ASH Conference 2021: Follicular Lymphoma Therapeutic Updates

From December 11th to 14th, the American Society of Hematology (ASH) held its Annual Meeting and Exposition as a hybrid event featuring invaluable educational content and thousands of scientific abstracts on some of the hottest topics in hematology. Many poster and oral presentations focused on advances made in the management of relapsed/refractory follicular lymphoma.
 
Connie Lee Batlevi, MD, PhD, a medical oncologist and clinical researcher at Memorial Sloan Kettering Cancer Center in New York City, shared her insight on some of these presentations and what the research findings mean for clinical practice.

Updated analysis of the dose-escalation study of the bispecific antibody glofitamab alone or in combination with obinutuzumab (ClinicalTrials.gov Identifier: NCT03075696) reported high response rates in patients with multiple instances of relapsed or refractory follicular lymphoma.¹ Are these data encouraging?

Glofitamab is a T-cell-engaging bispecific antibody, a subset of immune-based therapy. In follicular lymphoma, this class of drugs produces high overall and complete response rates. The class has a lot of promise.

Glofitamab is an engineered antibody that recognizes CD20 on one end and binds to CD3 on the other end. It essentially brings immune effector cells to lymphoma cells and asks them to induce an immune response.

Other existing antibodies that target CD20 are rituximab and obinutuzumab. Glofitamab and obinutuzumab combination therapy aims to use obinutuzumab to reduce some of the adverse effect profile of glofitamab.

Adverse effects such as transient fevers and cytokine release syndrome have been reported in patients receiving glofitamab, although they are milder than those seen with chimeric antigen receptor (CAR) T-cell therapy. Patients must be hospitalized if they experience cytokine release syndrome. Researchers used obinutuzumab to reduce the amount of antigen available so that patients experience less of an immediate immune response to the bispecific antibody.

The overall response rate was 81% among patients in the glofitamab and obinutuzumab monotherapy cohort and 100% among patients in the combination therapy cohort.  Rates of cytokine release syndrome did not differ significantly between the monotherapy and combination cohorts. We do not yet know whether the combination mechanistically had an effect.

In a study of the CD20 x CD3 bispecific antibody mosunetuzumab, clinically meaningful outcomes were reported for patients with relapsed or refractory follicular lymphoma (ClinicalTrials.gov Identifier: NCT02500407).² The drug induced complete responses lasting at least 18 months. What is the significance of these results? Are there differences between mosunetuzumab and glofitamab?

We do not yet truly know the difference between mosunetuzumab and glofitamab. Structurally, glofitamab has an extra section that binds to CD20 and is in a 2:1 configuration whereas mosunetuzumab has a 1:1 configuration.

Mosunetuzumab also typically has slightly lower rates of cytokine release syndrome and other complications, but we do see a slightly reduced overall response rate in some studies. It is not clear why.

Both drugs have a good duration of response, at least so far.

For most patients with follicular lymphoma who are in a position to receive a bispecific antibody for the next line of treatment, these are essentially equivalent options. That could change if other trials are conducted that combine these drugs with other agents to improve response or to mitigate adverse effects.

Turning now to a different treatment approach, a study of tisagenlecleucel in patients with relapsed or refractory follicular lymphoma showed high overall response rates as well. What is the significance of these data from this subgroup of the ELARA study (ClinicalTrials.gov Identifier: NCT03568461)?³ Would the patients eligible for CAR T-cell therapy vs bispecific antibodies differ?

CAR T-cell therapy is another immunotherapy option. T cells from the patient are genetically modified to recognize lymphoma — in this case, expression of CD19 — and are reinfused into the patient after lymphodepleting chemotherapy.

This ELARA study looked at tisagenlecleucel in relapsed/refractory follicular lymphoma and reinforced that CAR T-cell therapy is an effective treatment in this space.

Ultimately, all 3 CAR T-cell therapies used in the study — tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel — have a similar effect and durability of response in follicular lymphoma. It is the management of the adverse effect profile, including cytokine release syndrome and neurotoxicity, and the reliability of CAR T-cell generation that will be important.

We might also find that patients with follicular lymphoma benefit from CAR T-cell therapy in earlier lines of therapy. Those studies still need to be conducted.

What is important to remember is that in most CAR T-cell studies, including this one, patients with inherently high-risk follicular lymphoma still derived benefit. This includes patients who experienced early relapse, those with 5 or more prior lines of therapy, and those with high metabolic tumor volume. This treatment allows these patients to have some stabilization of their disease and some complete remissions. We cannot yet answer whether CAR T-cell therapy will be curative in follicular lymphoma.

When it comes to choosing between bispecific antibodies and CAR T-cell therapy, a lifestyle component will definitely come into play. Patients treated with bispecific antibodies must commit to attending a treatment center and receiving either intravenous or subcutaneous treatment. Initially, this would entail weekly visits that would transition to every 2 weeks and then once a month. For CAR T-cell therapy, everything is upfront with intense treatment for 6 to 8 weeks. Afterward, however, as long as the patient is in remission, they are followed only every 3 or 6 months. The extension of time between follow-up allows patients more freedom. The decision as to which treatment is best will differ for different age groups and different individuals.

Data from the primary analysis of the CITADEL-203 study (ClinicalTrials.gov Identifier: NCT03126019) regarding the PI3K inhibitor parsaclisib were also presented at this year’s meeting.⁴ How does this drug attack follicular lymphoma? What was the significance of these results?

There are immunomodulatory components of cancer by which the immune system can regulate cancers, but ultimately, cancer cells arise because of a genetic defect. These defects turn on molecular switches that cancer cells depend on. The switches are typically biological signaling pathways — like the PI3K (phosphatidylinositol 3′-kinase), JAK/STAT (Janus kinase/signal transducer and activator of transcription), or BTK (Bruton tyrosine kinase) pathways — or epigenetic modulation. These all have a role in the management of all cancers, not just follicular lymphoma.

Some single-agent studies have looked at PI3K inhibitors in follicular lymphoma, and all the inhibitors seem to elicit some response. However, the response is typically more of stable disease or partial response rather than a complete response. In addition, many of these inhibitors have similar adverse effect profiles; some are better, and some are worse.

Parsaclisib is somewhere in the middle. It has promising response rates but still has some of the classic adverse effects associated with PI3K inhibitors like diarrhea, neutropenia, colitis, pneumonitis, and rashes. These effects seem to be better managed as we learn more and use adjunctive medicine.

In the future, I think we will see an attempt to try combining immunotherapies with these molecular targeted therapies to augment some of these responses.

Which of these or other abstracts presented at the 2021 ASH Annual Meeting do you think will be the most clinically impactful?

The data presented on the bispecific antibodies are important in the sense that we will likely move these treatments to earlier settings with more limited durations of treatment. In these trials, patients were treated until they stopped benefiting from therapy or until the disease progressed. If we start these treatments earlier, we may find that we are able to achieve a more finite duration of therapy akin to chemotherapy. It may also be possible to combine these drugs with chemotherapy. These are questions we may have answers to in the next year or 2.