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Advances in FL

CE / CME

Current and Emerging Therapeutic Advances in Follicular Lymphoma: A Class in Session

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

John M. Burke
John M. Burke, MD
Jean Louise Koff
Jean Louise Koff, MD, MSc
CME/CE Information

Activity

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1
Course Completed

EZH2: A Histone Methyltransferase in FL

Jean L. Koff, MD, MSc:
In addition to the CAR T-cell therapies and bispecific antibodies, there are other treatment options for later lines of therapy in FL.

In normal B-cell biology, EZH2 is an important regulator of the germinal center formation in the lymph node. Research has shown that mutations in this histone methyltransferase can lead to the transformation of B-cells into malignant cells by locking them in the germinal center state or germinal B-cell state and preventing them from terminally differentiating. And of importance, we found that at least 20% of patients with FL have these EZH2 activating mutations.22 It is important to remember that EZH2 biology is relevant to FL development whether or not these mutations are present. Tazemetostat is an oral first-in-class EZH2 inhibitor that was developed for the treatment of FL based on the pathogenic role of EZH2.

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Tazemetostat Efficacy in EZH2 Mutant and WT R/R FL

Jean L. Koff, MD, MSc:
Tazemetostat was studied in R/R FL in an open-label, multicenter study enriched to include participants with EZH2-mutated FL.23 At baseline, patients had a median of 2 prior lines of therapy, and approximately one half of them were refractory to a rituximab-based regimen. The EZH2 wild-type group had a median of 3 prior lines of therapy, and approximately 60% were refractory to a rituximab-based regimen. Tazemetostat was effective for patients with both mutant EZH2 and wild-type EZH2. Patients with mutant EZH2 had a better ORR, which you might expect when they have the EZH2 mutation and so might be more susceptible to targeting that with the medication. They had an ORR of 69% and a CR rate of 13%, and their median PFS was approximately 14 months. In patients with EZH2 wild-type FL, the ORR was 35%, with a CR rate of 4%. However, they still had a relatively long median PFS in this type of R/R cohort of 11.1 months.

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Tazemetostat Safety in EZH2 Mutant and WT R/R FL

Jean L. Koff, MD, MSc:
Many times, when considering third-line therapy for FL, it is important to remember that patients have been through multiple therapies in the past. They may have lingering AEs from prior therapies. Therapies that are developed for the third line generally have their own associated AEs. However, tazemetostat appears to be an exception because it is well tolerated with very few grade 3/4 toxicities. Constitutional symptoms are a little more common, but this drug is well tolerated. Only 5% of patients on the trial discontinued treatment, and only 9% had dose reductions in their drug because of treatment-related AEs.

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Tazemetostat Adverse Event and Management

Jean L. Koff, MD, MSc:
AEs to keep in mind with tazemetostat include a small risk of secondary malignancies and risks of embryonic and fetal toxicity. It is important to counsel patients about using effective nonhormonal contraception. The other symptoms include constitutional symptoms and abdominal pain, so educating patients about these possible AEs is also important. As with many drugs, it is critical to remember not to use strong CYP3A4 inhibitors with tazemetostat and to think about adjusting the dose with moderate CYP3A4 inhibitors.

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SYMPHONY-1: Tazemetostat Plus R2 in R/R FL

Jean L. Koff, MD, MSc:
Because tazemetostat is well tolerated, it makes it a good candidate for combination therapy. The SYMPHONY‑1 trial in R/R FL has been evaluating tazemetostat in combination with the R2 regimen.24 The phase Ib study included 44 subjects who received tazemetostat and R2. Similar to the general FL population, 83.3% of patients had an EZH2 wild‑type tumor. There were no dose‑limiting toxicities with this combination regimen, and a recommended phase III dose has been delineated. And similar to the known profile of R2 and, to some extent, tazemetostat, the most common toxicities seen with this regimen were gastrointestinal toxicities, headaches, musculoskeletal complaints, and cytopenias. The observed toxicities were consistent with those reported for each agent individually. At a median follow-up of 11.2 months, a very high ORR of 97.6% and a very encouraging CR of 51.2% have been reported. As of now, the median PFS and median DoR have not been reached, which is also encouraging. Based on these findings, a randomized phase III trial evaluating tazemetostat plus R2 vs R2 alone is anticipated.

Tazemetostat offers a well-tolerated alternative in the R/R setting and has demonstrated efficacy even in patients with an EZH2 wild-type tumor.

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PI3K Inhibitors in R/R FL

Jean L. Koff, MD, MSc:
Another consideration for third‑line or later-line therapy in FL is the PI3 kinase inhibitor class. At present, copanlisib is approved by the FDA in this space. [Editor’s note: Other previously FDA-approved PI3K inhibitors in this setting have been withdrawn.] Copanlisib targets the alpha and delta isoforms of PI3 kinase. In clinical trials, the ORR in R/R FL patients is 50.7%, the median PFS is just over 1 year, and the median OS is relatively good at approximately 3.5 years.25

One of the main considerations for treatment with copanlisib are the AEs associated with this drug. Hyperglycemia and hypertension are specific to copanlisib and can be very difficult to control and should be monitored for carefully. And similar to other PI3 kinase inhibitors, diarrhea, a specific risk of pneumonia, and neutropenia can also be seen relatively frequently with this drug and can be limiting in terms of how long this therapy can be tolerated.

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Copanlisib AE and Management

Jean L. Koff, MD, MSc:
It is necessary to educate patients and caregivers about the potential infections and to alert their providers about fevers, chills, or shortness of breath. Skin peeling or rash may occur, which may necessitate the need for a dose reduction.26

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Newer Treatments in R/R FL

Jean L. Koff, MD, MSc:
In conclusion, although FL may not be curable for most patients, the recent additional modalities, such as CAR T-cell therapies, bispecific antibodies and small molecule inhibitors broaden the options for providers to be able to offer individualized options to prolong survival. Careful attention to patient characteristics, goals of therapy, and patient preferences can help ensure the most optimal outcomes for our patients.

A 77-year-old man was diagnosed with noncontiguous stage III FL. He received obinutuzumab plus cyclophosphamide/doxorubicin/vincristine/prednisone (O-CHOP) chemotherapy and had progressive disease after 15 months. Second-line therapy was initiated with lenalidomide and rituximab (R2). Eight months after completing the therapy, he developed symptoms, and biopsy confirmed relapsed FL. He has a past medical history of type 2 diabetes (A1C 7.3%) but is otherwise healthy and spends a lot of time with his adult son and grandchildren. During his consultation, he states, “I am concerned about these multiple recurrences and want a therapy I can start right away that isn’t associated with other malignancies.” Which of the following therapies would you recommend for this patient?

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