Medically reviewed by Dr. C.H. Weaver M.D.  6/2021

Patients with follicular lymphoma (FL) 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.

The following is a general overview of treatment for relapsed follicular lymphoma. A myriad of treatment options has emerged and patients with FL can expect to have their disease controlled for many years. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. 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.

Table 1 Types of Follicular NHL according to two classification systems, REAL and IWF

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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)
  • cyclophosphamide
  • chlorambucil
  • 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 target the lymphoma 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.

Rituxan® (rituximab)

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.1

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.2

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.3

Chemotherapy plus Rituxan: The addition of Rituxan to chemotherapy improves response rates, but also increases side effects. While approximately half of patients have an anticancer response to chemotherapy alone, the addition of Rituxan has been shown to improve upon these results; three clinical trials have shown that more than 80% of patients respond to the combination of chemotherapy and Rituxan.4,5,6,7

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.7

Cellular Immunotherapy and Stem Cell Transplant

Autologous and allogeneic stem cell transplant and CAR T cell therapy be used to prolong survival and potentially cure some patients with advanced refractory follicular lymphoma. These therapies are constantly being refined published data on their effectiveness significantly lags their utilization. Patients should be evaluated at a cancer program with expertise and not rely on the opinion of their community oncologist regarding the role and effectiveness. 

CAR T Cell Therapy

The US Food and Drug Administration (FDA) has approved several chimeric antigen receptor (CAR) technologies for the treatment of malignant lymphoma. The different agents utilize slightly different methods of genetic engineering to transform the patient’s T cells into CAR-T cells. However all agents produce CAR T cells that bind to the CD19 protein; an antigen found on the surface of B- cells.

Results from the phase II ELARA CAR T cell trial of Kymriah® (tisagenlecleucel) in patients with relapsed or refractory follicular were updated at the 2021 Annual American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting.

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The ELARA clinical trial was designed to evaluate Kymriah in adult patients with relapsed FL and was performed in 97 patients from over 30 sites in 12 countries worldwide. At the time of reporting 94 patients were evaluable with a median follow-up of 11 months. Kymriah led to responses for the majority of patients treated - 86% of patients responded and 66% achieved a complete response. The duration of response to Kymriah has not been reached.

Patients did experience well documented side effects of CAR T cell therapies including prolonged low blood cell counts and hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah.

References

  1. Schuster, S. et.al. Efficacy and Safety of Tisagenlecleucel in Adult Patients With Relapsed/Refractory Follicular Lymphoma: Primary Analysis of the Phase 2 ELARA Trial. Oral Presentation #7508. 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, June 4-8, Chicago, IL.

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.11

Table 2 High-dose chemotherapy with ASCT vs. conventional chemotherapy

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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.12

Table 3 Outcomes of allogeneic and autologous transplantation

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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.13
  • 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.14
  • 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.15

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.  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. 

References

  1. 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.)
  2. 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.
  3. 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.
  4. Hiddemann W, Dreyling M, Unterhalt M. Rituximab plus chemotherapy in follicular and mantle cell lymphomas. Seminars in Oncology. 2003;30 (Suppl 2):16-20.)
  5. Czuczman MS, Koryzna A, Mohr A, et al. Bituximab in combination with fludarabine chemotherapy in low grade or follicular lymphoma. Journal of Clinical Concolog y. 2005;23:694-704).
  6. 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.
  7. 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.
  8. 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.
  9. 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
  10. 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
  11. 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.
  12. Van Besien K, Loberiza FR, Bajorunaite R, et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood. 2003;102:3521-3529.
  13. Forrest DL, Thompson K, Nevill TJ, et al. Allogeneic hematopoietic stem cell transplantation for progressive follicular lymphoma. Bone Marrow Transplantation. 2002;29:973-978.
  14. Yakoub-Agha I, Fawaz A, Folliot O, et al. Allogeneic bone marrow transplantation in patients with follicular lymphoma: a single center study. Bone Marrow Transplantation. 2002;30:229-234.
  15. 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.logy. 2005; 23: 667-675.