Alan Skarbnik, MD

Because of the challenges we see, particularly with patients who have early disease progression, POD24 [progression of disease within 24 months], there are a number of clinical trials trying to address what may be the best way to salvage these patients and provide longer-term remissions.

The combination of novel agents with or without chemotherapy is being studied. CAR [chimeric antigen receptor] T-cell therapy as a second line for patients who present with POD24 is being studied as well to see if using that approach earlier provides a better outcome.

A number of these trials are single arm and are not being compared to what we have available or to stem cell transplantation. Hopefully in the future we’re going to have those types of comparisons to better understand what would be the best sequence for these patients.

There’s still a lot we don’t know. Choosing frontline therapy for follicular lymphoma is certainly less complicated than choosing a second or further line of therapy because of the options and to some extent because of head-to-head comparison between different approaches.

This needs to be tweaked patient to patient, looking at the goals of the patient, comorbidities, fitness, performance status, how long did it take for disease to recur, or how long the remission lasted.

Those are questions that are still open, and unfortunately we don’t have the right answers yet. Fortunately, we have options, and I do underline the importance of clinical trials. For patients who do present with relapsed disease, particularly POD24, if a clinical trial is available, I certainly recommend looking at the rationale for the clinical trial to see if it’s appropriate because it may provide benefits for the patients and also for the physicians to best understand how to treat this disease.

In general, my personal approach for treating follicular lymphoma is again, largely patient dependent and of course physician dependent, and experience with certain regimens versus not. For patients who can tolerate chemoimmunotherapy, I do prefer a bendamustine-based approach in the frontline setting. But for patients who present with very bulky disease, or where there is a concern for high-grade transformation but not proven, or patients who present with grade 3b disease, for these patients, I prefer a CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] approach.

For younger patients who are receiving bendamustine, I tend to use obinutuzumab as the bendamustine partner, but using rituximab is certainly a good option as well.

The question of maintenance versus no maintenance will be decided between physician and patient, understanding that maintenance does provide PFS [progression-free survival] improvement but does not provide overall survival improvement.

In the setting of the [COVID-19] pandemic, using an anti-CD20 monoclonal antibody for a prolonged period may be counterproductive, particularly with the untoward effects it has on the vaccination for SARS-CoV-2.

Now, for patients who are not fit or are not adequate for chemoimmunotherapy, I tend to choose rituximab alone or rituximab with lenalidomide in the frontline setting. For these patients I do tend to use the published regimen with rituximab.

For patients with early stage disease that is in a single site and who are younger, we may consider radiation therapy with a potentially curative intent, but certainly observation and active surveillance for these patients is also appropriate.

For patients with relapsed disease, again it depends whether the progression of disease happened within 24 months of initial therapy or not. For patients with POD24 who are fit, I do generally recommend referring to a transplant center and using an intense chemotherapy salvage regimen, followed by autologous stem cell transplantation consolidation, if a clinical trial is not available.

For patients who are not fit to undergo that approach, I do believe that lenalidomide plus rituximab, if they did receive a frontline chemoimmunotherapy, is a valid approach. For those patients who received lenalidomide in the frontline setting, then trying other novel agents may be more advisable if they’re not fit to undergo chemoimmunotherapy at that point.

A 60-Year-Old Man with Follicular Lymphoma

A 60-year-old man presents with a 4-month history of fatigue, decreased appetite, occasional fevers, and a 7-lb unintentional weight loss

PE: palpable right axillary lymph nodes, ~2.5 cm and bilateral cervical lymph nodes, ~3 cm, spleen palpable 4 cm below left costal margin

Labs: ANC 1.6 x 10^9, WBC 11.4 x 10^9, lymphocytes 42%, HB 9.7 g/dL, plt 97 x10^9, LDH 402U/L, 3.4 B2M ug/mL; HBV negative

Excisional biopsy of axillary lymph node on IHC showed CD20+, CD3+, CD5+, BCL2+, Follicular lymphoma grade 2

Bone marrow biopsy showed paratrabecular lymphoid aggregates, 38% involvement

PET/CT showed right axillary, bilateral cervical, and mediastinal lymphadenopathy (3.1 cm, 3.1 cm, and 2.6 cm respectively)

Patient was treated with obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. He completed 6 cycles and treatment was well tolerated.

He continued on obinutuzumab maintenance.

19 months later, he complains of fevers, chills, and worsening fatigue.

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An oncologist ruminates on emerging treatment options in follicular lymphoma and offers some clinical pearls.

Follicular Lymphoma: Emerging Treatments

 Nineteen months after diagnosis, the patient presented the same symptoms he had at baseline: chills, fever, worsening fatigue, highly concerning for relapse of disease.

Of all the patients with follicular lymphoma who present and are treated with a frontline chemoimmunotherapy, about 20% have early relapse, a little bit more in patients who receive CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] or CVP [cyclophosphamide, vincristine, prednisone] as the chemotherapy, a little bit less in patients who receive bendamustine as initial chemotherapy.

However, we see a higher rate of high-grade transformation in patients who receive bendamustine and present with early relapse, showing that bendamustine doesn’t necessarily prevent high-grade transformation but it does decrease the rate of early progression overall compared with what we see with CHOP or CVP.

This is of concern because there are studies showing that progression of disease within the first 24 months [POD24] post treatment is a high predictor of poor overall survival. There are a couple of different studies. The CONSORT study is the most cited one…. They have retrospective studies from the British Columbia Cancer Consortium evaluating patients. In their cohort it reflects the same findings. The likelihood of death in patients who present with POD24 is much higher than for those patients who present with longer-term relapse.

For instance, in the CONSORT study, for patients who presented with progression of disease less than 2 years after initial treatment, the 5-year overall survival was 50% versus 90% for those patients who presented with progression of disease beyond 2 years or did not have progression of disease at all.

This trend was capped after it was adjusted for FLIPI [Follicular Lymphoma International Prognostic Index] at baseline…. There was a 6 times higher chance of death for patients who had early progression compared with patients who did not have early progression. That’s very important when evaluating and treating patients with follicular lymphoma and certainly a concern we have with patients who have early relapse, or early progression.

That does not change whether patients are receiving maintenance therapy or not. Patients who do have progression with maintenance therapies still have a higher risk of death, a lower overall survival. The same results were found for patients who do not receive maintenance therapy. They also have a lower chance of overall survival if disease recurs, or progresses, or relapses within 24 months of diagnosis.

The outcomes for these patients are certainly inferior to patients who don’t present with early progression. In that setting, that’s when I personally consider more intensive therapies to try to overcome the poorer prognosis that these patients have at that time.

In patients who are fit, I would consider salvage chemotherapy, followed by autologous stem cell transplantation. Now for patients who have disease relapse after the second line, or third line, or further, CAR [chimeric antigen receptor] T-cell therapy may be an option for these patients, again trying to overcome the poor prognosis that these early recurrences portend.

In patients who are not fit, we have other treatment options, including induction with a different chemotherapy and/or an anti-CD20 [antibody] backbone, not with intent to transplant, using a lenalidomide-based salvage regimen.

, whether it’s wild type or mutated, has an important role in the development of follicular lymphoma. Tazemetostat may be used for these patients. We do have PI3 kinase inhibitors that may be used for these patients in relapsed disease. The newer PI3K inhibitors tend to be better tolerated than the first generation.

We do have a couple of different options for these patients. But again, in patients who present with progression of disease early on, my personal take, if feasible, is to provide them with more intensive treatment followed by consolidation with autologous stem cell transplantation, or CAR T if there are further lines of therapy.

For this patient who presented with early progression 19 months after treatment with obinutuzumab and CHOP, the expected outcome is certainly poorer than for a patient who would have longer control of the disease.

The age-adjusted hazard ratio for overall survival for patients with disease progression within 24 months versus those without disease progression is 12.2 based on studies previously published.

Again, because of a much poorer prognosis, this patient in particular would be someone who I believe would benefit from an intense salvage regimen followed by autologous stem cell transplantation. This patient, who is 60 and without any significant comorbidities, would be an appropriate candidate for the stem cell transplant approach.

Alan Skarbnik, MD, explains early relapse in follicular lymphoma and the available treatment options.

Treating Early Relapse in Follicular Lymphoma

For patients who are diagnosed with follicular lymphoma, I usually have a baseline laboratory imaging work-up. It is important to understand the tumor burden and have a benchmark for comparison post treatment to understand what degree of response the disease presented.

So obviously a CBC [complete blood count], a metabolic panel, LDH [lactate dehydrogenase], beta-2 microglobulin are important factors. If physicians have access to mutation panels, it does add prognostic tools to treatment, particularly with patients with more advanced disease. It does not really at this point guide the choice of therapy, but it is more information that may be useful, particularly for the intensity of monitoring following treatment.

I do prefer a PET [positron emission tomography] scan as the imaging modality for these patients. It gives me a better prognostic baseline at the end of treatment, so at the beginning of therapy compared to the end of therapy. After patients have finished the therapy, I do not customarily monitor with serial imaging. I will only do imaging if symptoms arise or there is obvious progression of disease on a physical examination or from patient history.

Early progression is the main concern for patients who receive treatment, particularly chemoimmunotherapy. There is significant evidence that progression of disease within 24 months [POD24] of finishing chemoimmunotherapy presents patients with a much poorer prognosis in terms of overall survival at that point, particularly for those who receive bendamustine as the backbone of therapy.

In induction, those who present with progression of disease within 24 months have a high rate of high-grade transformation to usually diffuse large B-cell lymphoma. It’s up to 76% in patients who present with POD24 and have received bendamustine as the chemotherapy agent in induction.

There are risk factors that may predict who will present with progression of disease within 24 months, or POD24. There are some that are more cumbersome. Now there are some prognostic models. There are some variables that are a little easier to do in clinical practice. For instance; FLEX [Follicular Lymphoma Evaluation Index], PRIMA-PI [PRIMA-Prognostic Index], m7-FLIPI [m7-Follicular Lymphoma International Prognostic Index]. Some of them require evaluation of the genetic mutation panel, including genes that are commonly mutated in follicular lymphoma.

Some of them use only a common laboratory work-up, such as PRIMA-PI, which uses beta-2 microglobulin to review if there is bone marrow involvement or not. Some use quantification of NK [natural killer] cells in the peripheral blood as part of the prognostication. They have different sensitivity, accuracy, and specificity levels between those prognostic models. As I said before, it depends on access to particular testing.

It is important to understand that baseline because it’s a discussion we can have with the patient. What are the risks? What are the concerns? How are we going to monitor the patient?

Following treatment, patients who do have a higher risk of early progression I tend to see in the office a little more frequently than patients who do not have those risks up front. But all these models need to be further validated prospectively, and they have been evaluated in different settings. Some of the models were evaluated in the setting where only CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] or CVP [cyclophosphamide, vincristine, prednisone] were the backbone therapy. Other models included bendamustine and then were validated in a CHOP and CVP cohort. Some models only used rituximab as the anti-CD20 [antibody]. FLEX particularly included obinutuzumab in the GALLIUM study.

So there are differences, and a lot of times in clinical practice it is hard to pick one. It will depend on the patient and what regimen is going to be used. Largely, I would recommend picking a model that physicians will be familiar with, has ease of use, and can be used for most patients without necessarily having to add more complex and costly tests to evaluate these patients.

An expert describes typical monitoring strategies in follicular lymphoma.

Monitoring Strategies in Follicular Lymphoma

 The GALLIUM study evaluated different anti-CD20 antibody strategies for patients with newly diagnosed follicular lymphoma. Centers could choose their chemotherapy backbone: bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], or CVP [cyclophosphamide, vincristine, prednisone]. Patients would then be randomized to use that chemotherapy backbone with either rituximab or obinutuzumab, and after 6 cycles of induction, patients would then receive 2 years of maintenance with the same anti-CD20 antibody they received in induction. The goal was to address changes in PFS [progression-free survival].

The study did meet the primary end point of improved progression-free survival, favoring obinutuzumab over rituximab. However, the improvement in the hazard ratio was different between younger patients and older patients. In patients particularly over the age of 65, the difference between obinutuzumab and rituximab was not as pronounced in terms of PFS. Those patients, particularly the ones who received bendamustine as a backbone, experienced more grade 3 to 5 infections during the maintenance period of obinutuzumab.

In other analyses trying to differentiate between the backbones of therapy, it seemed that patients who received bendamustine and received obinutuzumab as the anti-CD20 monoclonal antibody, the effect of an improvement in PFS was actually more pronounced than for the patients who received CHOP or CVP as the backbone, with a confidence interval across the 1 mark. It is questionable if obinutuzumab does improve PFS in patients receiving CHOP or CVP as a backbone. But again, patients receiving bendamustine have higher risk of infections in the maintenance phase. These are things that need to be discussed with the patient.

I have used obinutuzumab-based therapy for follicular lymphoma, particularly with bendamustine as the backbone, in young patients, patients younger than 60. I do have a discussion with these patients. Patients do prefer having the maintenance therapy because of the PFS gain, again making sure that it is understood that there is no overall survival gain.

In older patients, the discussion is a little bit different because there is a higher concern for infections in the maintenance phase. Some patients do prefer having maintenance at that point may consider having particularly prolonged antiviral prophylaxis. But during the pandemic, again, I do have concerns for ongoing maintenance with an anti-CD20 given the decreased efficacy of COVID-19 vaccines in this patient population. We have to have the discussion with patients in this age to address that issue as well, beyond just the outcomes and survival versus nonsurvival.

Dr. Alan Skarbnik reviews the use of obinutuzumab-based therapies for follicular lymphoma and highlights data from a phase III study.

Follicular Lymphoma: The GALLIUM Study

 In reviewing frontline therapy options, we fortunately have a number of treatments available, but sometimes choosing between treatments may be challenging.

Of course, an anti-CD20 [antibody] plus chemotherapy is usually the most used option, but we can use an anti-CD20 alone for patients who are more frail or with a lower bulk of disease. Some people use lenalidomide plus an anti-CD20. There are 2 anti-CD20s that are approved, obinutuzumab and rituximab, that can be used as frontline agents. Chemotherapy backbones could be bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], or CVP [cyclophosphamide, vincristine, prednisone]. There are a number of different options to treat these patients.

There are trials that aim to distinguish between those options, and largely bendamustine-based regimens are the most commonly used, based on the StiL and BRIGHT studies showing that bendamustine seemed superior to CHOP or CVP-based regimens in terms of progression-free survival [PFS] and is seemingly overall better tolerated during the induction phase. When there is a question of which anti-CD20 to use, both rituximab and obinutuzumab are both very good options.

The GALLIUM study, which compared rituximab with obinutuzumab with different chemotherapy backbones, showed an improvement in PFS favoring obinutuzumab but with no improvement in survival over rituximab-based treatments.

The study used maintenance strategies after induction with the same anti-CD20 that patients received up front. So 2 years of maintenance with obinutuzumab or two years of maintenance with rituximab, again showing differences in PFS but not in overall survival.

The study that compared rituximab maintenance versus no maintenance used a CHOP and CVP-based chemotherapy, did not include bendamustine, again showing an improvement in progression-free survival in favor of maintenance but no improvement in overall survival between maintenance and no maintenance. This showed that we can salvage patients who present with relapsed disease even without maintenance and provide a long-term PFS after recurrence, particularly if the recurrence happened beyond the initial 2 years post-treatment.

In this case, the patient was treated with obinutuzumab and CHOP chemotherapy. I tend to reserve CHOP-based chemotherapy for either patients who present with grade 3b disease, which would be closer to a diffuse large B-cell lymphoma, or if there is any significant concern for transformation of disease that I cannot prove with a biopsy.

For instance, patients who have widespread disease with very high SUVs [standardized uptake values] in sites that are not easy to biopsy or if patients have very bulky disease, I may favor CHOP. But in most patients, I do favor bendamustine as the chemotherapy backbone if I’m using chemotherapy for induction, given the results of improved outcomes with bendamustine over CHOP in a larger number of patients. But as I said before, there is heterogeneity in these presentations, so physicians may decide differently based on how a patient presents, their age, and other comorbidities.

The patient received obinutuzumab with CHOP chemotherapy and then continued on obinutuzumab maintenance, which is certainly an approved and used approach.

The question of maintenance versus no maintenance is still something that is debated. My opinion is that it should be discussed openly with patients. There are pros and cons. Using maintenance may prolong progression-free survival but again does not have an impact as far as we know on overall survival. But it comes at a cost of increased risk for infections, particularly if patients use bendamustine as the backbone of treatment.

In the setting of a pandemic, we do know that continued use of an anti-CD20 does decrease the efficacy of [COVID-19] vaccines, so it is something that needs to be evaluated with further care and concern for the situation we are in.

Challenges in treating patients with newly diagnosed follicular lymphoma include performance status, comorbidities, and again the heterogeneity of the disease. Patients who are older and frail may not tolerate a chemoimmunotherapy approach and may benefit from an anti-CD20 alone or in combination with lenalidomide. Whereas patients who can tolerate chemoimmunotherapy, sometimes the choice of agent may be challenging because of heterogeneity of the disease.

To mitigate adverse events in patients who have a high risk for cytopenias or neutropenic fever, using G-CSF [granulocyte colony-stimulating factor] support may be adequate. For some patients who may be at high risk for viral infections or viral reactivations, using prophylactic agents may be adequate as well. Of course antinausea medications and antihyperuricemic medications are used to decrease the risk of tumor lysis syndrome, particularly in the first cycle for patients with bulky disease. Constant monitoring of these patients, addressing adverse effects at each cycle, and adapting the treatments would be appropriate.

A key opinion leader discusses the considerations in choosing induction and maintenance therapy options for follicular lymphoma.

Induction Therapy Options in Follicular Lymphoma

: Hello, my name is Alan Skarbnik. I’m the director of the lymphoma and CLL [chronic lymphocytic leukemia] program at Novant Health Cancer Institute.

We are going to talk today about follicular lymphoma. I have a case to discuss. This is a 60-year-old man who presented with a 4-month history of fatigue, decreased appetite, occasional fevers, and a 7-lb unintentional weight loss; no significant past medical history.

Upon physical examination, the patient presented with palpable right axillary lymph nodes, maximum of 2.5 cm, and bilateral cervical lymph nodes up to 3 cm in size. The spleen was palpable 4 cm below the left costal margin.

In the clinical work-up, the patient presented with ANC [absolute neutrophil count] of 1600, white blood cell count of 11,000, with lymphocytes accounting for 42% of the white blood cell count, anemia with a hemoglobin of 9.7 g/dL, thrombocytopenia with platelets 97,000, LDH [lactate dehydrogenase] was elevated at 402 U/L, beta-2 microglobulin was 3.4 μg/mL, hepatitis B panel was negative.

An excisional biopsy of the axillary lymph node was performed, and on IHC [immunohistochemistry] it showed CD20-positive, CD3+, CD5+, BCL2+, follicular lymphoma grade 2. A bone marrow biopsy was performed and showed paratrabecular lymphoid aggregates with up to 38% involvement. Cytogenetics were positive for t(14;18). Molecular testing was performed, and 

A PET [positron emission tomography] scan showed right axillary, bilateral cervical, and mediastinal lymphadenopathy. The patient was characterized as Ann Arbor stage IV with an ECOG performance status of 1.

This patient was treated with obinutuzumab plus CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] and completed 6 cycles. The treatment was well tolerated. He continued on obinutuzumab maintenance. Nineteen months later, the patient complained again of fever, chills, and worsening fatigue.

The initial impression of this case is this is a patient with certainly advanced follicular lymphoma, presenting with B symptoms, splenomegaly, bone marrow involvement, cytopenias, lymphocytosis. This is not necessarily the most common presentation in patients. A number of times we see patients with asymptomatic lymphadenopathy, and upon biopsy we can diagnosis follicular lymphoma, and these patients can be monitored. Rarely, patients present with early stage disease, and we can treat with radiation or monitor. There’s high variability and heterogeneity in the presentation of follicular lymphoma. So we can see patients in all spectrums of the disease, but generally, patients don’t present with this much disease and this many symptoms, but it certainly can happen.

Alan Skarbnik, MD, presents the case of a 60-year-old man with newly diagnosed follicular lymphoma.

Alan Skarbnik, MD | Authors

Articles

Follicular Lymphoma: Emerging Treatments

Treating Early Relapse in Follicular Lymphoma

Monitoring Strategies in Follicular Lymphoma

Follicular Lymphoma: The GALLIUM Study

Induction Therapy Options in Follicular Lymphoma

Case Overview: A 60-Year-Old Man with Newly Diagnosed Follicular Lymphoma