Traditionally, advanced follicular lymphoma was treated with traditional chemotherapy regimens, either CHOP or CVP, which could induce remission but had little effect on overall survival. The discovery of the first monoclonal antibody, rituximab, altered treatment protocols fundamentally, causing much longer and more reliable responses to treatment. Relapsing follicular lymphoma may be treated with alternative drug regimens or an allogeneic or autologous stem-cell transplant. Several advanced new drugs show promise in treating the disease.

1. Watch & Wait (W&W) versus Immediate Treatment

Follicular lymphoma is indolent (slow-growing), and (at least for the moment) incurable. For this reason, studies have shown in the past that there is no benefit to beginning immediate treatment per se. The exception is in early, localized disease, when chemotherapy and radiation treatment may be able to effect a cure.

Most patients have advanced (Stage III or Stage IV) disease at diagnosis, but have no symptoms (are "asymptomatic") other than swollen lymph nodes. For such patients, the usual course of action is to monitor the disease for a period ranging from several months to several years, known as "watch & wait" (or, for those of us without white labcoats, "watch & worry"). This period involves regular scans and checkups with an oncologist or another responsible physician.

Typically, treatment begins once symptoms appear (night sweats, fever, and weight loss), when certain blood indicators change (e.g. LDH levels), and/or when the tumours grow to a certain size (one tumour over 5-10 cm long, or 3 tumours, each more than 3 cm long). Some oncologists also initiate treatment if the disease is present in the bone marrow.

2. First-Line Treatment for Follicular Lymphoma

Getting a good response to first-line therapy is important. According to a French study of pre-rituximab patients, as a general rule people who have a complete response to first treatment tend to outlive people with a partial response to first treatment.

The current standard is to combine an anti-CD20 monoclonal antibody, normally rituximab (Rituxan), with conventional chemical agents cyclophosphamide, vincristine (Oncovin), and prednisone, either with doxorubicin/Adriamycin (known as "CHOP") or without it (known as "CVP"). The decision to include or exclude doxorubicin is based on the oncologist's guess about whether it will be needed later in the disease, since doxorubicin causes serious cumulative heart damage and therefore cannot safely be used repeatedly. In general, R-CHOP has a response rate of about 95% (with 20% achieving complete remission), while R-CVP has a response rate of 80%-85% (with 40% achieving complete remission).

In older patients or patients unwilling to subject themselves to grueling chemotherapy, rituximab monotherapy (rituximab alone) is a viable treatment option. About 50% of patients will respond to rituximab alone, although the complete remission rate is much lower (about 6%). Still, this can be used to extend life and delay the need for riskier and more exhaustive chemotherapy.

There are a number of alternative first-line therapies. Widespread use of rituximab is only about 10 years old, and it is already on the brink of being superceded by more advanced monoclonal antibodies. Alternative therapies may involve replacement of traditional cytotoxic agents with alternative drugs like bendamustine (Treanda); replacement of rituximab with another anti-CD20 antibody (such as ofatumumab, Bexxar or Zevalin); or even elimination of traditional cytotoxic agents in favour of a combination of advanced new drugs. New drug regimens are often available through clinical trials, which randomize people to receive either the current standard of care or an experimental new treatment which has shown promise in earlier trials.

3. Consolidation for Follicular Lymphoma

Consolidation refers to a brief, supplementary therapy intended to convert partial response into complete remission and extend the length of progression-free survival time. Currently, consolidation is not a standard component of therapy, but some patients use radioimmunotherapy drugs such as Zevalin (ibritumomab) or Bexxar (tositumomab). Both of these are anti-CD20 agents, like rituximab, but are also carriers for a radioisotope (respectively, yttrium and iodine) which can kill cells the drug binds to. Both are also viable in monotherapy or combination therapy, in first-line treatment or to treat relapsed follicular lymphoma.

Bexxar is associated with more severe side effects, including a potentially increased risk of leukemia.

Currently, radioimmunotherapy is not used for consolidation treatment in the Canadian public healthcare system. Only British Columbia funds both Bexxar and Zevalin, and its protocols stipulate that the drugs are to be used only for third-line treatment.

4. Maintenance for Follicular Lymphoma

While consolidation is less common, maintenance therapy is an increasingly common strategy for treating follicular lymphoma following first-line treatment. Maintenance therapy involves giving chemotherapeutic dosages spaced out over a lengthy period of time, both to convert partial responses into complete remission but also to extend progression-free survival as long as possible. Currently, rituximab maintenance treatment is the most common choice. Cancer Care Ontario, for instance, provides eight doses of maintenance rituximab over 2 years, or one treatment every 3 months.
5. Second-Line (and Subsequent) Treatment for Follicular Lymphoma

Conventional wisdom is that follicular lymphoma is easy to treat, but hard to cure. Unfortunately, even patients in complete remission almost always relapse, usually within several years. (Whether this still holds true is a matter of some debate; at least some patients treated with rituximab and other new drugs go into long, deep remissions and may remain there permanently.) For this reason, planning treatment for follicular lymphoma also involves anticipating second- and subsequent-line treatments. 

Retreatment -- In many cases, and where cumulative toxicities or severe reactions don't rule it out, retreatment with one or more of the drugs used in the original treatment may be an option. As a general rule, retreatment can work but has both a lower success rate and a shorter response time.  

Fludarabine-Based Therapy 

Radioimmunotherapy -- Bexxar and Zevalin are appropriate treatments for relapsed follicular lymphoma patients, although they tend to have lower response rates and durations of response in this setting. Currently, the BC Cancer Agency funds both drugs for third-line use. They are not publicly funded in other provinces. 

Clinical Trials -- Clinical trials remain an option in relapsed lymphoma patients. Indeed, the most experimental new drugs are typically only available in this setting, on the brutal logic that people with relapsed disease have the most to gain and the least to lose from new treatments. See Part 8 for a discussion of experimental new drugs. 

Northoma has a page covering relevant clinical trials active in Canada

Stem Cell Transplant/Bone Marrow Transplant (SCT/BMT) -- Bone marrow and stem cell transplants are the logical endpoint of traditional chemotherapy. Rather than limit doses to allow some healthy marrow cells to survive, chemotherapy and radiation treatment are delivered intensively enough to wipe out the body's stem cells -- and, hopefully, the cancer along with them. Afterwards, healthy tissue or cells are then reintroduced, and hopefully enabled to replicate cancer-free. As a general rule, if a transplant is to be attempted it is better to do so relatively early on in the course of the disease (such as after first relapse). This is because, as chemotherapy options dwindle, the success rate of the transplant (which relies on chemotherapy to be effective) also falls. 

 There are two basic types of stem cell transplants used in the treatment of lymphoma. The first is an autologous bone marrow transplant, in which a sample of (hopefully) healthy cells are harvested from the body prior to the most intensive therapy, and then re-introduced afterwards. This is the least dangerous procedure, but is likely not curative in follicular lymphoma. An allogeneic transplant uses cells from a matched donor (ideally a sibling). Allogeneic transplants are curative, but much riskier because of the possibility of transplant-related reactions like graft-versus-host disease. 

6. Transformation 

The most important threat facing follicular lymphoma patients is disease transformation to a highly aggressive form of Diffuse Large B-Cell Lymphoma (DLBCL), which occurs in about 3% of follicular lymphoma sufferers per year. This is a fast-growing disease which requires urgent treatment, in accordance with the standard of care for that type of lymphoma. 

People with follicular lymphoma which transforms to DLBCL often have worse prognoses than people with primary DLBCL, although this may be because they have already been heavily treated (and are thus less sensitive to therapy). Some oncologists believe that the use of doxorubicin in up-front therapy reduces the risk of DLBCL transformation, while others argue that, since doxorubicin can often only be used once, it should be "saved" in case transformation occurs, so that emergency chemotherapy can be as powerful as possible. For this reason, the current standard protocol of the BC Cancer Agency is to use R-CVP for indolent lymphomas, and R-CHOP for aggressive lymphomas. 

7. New Therapies 

Lymphomas are particularly responsive to chemotherapy, and drug candidate research is highly active. Some of the most promising new drugs with effectiveness against follicular lymphoma include bendamustine, CAL-101, GA-101, inotuzumab ozogamicin, and ofatumumab. Northoma maintains a regularly updated page on New and Experimental Drugs

8. Alternative Medicine 

Alternative medicine is called that for a reason -- it's not proven to work. If it was known to work, you can be sure that Big Pharma would be falling all over itself to patent, purify, standardize, and synthesize every active ingredient. Which, in fact, it is, in those cases where there really are proven effects. Nevertheless, there are a number of published studies indicating a possible role for specific alternative medicines. 

These include Devil's Claw. More exotic options include urine therapy.

These are offered for education only; Northoma is highly skeptical of all alternative medicines. For further information, see Problems with Alternative Medicine. 

Further Reading 

See John Gribben, "How I Treat Indolent Lymphoma," Blood (2007). 

Other Lymphomas 

For mantle cell lymphoma, see Michele Ghielmini and Emanuele Zucca, "How I Treat Mantle Cell Lymphoma," Blood. For diffuse large B-cell lymphoma (DLBCL), see James Armitage, "How I Treat Patients with Diffuse Large B-Cell Lymphoma," Blood (2007); and Michael Pfreundschuh, "How I Treat Elderly Patients with Diffuse Large B-Cell Lymphoma," Blood (2010).