003;4(3):169-75.
 Magni M, Di Nicola M, Devizzi L, et al. Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood. 2000; 96:864-869.
 Lazzarino M, Arcaini L, Bernasconi P, et al. A sequence of immuno-chemotherapy with Rituximab, mobilization of in vivo purged stem cells, high-dose chemotherapy and autotransplant is an effective and non-toxic treatment for advanced follicular and mantle cell lymphoma. British Journal of Hematology. 2002;6:229-235.
 15 Mangel J, Buckstein R, Imrie K, et al. Immunotherapy with rituximab following high-dose therapy and autologous stem-cell transplantation for mantle cell lymphoma. Seminars in Oncology. 2002;29(Suppl 2):56-69.
 Gopal AK, Gooley TA, Maloney DG, et al. High-dose radioimmunotherapy versus conventional high-dsoe therapy and autologous hematopoietic stem cll transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis. Blood. 2003;102:2351-2357
 Friedberg JW, Neuberg D, Gribben JD et al. Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular Non-Hodgkin lymphoma. British Journal of Haematology.2002;117: 828-834.
 Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus host disease, and treatment-related mortality. Blood. 2001;98:3595-3599.