Treating Follicular Lymphoma (FL)

FL remains incurable, therefore the goals of treatment for FL include1,2:

  • Prolonged remission
  • Provide disease control
  • Improve quality of life
  • Reduce symptoms or side effects with supportive or palliative care

Indications for Treatment of FL

The GELF Criteria were established to help define FL patients with high tumor burden who are in greater need of treatment.3,4 If patients do not have these features, they may be managed with an observational, 'watchful waiting' strategy.4

GELF Criteria

Indicators for Treatment3,4

Patients must meet ≥1 criteria to be considered "high" tumor burden:

  • Any tumor mass > 7 cm
  • 3 nodes in 3 distinct areas each > 3 cm
  • Any B symptom
  • Splenomegaly
  • Organ compression, pleural effusion, or ascites
  • Leukemia (>5.0 × 109/L maligant cells) or cytopenia (leukocytes < 1.0 × 109/L and/or platelets < 100 × 109/L)
  • Elevated serum LDH or β2-microglobulin

Observation (Watchful Waiting)

Watchful waiting is typically is used when lymphoma is slow-growing, when it belongs to a subtype that does not respond well to chemotherapy or radiation, or when the disease is asymptomatic.5 During observation, patients receive periodic physical exams, lab tests, and imaging, with an emphasis on reportable symptoms.4,6

In FL, observation may be recommended if the potential toxicity of radiation therapy outweighs potential clinical benefit.4 Treatment following observation may be initiated when the patient experiences new symptoms or has progressive disease or disease transformation.4

Select Active Therapy Options for Follicular Lymphoma

If indicators for treatment are present, NCCN Guidelines® recommend that patients receive treatment. Types of treatment include4:

  • Immunotherapy ± chemotherapy regimens
    or
  • Clinical trial enrollment
    or
  • Palliative involved-site radiation therapy (ISRT), which delivers radiation specifically to the site where the tumor is located, therefore sparing many of the surrounding tissues from exposure7

For additional information on select treatments for FL, see the following sections:

Follow-up

For patients achieving a CR or PR to first-line therapy, maintenance therapy with anti-CD20 therapy (1 dose every 12 weeks) for up to 2 years is recommended.4

NCCN recommendations for follow-up in patients with FL include4:

  • History and physical exam and labs every 3-6 months for 5 years then annually or as clinically indicated
  • Surveillance imaging up to 2 years post-completion of treatment, including C/A/P CT scan with contrast no more than every 6 months or no more than annually >2 years post-completion
    • Exception: surveillance imaging should be performed whenever there are clinical indications
    • Routine surveillance imaging with PET-CT is not supported by evidence from published studies in lymphoma patients. A false positive rate of >20% for surveillance PET scans leads to unnecessary investigations, cost, and anxiety.8

Treatment of Relapsed/Refractory Follicular Lymphoma

  • If a patient demonstrates indications of disease progression during follow-up, they should be further assessed according to NCCN Guidelines©4
    • Assess for disease progression according to Lugano Response Criteria
      • If no disease progression: observation is recommended
      • If disease progression: assess for indications for treatment using GELF criteria to determine whether to initiate second line therapy

Clinical Connection

FL patients are likely to experience disease relapse, chemotherapy resistance, disease progression, and/or transformation into an aggressive disease.9

Patients who progress within 24 months of starting their first-line therapy have a worse prognosis than those patients who progress later. Approximately ~20% of patients with FL relapse within the first 24 months.10

Chemotherapy

Chemotherapy is one of the main treatments for all subtypes of NHL, including aggressive and indolent cancers.11,12
Typical treatment consists of one or multiple chemotherapeutic agents, often in combination with other drugs or involved site radiation therapy (ISRT) or surgery.12,13 Chemotherapy can be administered orally, by injection, intravenously, subcutaneously, or intrathecally (injected into the spinal fluid) for patients with CNS disease.13,14

Regimens vary by lymphoma subtype, stage (localized vs advanced disease), aggressive vs indolent forms, and patient characteristics.11-13

Radiation Therapy

External beam radiation therapy

Radiation therapy (RT) is most often done by external beam therapy (EBT), in which a carefully focused beam of radiation is delivered from a machine outside the body, uses high-energy X-rays, electrons, or protons to destroy cancer cells.15,16 Involved-site radiation therapy (ISRT) is a primary treatment in early stage FL and may be used as a palliative therapy for later sage FL.4

RT may be administered in the following scenarios4,17:

  • As an initial therapy
  • After or with chemoimmunotherapy
  • For palliative relief of tumor-related symptoms

The general side effects of EBT are typically mild and self-limited.17

Radioimmunotherapy (RIT)

Radioimmunotherapy is the administration of monoclonal antibodies (antibodies produced by a single clone of cells) with radioactive particles attached; the antibody seeks out the cancer cells, delivering toxic radiation.18


Radioimmunotherapy

Radioimmunotherapy

Targeted Therapy

Targeted therapies are designed to exploit certain characteristics of tumor cells, which may differ from patient to patient.19

Such tumor cell targets may include19:

  • Mutated genes
  • Proteins
  • Tissue microenvironment

The two most common types of targeted therapies are20:

  • small molecules
  • monoclonal antibodies (antibodies produced by a single clone of cells)

Targeted therapies have side effect profiles that may be different than other cancer treatments.19,20

Immunotherapy

Immunotherapies enable certain parts of the immune system to help the body fight cancer, infection, and other diseases. Such therapies either work with the patient’s own immune system or use man-made versions of the normal parts of the immune system to fight the cancer.21

Hematopoietic Stem Cell Transplant (HSCT)

A hematopoietic stem cell transplant, or HSCT, may be an option for some patients with FL whose disease is progressing or has relapsed (returned).4

In such cases, the doctor may feel that high-dose chemotherapy is necessary to stop the cancer. High-dose chemotherapy will kill the stem cells the person needs to make new blood. To manage this problem, HSCT is ordered after high-dose chemotherapy to add stem cells back into the person’s body and restore his or her ability to make new blood. In other words, HSCT allows the doctor to use higher doses of chemotherapy than a person would normally tolerate, increasing the likelihood of treatment success.22,23

There are two types of HSCT22,23:

  • Autologous (Auto) HSCT: People receive their own stem cells (harvested before chemotherapy) as a rescue after high-dose chemotherapy
  • Allogeneic (Allo) HSCT: People receive another person’s (donor) stem cells after high-dose chemotherapy. In some cases, patients may receive “syngenic” stem cells, which come from an identical twin donor

Clinical Trials

Because FL remains incurable as currently managed, clinical trials are in progress to identify novel therapies.24

Multiple clinical trials are utilizing new agents in attempts to develop additional treatment options for patients with newly diagnosed, relapsed, or refractory disease.24

According to the 2019 National Comprehensive Cancer Network (NCCN©) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-cell Lymphomas, clinical trials are highly recommended for patients with FL.4 Therefore, at the appropriate times in their treatment journeys, patients should be evaluated for and offered the option of entering a trial.

CNS, central nervous system; DLBCL, Diffuse large B-cell lymphoma; FL, follicular lymphoma; LDH, lactate dehydrogenase; MCL, Mantle cell lymphoma; RT, radiation therapy.

References: 1. Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of follicular lymphoma. J Clin Invest. 2012;122(10):3424-3431. 2. Lymphoma Australia. Treatment. https://www.lymphoma.org.au/page/22/treatments. Accessed September 20, 2018. 3. Sebban C, Mounier N, Brousse N, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood. 2006;108:2540-2544. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.4.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed July 10, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 5. Armitage JO, Longo DL. Is watch and wait still acceptable for patients with low-grade follicular lymphoma? Blood. 2016;127(23):2804-2808. 6. Leukaemia Foundation. "Watch and wait" management of indolent non-Hodgkin lymphomas. http://patientinfo.org.au/patientinfo/Watch-and-Wait-Management-Tool-10454.pdf. Accessed January 5, 2019. 7. Sasai K, Oguchi M. ISRT: a new radiation therapy for malignant lymphomas: Introduction to the review article by Specht and Yahalom. Int J Clin Oncol. 2015 Oct;20(5):847-8. 8. Cheson BD, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3067. 9. Lackraj T, Goswami R, Kridel R. Pathogenesis of follicular lymphoma. Clin Hematol. 2017;31:2-14. 10. Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the national LymphoCare study. J Clin Oncol. 2015; 33(23): 2516-2522. 11. Rummel P. Non-Hodgkin lymphoma and Hodgkin lymphoma: the role of the nurse navigator in improving patient outcomes. The Oncology Nurse. http://theoncologynurse.com/categories?view=article&secid=15168:best-practices-in-patient-navigation-first-issue-lymphoma-edition&artid=16419:non-hodgkin-lymphoma-and-hodgkin-lymphoma-the-role-of-the-nurse-navigator-in-improving-patient-outcomes. Updated May 27, 2015. Accessed January 5, 2019. 12. Merck Manual. 20th ed. Lane KAG, ed. Rahway, New Jersey: Merck & Co., Inc. 2018. 13. American Cancer Society. Chemotherapy for Non-Hodgkin Lymphoma. https://www.cancer.org/cancer/non-hodgkin-lymphoma/treating/chemotherapy.html. Updated August 1, 2018. Accessed June 14, 2019. 14. Cheung CW, Burton C, Smith P. Central nervous system chemoprophylaxis in non-Hodgkin lymphoma: current practice in the UK. Br J Haematol. 2005;131:193-200. 15. American Cancer Society. Radiation Therapy for Non-Hodgkin Lymphoma. https://www.cancer.org/cancer/non-hodgkin-lymphoma/treating/radiation-therapy.html. Updated August 1, 2018. Accessed May 16, 2019. 16. NIH. National Cancer Institute. External beam radiation therapy for cancer. https://www. cancer.gov/about-cancer/treatment/types/radiation-therapy/external-beam. Accessed June 14, 2019. 17. Justice TE, Martenson JA, Wiseman GA, et al. Safety and efficacy of external beam radiation therapy for non-Hodgkin lymphoma in patients with prior 90Y-ibritumomab tiuxetan radioimmunotherapy. Cancer. 2006;107:433-438. 18. Cancer.net. Lymphoma – Non Hodgkin: Treatment Options. https://www.cancer.net/cancer-types/lymphoma-non-hodgkin/treatment-options. Accessed September 26, 2019. 19. National Cancer Institute. NCI Dictionary of Cancer Terms. https://www.cancer.gov/publications/dictionaries/cancer-terms. Accessed June 12, 2019. 20. Røsland GV, Engelsen AST. Novel points of attack for targeted cancer therapy. Basic Clin Pharmacol Toxicol. 2015;116:9-18. 21. National Cancer Institute. Immunotherapy to Treat Cancer. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy. Accessed February 8, 2019. 22. American Cancer Society. High-Dose Chemotherapy and Stem Cell Transplant for Non-Hodgkin Lymphoma. https://www.cancer.org/cancer/non-hodgkin-lymphoma/treating/bone-marrow-stem-cell.html. Updated August 1, 2018. Accessed June 14, 2019. 23. National Cancer Institute. Stem Cell Transplant. https://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant. Accessed June 1, 2019. 24. Ansell SM. Non-Hodgkin lymphoma: diagnosis and treatment. Mayo Clin Proc. 2015;90(8):1152-1163.