CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: March 06, 2023
Expiration: March 05, 2024
Jean L. Koff, MD, MSc:
FL is a common indolent lymphoma in the Western world. As it can be more of a slow-growing disease, some patients with advanced-stage FL may not require immediate treatment.1 Rates of FL cases and deaths have been declining since the 1990s and have improved since the introduction of R2. Patients typically respond well to initial therapy, but for the majority of patients with advanced disease, curative therapy is not available.2 Various prognostic models and indices may be used in risk assessment and aid in treatment decision-making, such as the Follicular Lymphoma International Prognostic Index (FLIPI).1,2 Patients with progression or relapse of FL within 2 years of frontline chemoimmunotherapy (POD24) tend to have worse overall survival (OS).3 The goals of treatment involve controlling the disease while maintaining quality of life. Fortunately, several new treatments are available for managing patients with disease recurrence.
Jean L. Koff, MD, MSc:
This is the current treatment landscape for patients with FL. As can be seen from the list of first-line and second-line treatment options, there is no one‑size‑fits‑all approach for patients with FL, even in early lines of therapy. Chemoimmunotherapy or lenalidomide plus rituximab (R2) are preferred options in patients who are fit and able to tolerate these regimens. Chemoimmunotherapy options include bendamustine in combination with either rituximab or obinutuzumab, R/O-CHOP, or R/O plus cyclophosphamide/vincristine/prednisone. The R2 regimen was compared with chemoimmunotherapy as frontline therapy in FL in the phase III RELEVANCE trial that demonstrated similar CR and PFS rates. R2 is not currently approved in the frontline setting because this trial failed to show the superiority of R2.4 After 6 years of follow-up, OS was estimated at 89% in both groups.5 However, considering the available data, R2 may be an option for patients who may not be suitable for frontline chemoimmunotherapy. R2 as a single agent can be considered as first‑line treatment for older or frail patients who are not expected to tolerate chemoimmunotherapy or even R2.
Consolidation with an anti-CD20 monoclonal antibody is considered optional. There are long-term studies that show improved PFS with 2 years of maintenance anti-CD20 monoclonal antibody, but even with extended follow-up out to approximately 10 years or more, maintenance therapy has not improved OS.
Maintenance therapy with an anti-CD20 monoclonal antibody increases the risk of poor immune response to vaccines such as the COVID-19 vaccine and thus exposes patients who are on this therapy to an increased risk of life‑threatening infections with a virus such as COVID-19.
In terms of second‑line therapy, for patients who have enjoyed a reasonably long PFS after initial therapy (≥2 years), an alternative chemoimmunotherapy regimen not used in the first-line setting can be considered. R2 is also a good option in this setting. For patients who are not expected to tolerate chemoimmunotherapy or R2 well, tazemetostat is approved for adults with R/R FL and who have no satisfactory alternative treatment options available to them.6 In this setting, tazemetostat is an alternative without regard to EZH2 mutation status.7 Tazemetostat is also indicated for adult patients with R/R FL whose tumors are positive for an EZH2 mutation and who have received ≥2 prior systemic therapies.6
After ≥2 lines of therapy, there are several options for therapy in FL, including copanlisib, CAR T-cell therapies (axicabtagene ciloleucel, tisagenlecleucel), and mosunetuzumab-axgb. The choice of agent in this setting depends on multiple factors, including patient‑specific characteristics, consideration of the different adverse event (AE) profiles, and efficacy of each of the agents.
Jean L. Koff, MD, MSc:
Let us discuss a representative case of a patient needing additional therapy for FL. This is a 72-year-old woman who presented with palpable cervical lymphadenopathy, night sweats, and unintentional weight loss of 20 pounds for 3 months. Based on her workup, she was diagnosed with stage III FL.
Given that she was symptomatic, she was started on bendamustine and obinutuzumab chemoimmunotherapy shortly after diagnosis. Her provider had concerns about prolonged immunosuppression during the COVID-19 pandemic, and as a result, the decision was made not to pursue maintenance obinutuzumab. She tolerated frontline treatment well and achieved a CR. However, approximately 1 year after that posttreatment PET scan, she again developed B symptoms and was found to have a relapse of her FL that was confirmed with a biopsy.
Jean L. Koff, MD, MSc:
This patient then received R2 as second‑line therapy. She tolerated R2 well in terms of symptoms but ultimately had to discontinue lenalidomide after 8 months of therapy when she developed cytopenias that did not respond to dose reductions of the lenalidomide or interruptions in therapy.
Her counts eventually recovered completely once the lenalidomide was stopped, but unfortunately, her FL progressed after she had been off the lenalidomide for 4 months. She experienced B symptoms again, and there was a reappearance of her cervical lymph nodes. Now she needs another line of therapy. What factors should we consider for our recommendation? One factor may be the EZH2 mutation status of her lymphoma whose testing showed to be wild-type EZH2.
Other relevant patient history and information that might be important for selecting her next line of care are that she is a relatively healthy woman with a past medical history of dyslipidemia. Her Eastern Cooperative Oncology Group (ECOG) performance status is 1, with the decrease mainly because of her B symptoms. She lives with her husband and has a close relationship with her 2 adult children who live nearby.
During an interdisciplinary planning of care meeting with the patient and her family, the goals of care and the therapeutic options available for a patient with FL requiring third‑line therapy are discussed. The patient states, “I need a treatment that will control my lymphoma for a long time. I’m okay with some short‑term AEs like I had with my first chemotherapy if it means that I don’t need to be on treatment for months on end.”
Jean L. Koff, MD, MSc:
There are 2 CAR T-cell therapy agents approved for patients with R/R FL as third-line or later-line treatment options. The first to be approved was axicabtagene ciloleucel based on the results of the ZUMA‑5 trial. This was a single-arm phase II trial that included patients with R/R FL (grade 1-3a) or marginal zone lymphoma. All patients had received ≥2 prior lines of therapy. The primary endpoint was ORR, which was 94% in the FL cohort at 17.5 months, with 79% having a CR.8
Jean L. Koff, MD, MSc:
At the last trial update with a median follow-up of 40.5 months, the median PFS in patients with R/R FL was 40.2 months. The OS in this cohort of patients was also very good, with the median not yet reached.9
Jean L. Koff, MD, MSc:
An important consideration in CAR T-cell therapy is the safety profile since this can be a more toxic therapy than other third-line options. As we might expect, the most common grade ≥3 toxicities include neutropenia, anemia, and thrombocytopenias. These cytopenias can result from the lymphodepleting therapy that is part of the CAR T-cell process but also sometimes can be an AE of the CAR T-cell therapies themselves. Although CAR T‑cell–specific AEs such as CRS occurred in the majority of patients, it was grade ≥3 only in 6%. All CRS events resolved with the exception of one. Another key toxicity we consider with CAR T-cell therapy is neurotoxicity. Again, more than one half of patients experienced some sort of neurotoxicity, but it was grade ≥3 in only 15% of the patients with FL. The median duration of the neurologic event was approximately 14 days, and there was no evidence of CRS or neurologic events of any grade after the 2‑year analysis.
Jean L. Koff, MD, MSc:
The second CAR T-cell agent that has been approved for R/R FL is tisagenlecleucel, which was evaluated in the phase II ELARA trial. The ELARA trial enrolled patients with R/R FL (grade 1-3a) with no prior CD19-targeted therapy or allogeneic hematopoietic stem cell transplant (HSCT).10 There was an optional bridging chemotherapy that could occur after apheresis, but similar to the ZUMA-5 study, lymphodepletion was followed by the CAR T-cell infusion. The primary endpoint in this study was CR rate, but the study also looked at other important endpoints, including ORR, duration of response (DoR), safety, and OS.
Jean L. Koff, MD, MSc:
Tisagenlecleucel was very effective in FL, with an ORR of more than 90% and a very high CR rate in this population of 72%. This is with 16.9 months of median follow-up, and, to date, the median DoR, PFS, and OS have not been reached, which is also very encouraging.11 Another consideration is that almost one half of the patients who initially achieved a PR eventually converted to a CR, and many of those occurred between Months 3 and 6 after therapy.
Jean L. Koff, MD, MSc:
In terms of CAR T-cell–specific toxicity, this is very encouraging data. Almost half of the patients experienced some degree of CRS, but there were no occurrences of grade ≥3 CRS. Some neurologic event was experienced by 37% of patients, but only approximately 3% of those had a grade ≥3 neurologic event. It is important to note that these safety results were achieved with the help of tocilizumab, which was used in 34% of cases of CRS, and steroids, which were used in 6.4% of cases of neurotoxicity.
Of note, another CAR T-cell therapy, lisocabtagene maraleucel, is approved for patients with FL grade 3b, which is considered comparable to diffuse large B-cell lymphoma and thus is managed as a distinct disease entity.
Jean L. Koff, MD, MSc:
What makes a patient with FL a good candidate for CAR T-cell therapy? The current FDA indications for CAR T-cell therapy in FL are patients who have received ≥2 lines of systemic therapy. I would consider CAR T-cell therapy for patients who relapsed less than 24 months after initial therapy (POD24.) In FL, this has been shown to be an especially high‑risk group that may need an alternative form of therapy if they do not respond well or do not have a longer‑term response to initial chemoimmunotherapy.3 If your institution has clinical trials available for CAR T-cell therapy, patients with high‑risk disease such as POD24 might be good candidates. The candidacy for CAR T‑cell therapy, especially in FL, is much more inclusive than historic HSCT eligibility. If older patients do not have major organ dysfunction comorbidities and have a relatively good functional status, even if they would not be HSCT candidates, they might still be eligible for CAR T-cell therapy because the toxicities are more easily tolerated. Patients with a very poor performance status, such as ECOG performance status ≥3, probably should be considered for alternative therapies, if possible.
CAR T-cell therapy is manufactured from a patient’s own T‑cells that are obtained through a leukapheresis process and then sent for CAR T-cell manufacturing. Thus, this is not an off‑the‑shelf product. There is a lead time between when the patient is identified as a candidate, enrollment, apheresis, and manufacture. If the patient has rapidly progressing disease, therapy either before apheresis or bridging therapy between apheresis and CAR T-cell therapy infusion may be needed to keep their disease under control while waiting for the CAR T-cell therapy infusion.
It is important to avoid very myelosuppressive agents just before apheresis. For instance, bendamustine is not a good agent to use before apheresis because the recovery of T-cells may be poor following the therapy with this myelosuppressive agent. Patients with R/R FL who have received many previous lines of therapy are more likely to experience longer‑term cytopenias as a result, and cytopenias are definitely a major risk of CAR T‑cell therapy. Patients need to have adequate cell counts to ensure that they can be apheresed successfully and to minimize their risk for long-term, profound cytopenias and increased susceptibility to infection after CAR T-cell therapy infusion.
Patients should not have an active infection before undergoing infusion with CAR T-cell therapy because this leads to much higher risk of complications related to CRS. Comorbidities that should raise concern regarding CAR T-cell therapy are cardiac dysfunction and any sort of symptomatic neurologic symptoms, including dementia or even mild cognitive impairment. These patients will be at increased risk for neurologic toxicity from the CAR T-cell therapy, and it can also make assessment of possible neurotoxicity very difficult if there is a competing preexisting diagnosis. Social support is an important part of candidacy considerations. Since patients can have long-term toxicities related to the CAR T-cell therapy even after they are discharged from the hospital, it is essential they have a caregiver who can take them to follow-up appointments in the weeks after CAR T-cell infusion and monitor them for CAR T-cell therapy AEs, such as CRS or neurologic symptoms that may occur after that immediate postinfusion period.
Jean L. Koff, MD, MSc:
A consensus grading system has been developed for CRS, accounting for fever, hypotension, and hypoxia.12,13 Higher grades of CRS are defined by the need for vasopressor and airway support.
Jean L. Koff, MD, MSc:
It will be important for practitioners to rule out other potential causes of systemic inflammatory symptom response, such as disease progression or infection.13 The management of CRS is algorithmic based on grade. Upon recognition of CRS and grading, prompt intervention and supportive care are recommended. Approaches include withholding the current infusion and administration of tocilizumab and corticosteroids, depending on severity.
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