Follicular non-Hodgkin's lymphoma

 

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Follicular lymphoma

This is the most common of the indolent lymphomas and accounts for about 70% of them, and about 22% of all lymphomas in North America and Europe. At the bottom of this page is an explanation of where the name follicular comes from and what it looks like under the microscope.

Follicular lymphoma is divided into 3 grades. Grade 1, 2 or 3. However Grade 3 is somewhat blurry because it can appear to the the indolent form of follicular lymphoma or it can appear to be the more aggressive form. The grade refers to the number of large cells that appear under the microscope. Large cells tend to behave a bit more aggressively than small cells. Although more large cells appear in Grade 2, it is for all intents and purposes considered the same as Grade 1 from a prognosis and treatment point of view. See more information below about grade 3 follicular. If you are confused about the difference between grade and stage you are not alone. Here are links to the two definitions.

Grade explanation

Stage explanation

 

Diagnosis and Prognosis

Follicular lymphoma is a slow growing type of NHL which responds very well to treatment, but can rarely be cured. Despite the fact that it cannot be cured, the prognosis is generally very good and the median survival is about 8-15 years according to the NCI. However the Stanford University school of medicine has authored a long term study showning that since 1960 the median survival has increased from just 11 years in that decade, to over 18 years in the pre-Rituximab era, and in the current Rituximab era the median has not been reached after about 12 years of follow up. This study was published in June 2013 Presumably once enough years have passed since Rituximab was introduced (1997) enough years will have passed to have updated data. Maybe we will find overall survival is over 20 years.

Read the Stanford study here.

Another recent study looks at the dramatic improvement in survival over the past 3 decades with the introduction of Rituxan in the late 1990's.

Patterns of survival of follicular lymphomas at a single institution through three decades

Age also plays an important role in the prognosis. Recent data from the 2011 ASH convention has shown that the median cause specific survival for patients under the age of 40 is 24 years. Cause specific survival refers to the people who did, or did not die of their follicular lymphoma as opposed to other causes of death. Here is the study which examines the role of age on survival. Again, it is important to note the cause specific survival as opposed to overall survival. Quite simply put, those over 60 are obviously at higher risk of dying of "something" than those under 40.

 The Importance of Age in Prognosis of Follicular Lymphoma: Clinical Features and Life Expectancy of Patients Younger Than 40 Years

Despite the fact that fNHL is considered incurable it can usually be managed very well and it responds well to treatment. Some even consider it a chronic disease rather than a terminal one. The choice of treatment depends on many factors, but usually a watch and wait approach is appropriate for patients who are not exhibiting any symptoms, who do not have bulky disease, or who do not have any major organs threatened by their tumours. Some patients may be uncomfortable with W&W and prefer to take some active action against their disease. However studies have consistently shown that the survival is the same whether treatment is initiated immediately or deferred until needed. Similarly, treating aggressively upfront does not improve the survival over treating with minimal necessary treatment. Patient and doctor preferences must both be considered when choosing treatment.

One of the primary concerns for any patient with follicular or other indolent lymphoma is transformation to a more aggressive lymphoma such as diffuse large B-cell lymphoma. Click the link below to read more about transformation.

Information about Transformation

Below is a detailed description of the pathology of follicular lymphoma. It may help to give a better understanding of exactly how it occurs and some of the challenges understanding it.

How follicular lymphoma develops

One of the key points to remember about lymphoma is that there is no single cause. You cannot point at any single risk factor such as pesticide exposure and say, "THAT" caused my lymphoma. It takes multiple mutations to the cell before it becomes cancer. As a case in point, the t(14:18) chromosomal mutation is the hallmark of follicular lymphoma. Virtually all follicular lymphoma patients have that mutation. But surprisingly so do many of the healthy population. Some of those healthy people go on to develop follicular lymphoma and others do not.  Here are some detailed articles on that topic and what else is necessary to develop fNHL.

Nature and importance of follicular lymphoma precursors

 

Next is a study about the t(14:18) mutation.

Human t(14;18)positive germinal center B cells: a new step in follicular lymphoma pathogenesis?

Here is a peer review that discusses what the above link means.

 

Molecular pathogenesis of follicular lymphoma

 

Grade 3 follicular

This type of follicular lymphoma has commonly been associated with a worse overall survival rate. But this is highly controversial, and different studies show different results.  The follow study reveals that dividing grade 3 into 3a (similar to grade 1 & 2) versus grade 3b (similar to diffuse large B-cell) is not exact enough. It must be divided into grade 3 with less than 50% diffuse component, versus grade 3 having more than 50% diffuse component. Grade 3 with <50% has an outcome very similar to grade 1 & 2.

Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience

Here is more information about low grade and grade 3 fNHL

A very recent study looks at the genetic features of Grade 3 follicular lymphoma.  While it does not make ground breaking conclusions it does find additional information about the features of this type of NHL. It finds that some grade 3B follicular lymphoma's are purely follicular, while others are really DLBC with a grade 3B follicular component. As always however, diagnosing this is an advanced art, and requires detailed molecular and genetic testing which is not routinely done on every follicular patient.

Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles

Here is a peer review of the above article by another lymphoma specialist.

Follicular lymphoma grade 3B: is it a real disease?

 

Treatments
Watch and wait

In many cases treatment may be deferred and a watch and wait approach is appropriate. Studies have consistently shown that there is no survival benefit to treating immediately versus waiting until treatment is necessary.  In this first study they confirm that for low tumour burden patients watch and wait is still a valid choice.

Watchful Waiting in Low–Tumor Burden Follicular Lymphoma in the Rituximab Era: Results of an F2-Study Database

What confuses the issue however is the availability of low toxicity treatment like Rituxan or radioimmunotherapy.  With their low toxicity and high efficacy it might be time to abandon watch and wait in favour of these therapies. It is known that they will delay the time until more aggressive chemotherapy is required. However it is still too early to say with any certainty that they will improve the overall survival. Here is a large study that reviews watch and wait versus treatment with Rituxan.

Has the time come to leave the "watch-and-wait" strategy in newly diagnosed asymptomatic follicular lymphoma patients?

Some of the factors that may indicate the need for treatment include:

  • Presence of B symptoms
  • Loss of quality of life
  • Bulky tumours >10cm
  • Tumours which are threatening major organs
  • Patient preference

That last reason is a common one. There are many people who just cannot wrap their head around the concept of having cancer and doing nothing about it. This is a valid option for those who so desire.  A recent study does show that using Rituximab plus Rituximab maintenance does delay the time until chemotherapy is needed, but it does not give a survival advantage. Patients must balance the disadvantage of going for Rituxan infusions every few months, versus delaying the need for chemotherapy with all its side effects. Read the study here:

When treatment is initiated there are many options to choose from. There are no right or wrong choices and patient preference often plays a role. Some prefer the mildest effective treatment to preserve lifestyle and healthy living, others prefer more aggressive upfront treatment for peace of mind and the feeling of eradicating the disease. Both approaches have merit. Listed here are options from mild to more aggressive.

Oral Chlorambucil is a very effective treatment though it has fallen out of favour. Lack of profit for the prescription drug is a motivating factor. Nevertheless this alkyating agent is highly effective in fNHL, very convenient, and has an excellent side effect profile.

Single agent Rituxan is another choice. Rituxan is a monoclonal antibody therapy and not chemotherapy. You can read more about monoclonal antibodies by clicking here.  Although single agent Rituxan has only moderate efficacy it is very mild in terms of treatment and does not burn any future treatment options. It can be an excellent choice for those who need treatment but are wishing for minimal intervention. Where it really shines though is when combined with chemotherapy. In that setting there appears to be a highly synergistic effect.

Next would be combination chemotherapy such as:
  • Bendamustine + Rituxan (B-R)
  • CVP+Rituxan (R-CVP)
  • CHOP + Rituxan (R-CHOP)
  • Radioimmunotherapy such as Bexxar or Zevalin (note: Bexxar was discontinued in 2014)
  • Fludarabine + Rituxan (RF)
  • Fludarabine combination such as FND, FM or FC; both with Rituxan

Historically CVP+Rituxan and R-CHOP have been the most widely used treatments when therapy is required. CVP is highly effective and reserves the option of using the anthracycline (the Doxorubicin) in CHOP for later if required.

However recent data shows that Bendamustine+Rituxan may be superior to R-CHOP. Although Bendamustine has been around for many decades in Europe, it has only recently (around 2007) started to be used in North America. A study published at the 2009 ASH convention shows clearly superior response rates, and progression free survival with B-R as compared to R-CHOP. Lower toxicity is another benefit.

Read the B-R versus R-CHOP ASH study here:

A second study released in 2013 shows a clear superiority for Bendamustine and Rituxan versus R-CHOP.

Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomized, phase 3 non-inferiority trial

There still remain some unanswered questions about Bendamustine+Rituxan. The first question is with respect to secondary cancers years down the road. Most chemotherapy regimens are known to significantly increase the risk of secondary cancers 10-15-20 years down the road. It will take many years before we know if Bendamustine makes that risk higher, or lower.

The other unanswered question is whether or not using Bendamustine will reduce the effectiveness of future therapies when they are required. This too is a question that will take many years to answer.

The Cancer Network has a thorough review of the management of follicular lymphoma in the upfront and relapse setting. Although you need to create an account with the Cancer Network, it is free. This review is a comprehensive review of current practice throughout the world, and in clinical trials. It reviews the commonly used treatments, the outcomes of those treatments, the patient characteristics and future directions. This is a must read.

Management of Follicular Lymphoma in the Up-Front and Relapsed Settings from the Cancer Network

Here are two articles from two prominent experts in lymphoma. In each article they discuss the current approaches to treatment and management of follicular lymphoma. What is most notable is that even in this modern era there is still no once size fits all approach. With many treatment options that are highly effective, the decision often becomes a consensus discussion between the patient and their doctor.

Bruce D. Cheson, MD: How I Manage Follicular Lymphoma

Therapy of newly diagnosed follicular lymphoma

 

Treatment consolidation

After initial treatment has been completed it is is becoming increasingly common to consolidate that treatment by including maintenance Rituxan or consolidation with radioimmunotherapy in the form of Zevalin or Bexxar. All three forms of consolidation have shown quite conclusively to prolong progression free survival. Whether the improve overall survival is still not clear, but it is hope that this proves true.  The USA National Comprehensive Cancer Network has now included all three forms of consolidation as a Category 1 level of evidence and consensus as frontline treatment for follicular lymphoma. This is their highest category indicating that there is ample evidence to support their recommendation and there is uniform consensus from their panel of experts. It will not be surprising to see this approach used for other types of indolent lymphoma as well. 

Another option that is becoming increasingly promising is upfront radioimmunotherapy (Zevalin or Bexxar). The lower toxicity than chemotherapy along with impressive results are beginning to make this a very attractive choice.

Vaccines are becoming increasingly investigated to maintain remissions. It just makes sense that if you can achieve remission with treatment, then a vaccine can prevent it from coming back. Visit our vaccines page for details about many of the vaccine options. A recent study from 2011 looks at the possibility of using a vaccine instead of maintenance Rituxan to maintain a remission. This appears to be a promising option but it is still too early to know if it can replace maintenance Rituxan. Click the link below to read the study.

Idiotype Vaccination As Consolidation Therapy: Time for Integration Into Standard of Care for Follicular Lymphoma?

Click here to see a complete list of common chemotherapy protocols for NHL

 

Stem cell transplants for follicular lymphoma

What about Stem Cell Transplants? Should they be used for follicular lymphoma?  This has long been a controversial issue with many differing opinions. However in 2013 the European group for Blood and Marrow Transplantation did an in-depth study and analysis with many expert haematologists to come up with a recommendation for the proper time to use SCT for fNHL.

Simply put they do not recommend SCT as first line therapy even for high risk patients. They do recommend it for patients in first relapse who had a short remission.  They also have additional recommendations. Read the study below.

Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party

Below is a link to an experts review of the above study. Sometimes a non technical review helps put things in better perspective.

Transplantation in follicular lymphoma: not “yes or no” but “whom and when”

Here is some additional information on this very controversial topic from the Journal of Clinical Oncology. It is a very provocative discussion.

Should We Transplant Indolent Lymphoma?
http://www.jco.org/cgi/content/full/23/25/6263-a

 

The reply from the author of the original study (see below)

http://www.jco.org/cgi/content/full/23/25/6264

 

The original study

Moderate Increase of Secondary Hematologic Malignancies After Myeloablative Radiochemotherapy and Autologous Stem-Cell Transplantation in Patients With Indolent Lymphoma: Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group

 

Rituximab Purging and/or Maintenance in Patients Undergoing Autologous Transplantation for Relapsed Follicular Lymphoma: A Prospective Randomized Trial From the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

 

What Is the Role of Stem-Cell Transplantation for Follicular Non-Hodgkin Lymphoma in the Rituximab Era?

The following study looks at the results of using SCT versus more traditional chemotherapy for follicular lymphoma patients in their first relapse. The SCT arm has dramatically improved results.

Impact of the use of autologous stem cell transplantation at first relapse both in naïve and previously rituximab exposed follicular lymphoma patients treated in the GELA/GOELAMS FL2000 study

 

Here is a study that looks at the long term outlook for people who have had a relapse after an SCT. It also reports on the risk of relapse after SCT (less than 50% relapse rate.)

Characteristics of relapse after autologous stem-cell transplantation for follicular lymphoma: a long-term follow-up

 

A 2010 study examines the role of mini-allogeneic transplants using in-vivo purging and Donor Leucocyte Infusions. The patients in this study had been heavily pre-treated with a median of 4 prior therapies including some patients who had an autologous SCT previously.

They first deplete the patients T-cells using Fludarabine, and Alemtuzumab to help promote full donor chimerism after the transplant. They hypothesize that a significant percentage of their patients are cured using this approach.

T-Cell–Depleted Reduced-Intensity Transplantation Followed by Donor Leukocyte Infusions to Promote Graft-Versus-Lymphoma Activity Results in Excellent Long-Term Survival in Patients With Multiply Relapsed Follicular Lymphoma

 

Other information

 

Is follicular lymphoma incurable?

Perhaps this is not as true as it has been in the past. Below are some recent studies which show how long term survival is becoming more common for follicular lymphoma.

From the Cancer Network (free membership is required) an expert article that discusses several types of lymphoma. But for follicular lymphoma they examine the data that shows the median survival 25 years ago was only 5-10 years, and now it is approaching 20. This means that most people with fNHL are not likely to die from the lymphoma.

Retrospective on the Last Quarter-Century in Hematologic Oncology

Aiming for a curative strategy for follicular lymphoma

New Treatment Options Have Changed the Survival of Patients With Follicular Lymphoma

Improvement of Overall and Failure-Free Survival in Stage IV Follicular Lymphoma: 25 Years of Treatment Experience

 

The following retrospective study looks at the dramatic improvement in survival over the past 3 decades, with the Rituxan era showing a huge improvement of 5 year survival from 80% in the 1970's to 91% in the Rituxan era.

Patterns of survival of follicular lymphomas at a single institution through three decades

Following is a review of the potential curability of advanced fNHL by Fernando Cabanillas from MDA

Curability of Advanced Indolent or Low-Grade Follicular Lymphomas: Time for a New Paradigm?

A response from another expert (Ian Edwin Haines)

Should the Paradigm Shift for Low-Grade Follicular Non-Hodgkin Lymphoma Be Toward Less Therapy?

And finally a response from the original author Fernando Cabanillas

 

Here is an excellent Continuing Medical Education article (CME) which discusses whether or not radioimmunotherapy offers the chance to cure follicular NHL. (Paid subscription required)

Radiolabeled and Native Antibodies and the Prospect of Cure of Follicular Lymphoma

  

Next is a 2012 study that has over 11 years follow-up. In this study they used a non-myeloablative allogeneic stem cell transplant to achieve a 78% progression free survival at a median of 11 years follow-up. That is very impressive.

Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results

  

In 1998 a study was started which examined using extended Rituximab to see how it would affect survival of patients with fNHL. The first results from that study were published in Blood in 2004 with impressive results. Here is that study.

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

 

In 2009 follow up results were published at the ASCO convention. Those results confirmed the earlier results. Here is that abstract.

Long-term follow-up of patients with follicular lymphoma (FL) receiving single agent rituximab at two different schedules in study SAKK 35/98

 

Medscape has an excellent article which discusses the above study and puts it into perspective and how a cure may actually be achievable. Medscape requires a membership to view its articles, but membership is free and takes only a minute to setup.

ASCO 2009: Prolonged Rituximab Extends Remission in Follicular Lymphoma

 


 

Here are some links to additional information about follicular lymphoma.

E-medicine follicular lymphoma

NCI information about indolent lymphomas
 
The tumour microenvironment is currently a very hot area of research. This is referring to the role the healthy cells in the tumour behaviour and prognosis of follicular NHL.

Click here for more detailed information about the microenvironment

 


 

Where the name "follicular" comes from

The name of this lymphoma derives from the location and behaviour of the cancerous cells. They usually originate in the lymphoid follicles, but more important is that they grow in a follicular pattern. This means that the cells tend to clump together or "stick" together.

 

normal lymph node

Above is an image of a normal lymph node slice at a medium magnification. Notice how it has those round "follicles" around the outer top edge. They are the pale purple circles you see.  That is what a normal lymph node should have. For a drawing of the same thing click here:

 

follicular

Here is slide of a lymph node with follicular lymphoma. Notice how many more of those follicles there are! And notice how tightly packed they are throughout the node, rather than just at the outer edge.

While follicular lymphomas very often form outside of the lymph nodes, it is this follicular pattern of growth that gives it its name. (past classification systems called it nodular) 

 

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