Current Approach to the Disease Journey of Patients with Relapsed or Refractory Follicular Lymphoma: Focus on the Key Manifestations, Risk Stratification, and Management Patterns

Tycel J. Phillips, MD
Clinical Associate Professor
University of Michigan Rogel Cancer Center
Ann Arbor, MI
Peg Rummel, MHA, RN, OCN, NE-BC
Oncology Nurse Navigator
Hematology/Head & Neck Clinical Services
University of Pennsylvania Abramson Cancer Center
Philadelphia, PA
Andrew D. Zelenetz, MD, PhD
Medical Oncologist and Medical Director
Quality Informatics, Memorial Sloan Kettering Cancer Center Professor of Medicine, Weill Cornell Medical College Chair, Lymphoma Research Foundation, Scientific Advisory Board
New York, NY

Introduction

Follicular lymphoma (FL) is a low-grade type of B-cell non-Hodgkin lymphoma (NHL) and the second most common malignancy within NHLs.1,2 The development of chemoimmunotherapy has yielded solid positive clinical treatment outcomes for FL patients; however, this disease is usually considered to be incurable. Basic and translational research advances have identified several genomic and genetic alterations, as well as dysregulation of various signaling pathways and processes, including epigenetic modifications, that are inextricably entwined in the mechanisms of tumor initiation and progression in FL.3 This spawned the development and testing of numerous novel targeted agents in this disease. Setting the stage for our understanding of these exciting developments in the management of FL, in this article, Andrew Zelenetz, MD, PhD, Medical Director, Quality Informatics, and a medical oncologist specializing in lymphoma at Memorial Sloan Kettering Cancer Center (New York, NY); Tycel Phillips, MD, Clinical Associate Professor in Hematology and Medical Oncology and a medical oncologist at the Rogel Cancer Center of the University of Michigan (Ann Arbor, MI); and Margaret (Peg) Rummel, MHA, RN, OCN, NE-BC, Oncology Nurse Navigator at the Hematology/Lymphoma and Head and Neck Services and Cancer Network Administrator at the Abramson Cancer Center of the University of Pennsylvania Health System (Philadelphia, PA), discuss key information on FL, its clinical manifestations, prognostication, and therapeutic options, particularly in patients with relapsed or refractory disease. They also help us embrace the personal journey of patients with advanced FL and their caregivers, as patterns of care shift and new therapies are being introduced in select candidates hoping for better clinical outcomes. The role of support with oncology nurse navigators coordinating communication and education given the current landscape of these complexities is also presented and discussed.

Question: How would you compare the epidemiology and survival outcomes for FL versus more commonly diagnosed malignancies?

Andrew Zelenetz, MD, PhD: Follicular lymphoma represents a unique challenge to the community oncologist. This is a disease they don’t often see. The natural history of the disease is quite long, and patients will be coming back for treatment over a period of many years. Currently, the overall survival of patients actually approaches that of age- and sex-matched controls in the general population, but that’s as a consequence of repeated rounds of therapy because this is a chronic illness with a remitting and relapsing natural history. This is a disease that is going to require multiple courses of therapy over a long period of time, and this is quite different than some of the other, more common malignancies that a community oncologist is going to face.

Tycel Phillips, MD: As far as things on the ground that may be driving worse outcomes for patients’ follicular lymphoma, I think we know that there are a group of patients who do worse than others, a group that segregates out. We’ve had a very hard time delineating these patients out correctly through various prognostic scores to identify who these true high-risk patients are, and I think it’s something that further research is still looking into. But as of right now, if I see a patient in clinic, I can’t necessarily identify a truly poor-risk actor right away for a newly diagnosed follicular lymphoma patient.

Question: What is the spectrum of symptoms in patients with newly diagnosed FL and the role of optimal coordination of care at their initial presentation?

Tycel Phillips, MD: What sort of symptoms leads to the initial diagnosis for follicular lymphoma? I think we have a textbook answer and we have a real-world answer. I think in reality, most patients are incidentally found by presenting to the emergency room or whatever health professional they see for an alternative problem. And which is the nature of what we consider defensive medicine in the US. They consistently get CAT scans and other things which identify asymptomatic lymphadenopathy, which biopsy will lead to diagnosis of such as follicular lymphoma. It is an indolent lymphoma.

When we start thinking about symptoms, when the few patients who do have symptoms at diagnosis, these are your classical B symptoms. Fevers, night sweats, could be abdominal discomfort, weight loss. Very rarely will you see a patient present with all of these features, more commonly patients will come in and complain of fatigue, which is a very hard symptom to tease out in the US.

But large lymph nodes are one key characteristic. Again, fevers, night sweats, weight loss. Sometimes patients will be fatigued because of bone marrow involvement leading to anemia. It could be a splenomegaly causing left side abdominal discomfort, etc.

Andrew Zelenetz, MD, PhD: I agree. I think that the most common presentation is the asymptomatic patient that’s incidentally found. Some patients are going to find things themselves. They’ll identify a peripheral lymph node. They’ll be shaving and they’ll find a lymph node. They’ll be showering and they’ll palpate an axillary lymph node.

And I agree with Dr. Phillips, the symptomatic patient is the less common one, but they do present. And occasionally, they’ll present with the classic B symptoms of fever, night sweats, weight loss. But that’s relatively uncommon in newly diagnosed follicular lymphoma.

Peg Rummel, MHA, RN, OCN, NE-BC: The 2 things that I hear most from patients is they found a lump somewhere and they don’t know what to do with it. And they need to get seen by somebody. And they’re complaining of being fatigued and tired. And as a nurse navigator, I try to assess them and find out what’s been done. Have they had a biopsy? Who have they seen? And then that after discussing it with the patient, that helps me direct them to get them to the correct provider.

If they need to get in to get a biopsy, I’ll get them in to see a surgeon to get the biopsy done. If they already have a confirmed diagnosis, then I’ll work with them with getting records and getting them connected to the proper provider.

Question: How would you describe the nature of dysregulation of B-cell signaling in FL and its role in the initiation and progression of this malignancy?

Andrew Zelenetz, MD, PhD: Follicular lymphoma is derived, we think, from abnormalities of B-cell maturation. One of the early events is the translocation of the BCL2 gene to the immunoglobulin heavy chain locus, that’s seen in about 90% of cases. However, we know from experimental models that’s not enough to create lymphoma. There are multiple other steps, including very common mutations in chromosome-modifying genes like KMT2D, CREBBP, and EZH2. And what we see clinically is typically the presentation of diffuse adenopathy frequently about 50% to 70% of the time with bone marrow involvement as well. The B-cell signaling is important in this disease. There are a number of critical pathways in the biology of follicular lymphoma, including the CXCR5 pathway, as well as signaling through mTOR, Akt, and PI3-kinase.

Tycel Phillips, MD: Some of the signaling and pathways, unfortunately, have not translated over to easily targetable things that we can help to treat our patients with.

Question: What are the key criteria used to guide treatment decisions and choice of therapeutic agents in patients with relapsed or refractory FL?

Andrew Zelenetz, MD, PhD: The decision to treat is similar at all lines of therapy, including first line and second line. We typically are looking for patients who either are symptomatic, or who meet the Groupe d’Etude des Lymphomes Folliculaires (GELF) Criteria. The GELF Criteria include measurements of size of lymph node. So, 3 >3-cm lymph nodes, a single 7-cm lymph node, massive splenomegaly, cytopenias indicating involvement of the bone marrow with disease. There are some odd ones like malignant effusion, which are pretty rare in follicular lymphoma.4,5

Basically it’s, is there a lot of disease? Are patients getting symptomatic? There is some controversy about should you be using the GELF Criteria in the relapse setting? Or if there’s relapsed disease, should you just immediately treat? I think that the data support that in the asymptomatic patient, even in the relapse setting, you can continue to use the GELF Criteria to determine treatment. And this is actually what’s reflected in national guidelines, including the NCCN guidelines.6

Tycel Phillips, MD: In regard to the utilization of the GELF Criteria as far as treatment modality, I don’t think I have anything else really special to add. Just from a perspective for the community of oncologists, they should know that this isn’t a hard and fast rule, and obviously just guidelines to help you guide when and if you did need to treat your patient. But just because you have a patient with 3 lymph nodes >3 cm but the patient is otherwise well, doesn’t mean you necessarily have to treat that patient at that point. The goal in this, it’s a non-curative cancer. It’s to fix a problem when the problems present.

Question: How would expanding the choice of therapies for patients with relapsed or refractory FL help lead to an optimal personalized treatment choice, and what is the role of reinforcing patient/caregiver-directed education for successful disease management?

Tycel Phillips, MD: The benefit for patients, obviously is to have more effective and durable treatments, especially ones that are not necessarily based on cytotoxic agents. This is a disease where if things go right, patients are living as long as they should if they were not diagnosed with follicular lymphoma. Along those lines, obviously since we know that these patients will require multiple treatments throughout the course of their lifetimes, what we want to do is make sure that once we treat these patients, we’re providing treatments that are effective putting them into remissions, but also not necessarily burdening them with other comorbidities and toxic complications that may shorten their life span. Some of the things with chemotherapy drugs, depending on what we choose, can cause nerve damage, heart damage.

There’s always the risk of secondary cancers that can come with some of these agents. Not to mention the infectious complications, especially as follicular lymphoma is a disease of older patients. So again, those are some of the complications and risks that we want to avoid if we can. With some of these newer treatment options, it’s a bit of a trade-off. You’re trading a longer treatment in some situations with better tolerance with hopefully equivalent, if not better remission durations, which will allow us to, again, start treating these patients again later. And the one key thing I tell all my follicular lymphoma patients and what we all should consider, my goal is just to buy you more time, more time typically buys more treatments, which are better tolerated and generally more effective than what we had previously.

Peg Rummel, MHA, RN, OCN, NE-BC: With all the new therapies that are coming out and when patients call and are diagnosed with cancer, any type, they’re really scared and they have a high anxiety level. And part of what I do is really to find out what their status is. Are they able to come safely to the clinic every week for chemo? Or are they better off with an oral agent? What is their support system? Can they get back and forth to treatment? If they’re elderly, do they live alone? What kind of support do they have? Those types of things.

And I try to do an assessment, and then talk to our interdisciplinary team to figure out what the patient’s sharing with me. And as we have our case conferences and various discussions about our patients, what is the best therapy for the patients? And patients do a lot of research on “Dr Google,” and they think Dr Google is the best and knows everything. And part of what I try to do is talk to them about evidence-based research and the therapies that have been out there and proven and are in clinical trials.

Question: How do you apply tools that exist to predict high-risk disease in patients with relapsed FL, such as the POD24 metric (ie, patients with disease progression within 24 months) and repeat biopsy to exclude histologic transformation to a high-grade lymphoma?

Andrew Zelenetz, MD, PhD: A number of years ago, we undertook the LymphoCare Study, which was an observational study of thousands of patients with lymphoma.7 And that database allowed us to identify a group of patients who had been treated with a combination of rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone (R-CHOP) chemotherapy for follicular lymphoma, who did particularly poorly. These patients progressed within 24 months of their original diagnosis, despite treatment with R-CHOP chemotherapy. This group of patients had a median progression-free survival of about 5 years compared to the patients who did not progress within their first 24 months, who had a median progression-free survival that still has not yet been reached now more than 10 years well into the study period. It’s been changed over the years. Most people now use a definition of 24 months from the initiation of treatment.8 I think that’s a reasonable modification of the original definition, but clearly it represents a poor-risk patient population.

This has been identified by the Clinical Trials Network as the highest priority in follicular lymphoma to address patients with progression within the first 24 months. This group of patients frequently has a higher risk of transformed disease. And identification of those patients with more aggressive disease is critically important. Biopsies are essential for patients who progress within 24 months of their initial treatment. But even for the patients who still have follicular lymphoma and are progressing in this period, they don’t do as badly as the patients who transform clearly, but they still have an inferior outcome to patients who remain progression-free more than 2 years after their treatment.

Tycel Phillips, MD: I would say the only thing to add to what Dr Zelenetz already discussed in POD24 patients’ biopsies are essential, is that you don’t want to miss a transformative event. So as far as predictive measures, unfortunately we can’t predict these patients at start of treatment. If we did, we’d be much better off, but no, unfortunately these group of patients segregate themselves out after treatment as Dr Zelenetz discussed. These are the patients who are relapsing very quickly after initiation of chemoimmunotherapy. And they tend to be the worst actors, irrespective of transformation or not. Moving forward, obviously, we had a very big emphasis on trying to figure out better treatment strategies for these patients where I think we do have some strategies that seem to be effective in some situations. I think the biggest thing we’ve taken away from a lot of these early ventures is the percent of these patients who are probably transforming to diffuse large B-cell lymphoma was probably a lot higher than a lot of us predicted earlier on.9-12

Question: How do you select patients with relapsed FL for active surveillance and how do you best integrate active surveillance with the choice and timing of later lines of therapy? What do you consider the role of oncology nurses/nurse navigators to be in reinforcing therapeutic plans in patients with FL?

Tycel Phillips, MD: Follicular lymphoma is not a curative cancer so again, the initiation of treatment in and of itself should be embarked upon when you are improving upon some symptom that’s affecting the quality of life of the patient.

Because again, there’s a cost in any treatment that we give a patient. I mean, there are no free lunches, as people like to say, when it comes to administering these types of medications that are required to treat. Some of the bigger issues now that are taken into account include the psychosocial situation and sometimes patients have a very hard time living with the cancer and knowing that it’s there and we’re not doing anything about it, even though all of the studies that we’ve compared and looked at, there is no survival benefit to treating an asymptomatic patient. At least nothing definitive has shown that early intervention necessarily has improved outcomes in these patients, even though there’s some push to say that there are some benefits to treating some of these patients.

Again, as of now, the long-term data doesn’t support there’s a survival advantage in these situations. So again, it’s weighing the situation of, is your patient the type of patient that is okay living with this cancer and can function and resume their daily life without any hindrance from knowing that this cancer is present? Or if somebody’s very fixated on the cancer and can’t move on without having something done to at least put this cancer into some sort of remission.

So I think that’s the situation we are in right now, which obviously should, given the current situation with the pandemic, should also take a different light, especially because of the treatments that we use affect B-cells and as we’ve seen in this situation, patients with immune deficiencies, whether induced by us or induced by something they inherited, do fair very poorly in these situations with this virus compared to those who have intact immune systems.

Andrew Zelenetz, MD, PhD: There’s always been a question, whether there is a role for active surveillance. I happen to not like the term watch and wait, and I’ll explain why in a second, in the relapse setting. First, the reason I like active surveillance is because it is something we’re doing. We’re not telling the patient, “Come back when you’re symptomatic. If you have a big lymph node, give me a call.” We are actively watching patients. We can intervene at any time, and this actually helps an awful lot of patients get over that anxiety.

By telling them that you’re doing something active actually really helps them accept the fact that yes, early intervention is not going to change their long-term outcome, but they know that you’re watching them carefully and that it’s part of their treatment.

We recently published a paper with my former fellow, Dr Jake Soumerai,13 that demonstrated that the role of active surveillance was important in the relapse setting because if you think about the survival of patients, it’s the time that they’re on treatment plus the time they’re in remission. Plus, the time that they’re out of remission that could be on active surveillance before they need their next treatment.

If you reduce all of those terms, all of those opportunities to surveil a patient and reduce them to zero, you have to have much more effective therapies and we actually showed that by eliminating active surveillance, you could actually compromise a long-term outcome. So, I believe that there is a role of active surveillance in the relapse refractory setting. That’s why we use the GELF Criteria again in the relapse refractory setting. It gives us a means by which to decide about treatment.

Now, Dr Phillips elegantly said that these are not hard and fast criteria, and they are absolutely not hard and fast criteria. These are, it’s not aligned in the sand, it’s a way of approaching a patient and thinking about a patient. There are certainly patients with relapse refractory disease where you might want to start sooner because you can avoid having to use more toxic chemotherapy. Or there may be a situation where it’s most appropriate to try to defer treatment because, as Dr Phillips pointed out, we’re in the middle of a pandemic. It’s not over and compromising the immune system if it doesn’t need to be compromised is doing harm to the patient.14-16

Peg Rummel, MHA, RN, OCN, NE-BC: I agree with the active surveillance and patients are just really scared because they feel like we’re not doing anything with active surveillance and yet I tell them that is part of their plan and each patient’s care is individualized for them and this is the best plan that their treatment team has determined for them.

And as far as the anxiety and the worriment about not getting treated, as a navigator, I have them reach out to me. I try to get them connected with support services if I feel it’ll be beneficial for them to have other people to talk to in our support groups, and different things like that. I try to maximize my resources for my patients and really just be there for them to allow them to call me with questions and just reinforce the plan of care that this is the best plan for them at this time.

Concluding Remarks

In this article, our discussants touched upon various key aspects of the diagnosis, prognostication, care “flow,” and overall management of patients with advanced FL. In summary, we learned about the considerable unmet medical needs in patients with relapsed or refractory disease, and the challenges patients with this essentially still incurable malignancy continue to face and how considerate and coordinated care by several expert clinicians in a team setting can help optimize the experience of FL patients along their disease and therapeutic journey. Optimal communication with and education of the patient by the clinical team members is key in achieving optimal management and follow-up. Further advances in clinical and translational research with novel targeted drugs in FL will hopefully expand their role in combatting this disease in progressively less-advanced settings, when used alone or in combination with other anti-lymphoma drugs.

References

  1. American Cancer Society. Types of B-cell lymphoma. Updated July 24, 2020. www.cancer.org/cancer/non-hodgkin-lymphoma/about/b-cell-lymphoma.html. Accessed August 8, 2022.
  2. Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of follicular lymphoma. J Clin Invest. 2012;122:3424-3431.
  3. Green MR. Chromatin modifying gene mutations in follicular lymphoma. Blood. 2018;131:595-604.
  4. Brice P, Bastion Y, Lepage E, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1997;15:1110-1117.
  5. Solal-Céligny P, Lepage E, Brousse N, et al. Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d’Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol. 1998;16:2332-2338.
  6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): B-Cell Lymphomas. www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed August 8, 2022.
  7. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the national LymphoCare Study. J Clin Oncol. 2009;27:1202-1208.
  8. Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27:4555-4562.
  9. Boughan KM, Caimi PF. Follicular lymphoma: diagnostic and prognostic considerations in initial treatment approach. Curr Oncol Rep. 2019;21:63.
  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;33:2516-2522.
  11. Lansigan F, Barak I, Pitcher B, et al. The prognostic significance of PFS24 in follicular lymphoma following first-line immunotherapy: a combined analysis of 3 CALGB trials. Cancer Med. 2019;8:165-173.
  12. Casulo C, Dixon JG, Le-Rademacher J, et al. Validation of POD24 as a robust early clinical end point of poor survival in FL from 5225 patients on 13 clinical trials. Blood. 2022;139:1684-1693.
  13. Soumerai JD, Ni A, Alperovich A, et al. Time from diagnosis to 2nd treatment is a promising surrogate for overall survival in patients with advanced stage follicular lymphoma. Leuk Lymphoma. 2020;61:2939-2946.
  14. Casulo C. Follicular lymphoma: is there an optimal way to define risk? Hematology Am Soc Hematol Educ Program. 2021;2021:313-319.
  15. Batlevi CL, Sha F, Alperovich A, et al. Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups. Blood Cancer J. 2020;10:74.
  16. Qualls D, Salles G. Prospects in the management of patients with follicular lymphoma beyond first-line therapy. Haematologica. 2022;107:19-34.

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