• When follicular lymphoma (FL) returns after initially responding to treatment, it is known as relapsed.
• When follicular lymphoma is resistant to treatment, it is called refractory.
• People with relapsed or refractory follicular lymphoma may receive treatments such as chemotherapy, antibodies, radioimmunotherapy, or stem cell transplants.

Many treatments are used to fight follicular lymphoma, a common type of non-Hodgkin lymphoma. Doctors consider several factors when recommending a treatment option that will likely work best for you, including your age, your symptoms, which parts of your body are affected, how much your lymphoma has grown, any other health conditions you may have, and your own personal preferences.

FL is usually slow growing. In some cases, treatment can safely be delayed. Other people will receive various treatments or combinations of treatments for FL, such as radiation or chemotherapy. Treatments may effectively kill all of the cancer cells and induce remission. Other times, follicular lymphoma doesn’t respond to treatment — known as refractory FL. Even after remission is obtained, FL often grows back again — known as relapsed FL. Relapsed or refractory FL may require more aggressive treatments.

Relapsed Follicular Lymphoma

For many cases of follicular lymphoma, and especially for advanced stage cancers, treatment works in a few phases. Induction therapy, also called frontline or first-line therapy, is the very first treatment used to try to reduce or eliminate tumors. If this first treatment is effective, consolidation or maintenance therapy aims to keep the cancer cells away and extend the length of time a person is in remission.

Usually, induction treatment will help. Many of the cancer cells will die, the tumor will shrink, and the lymphoma may even go away completely. This is called remission. However, sometimes the cancer grows back. This is known as a relapse. If you have a relapse, you may start experiencing symptoms again, and your doctor may recommend that you undergo more treatments.

Most people with follicular lymphoma will have a relapse at some point after receiving treatment and going into remission. Within two years of diagnosis, about 20 percent of people with follicular lymphoma will relapse. Within five years, the majority of people with advanced stage FL will have a relapse.

Read more about how follicular lymphoma is assessed for stage, grade, and prognosis.

Refractory Follicular Lymphoma

Sometimes, lymphoma cells are resistant to treatment. The lymphoma may not improve at all, or it may start to go away and then quickly come back. When a cancer doesn’t respond well to treatment, it is described as refractory. If your follicular lymphoma is refractory to your induction treatment, your doctor may change your treatment plan.

Treatments for Relapsed or Refractory Follicular Lymphoma

If initial induction therapy doesn’t work, a doctor may recommend a different set of treatments known as second-line therapy. The goal of second-line treatments is to help people with relapsed or refractory lymphoma obtain remission.

When deciding on a second-line treatment plan, your doctor will consider additional factors such as:

• Which treatments you used before
• Whether or not your previous treatments helped
• Any side effects of your past treatments

Watchful Waiting

If lymphoma has relapsed but is not causing symptoms, doctors may recommend a watchful waiting approach. In watchful waiting, your condition will be carefully monitored, but treatment will be delayed until there are signs your lymphoma is getting worse. Watchful waiting helps you avoid medication side effects. If you use this approach, it is important to have frequent follow-up appointments with your doctor to keep an eye on your disease.

Chemotherapy

If you have advanced lymphoma (stage 3 or stage 4), you will probably receive chemotherapy medication as a first-line treatment. If your lymphoma relapses, your doctor may recommend a different type of chemotherapy for a second-line treatment.

Chemotherapy drugs may be given alone or in groups. Some of the more common chemotherapy treatment plans include:

• CVP — Cytoxan (cyclophosphamide), Oncovin (vincristine), and Deltasone (prednisone)
• CHOP — Cytoxan (cyclophosphamide), Adriamycin (doxorubicin), Oncovin (vincristine), and Deltasone (prednisone)
• Treanda (bendamustine)

Antibody Therapies

Antibodies can also help people with lymphoma by recognizing and killing cancer cells. Antibodies are proteins produced by B cells that allow the immune system to develop immunity to viral and bacterial infections. Drugs manufactured using these proteins are known as monoclonal antibodies or biologics. The U.S. Food and Drug Administration (FDA) first approved monoclonal antibodies, including Rituxan (rituximab) and Gazyva (obinutuzumab), to help treat people with relapsed or refractory lymphoma. Today, they are also used as a first-line treatment. You may be prescribed rituximab if:

• You did not use rituximab during the first round of treatment.
• This drug seemed to help during the first round of treatment.

If rituximab did not seem to work well the first time around, your doctor may suggest that you try gazyva.

Radioimmunotherapy

Radioimmunotherapy is a combination of a radioactive material and a cancer-attacking antibody. Radioimmunotherapy may be a good option for people who can’t have chemotherapy, such as people who are older than 65 or have other health conditions. Zevalin (ibritumomab tiuxetan) is a type of radioimmunotherapy that has been approved to treat relapsed or refractory follicular lymphoma.

Other Medications

Another class of medications to treat refractory or relapsed lymphoma work by blocking a protein called phosphoinositide 3-kinase (PI3K). Many cancerous B cells need PI3K to grow and survive. Medications in this category include Zydelig (idelalisib), Aliqopa (copanlisib), Copiktra (duvelisib), and Ukoniq (umbrasilib).

Revlimid (lenalidomide) is a thalidomide analogue. Revlimid is believed to work by altering the immune system and blocking signals that tell cells to grow. Revlimid may be prescribed in combination with Rituxan to treat follicular lymphoma that was previously treated.

Tazverik (tazemetostat) interferes with the functioning of a gene known as enhancer of zeste homolog 2, or EZH2. Tazverik is believed to work by denying cancer cells molecules needed for growth.

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cells help produce all of the other blood cells, such as red blood cells and white blood cells. In many people with lymphoma, hematopoietic stem cells develop genetic mutations that result in cancer. Replacing cancerous hematopoietic stem cells with healthy ones is a high-risk procedure, but it can effectively treat or even cure some cases of lymphoma.

There are two forms of stem cell transplantation, autologous and allogeneic.

Autologous Stem Cell Transplantation

Autologous stem cell transplantation involves the removal of a person’s own hematopoietic stem cells from the body, followed by high doses of chemotherapy. Healthy stem cells are then infused back into the body.

Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation involves a similar process, except that the healthy stem cells infused after chemotherapy are sourced from a donor.

People who have relapses of follicular lymphoma may have stem cell transplants. Younger people are typically considered good candidates for this treatment.

Ongoing Research and New Treatments

People with refractory or relapsed follicular lymphoma may be able to try new treatments by participating in clinical trials. These treatments are still being studied, so it’s less clear how effective they may be. New therapies may end up not working well, or they could be even more effective than other current treatments.

One new treatment option for people with lymphoma is chimeric antigen receptor T cell (CAR-T cell) therapy. This treatment helps train a person’s own immune system to kill cancer cells. CAR-T cell therapy has a few steps:

• Immune cells called T cells are removed from the body.
• The genes in the T cells are modified to help them recognize lymphoma cells.
• The person with lymphoma receives low-dose chemotherapy.
• The altered T cells are returned to the body, where they attack cancer cells.

Other medications being studied in clinical trials for relapsed follicular lymphoma include:

• Imbruvica (ibrutinib) — A medication that may block B cells from growing
• PD1 or PD1L inhibitors — Medications that help the immune system better find and kill cancer cells

Read more about how follicular lymphoma develops and common FL symptoms.

Talk With Others Who Understand

For those living with a chronic health condition, it can help to talk to other people who understand what you’re going through. When you join MyLymphomaTeam, you will have a community of more than 7,000 people living with lymphoma.

Are you currently treating relapsed or refractory follicular lymphoma? Comment below or start a conversation on MyLymphomaTeam to share your own experiences, ask questions, or offer advice.