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FAQs: CAR T-Cell Tx in Lymphomas
Experts Answer Questions on Integrating CAR T-Cell Therapy Into the Management of DLBCL, FL, MCL, and CLL/SLL to Improve Outcomes

Released: June 27, 2023

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Key Takeaways
  • Better communication with and education of referral centers is essential to improve management of cytokine-release syndrome and neurotoxicity associated with CAR T-cell therapies.
  • Risk stratification remains crucial to identifying patients with lymphoma at highest risk of relapse who would benefit from receiving CAR T-cell therapy earlier in the course of their disease.
  • With the growing availability of choices, a shared decision-making approach between patients and CAR T-cell providers is essential to the integration of CAR T-cell therapy for patients with lymphomas (DLBCL, FL, MCL, and CLL/SLL).

As CAR T-cell therapies continue to become part of the standard of care for patients with relapsed/refractory (R/R) lymphoma, many healthcare professionals (HCPs) have questions about identifying patients with relapsed disease who may benefit from CAR T-cell therapy. Moreover, managing toxicities with CAR T-cell therapy (cytokine-release syndrome [CRS] and neurotoxicity) and sequencing of available options remain top of mind among HCPs. In this commentary, experts answer frequently asked questions on how to best integrate CAR T-cell therapy into the management of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that were submitted by an audience of HCPs during an educational webinar on this topic.

What are your thoughts on the current incidence and severity of adverse events with CAR T-cell therapy?

Michael R. Bishop, MD:
Earlier in the development of CAR T-cell therapy, we observed higher incidence of CRS and immune effector cell‒associated neurotoxicity syndrome (ICANS). Most recently, I have noted a downward trend in these CAR T-cell‒related toxicities, presumably because we know now what to expect and how to manage it.

Establishing strong relationships with both the referral centers and the referring centers remains imperative. This is one area where we still have some work to do. In particular, we need to better prepare the referring centers to manage long term toxicities associated with CAR T-cell therapy. This is important because we know that anti-CD19 CAR T-cell therapies can lead to high rates of durable remission with improved overall survival in patients with aggressive B-cell malignancies, even curing some of those patients.

Julie M. Vose, MD, MBA:
I agree. Although we are much better at managing toxicities from CAR T-cell therapies, I do not think we should take that for granted, because some patients still experience severe toxicities. So, it is still important to ensure that patients receive care in centers that are familiar with managing those toxicities.

Kathleen Dorritie, MD:
Also, it is important to mention that we are encountering some of the same toxicities observed with CAR T-cell therapy in patients receiving bispecific T-cell engager (BiTE) therapy, albeit not as severe. I also would advocate for referral centers and community HCPs to gain experience on managing toxicities with BiTE therapy.

What are your thoughts on CAR T-cell therapy and long term risk of infection? Any hesitation to give CAR T-cell therapy earlier in the paradigm because of this?

Michael R. Bishop, MD:
I do not know whether giving CAR T-cell therapy earlier in the disease course would necessarily change the inherent risk of infections. The more important thing is to remember that there is a risk of infections with CAR T-cell therapy, particularly in the scenario of B-cell hypoplasia, because the long term infection risks are viral related. A group at Stanford University has published data on this topic.

Julie M. Vose, MD, MBA:
That is true—infection risk—for many of our treatments. For instance, with a transplant or use of BTK inhibitors, infection risk is there for everything. I think with CAR T-cell therapy we may see slightly distinct types of infections, but we need to keep that in mind for all of our patients regardless of the treatment being given.

Michael R. Bishop, MD:
I completely agree.

In MCL, would you consider BTK inhibitor cycling vs CAR T-cell therapy in your patients with relapsed disease?

Julie M. Vose, MD, MBA:
That is not something I typically would do other than for toxicity reasons. As far as response, if they did not respond well to a traditional BTK inhibitor, there is a noncovalent BTK option. That might be a “cycling” approach we think about for the future.

Michael R. Bishop, MD:
If they are resistant to a BTK inhibitor, my success in trying to switch to another covalent option has not been great.

Julie M. Vose, MD, MBA:
However, we do not yet know what to do post CAR T-cell therapy in a patient who previously experienced BTK inhibitor resistance and where venetoclax fits into that.

Kathleen Dorritie, MD:
Agree.

Where does venetoclax stand in the treatment landscape of R/R MCL?

Julie M. Vose, MD, MBA:
As a single agent, venetoclax has some activity, but in most patients it may not be enough. Venetoclax has potential for combination in some patients, but I am not a big user of venetoclax in MCL. Dr Dorritie, what do you think?

Kathleen Dorritie, MD:
Agree.

Could you elaborate on the potential role and place of CAR T-cells in the CLL/SLL treatment algorithm once approved?

Kathleen Dorritie, MD:
We have excellent results with BTK inhibitors and BCL2 inhibitors in CLL/SLL. So, I would see a role for CAR T-cell therapy in patients who have experienced treatment failure with both of those options. Something that also remains to be determined is where BiTE therapy will fit in—both CD19 and CD20 directed. We all know that CLL/SLL is a disease of older adults, so a lower toxicity profile and equivalent efficacy would be key to determining whether we go first to a BiTE therapy or whether we choose CAR T-cell therapy.

Julie M. Vose, MD, MBA:
I agree. Good to have options.

Would you use CAR T-cell therapy as a first line option in DLBCL, FL, MCL, or CLL?

Michael R. Bishop, MD:
I think for DLBCL.

Julie M. Vose, MD, MBA:
For me, the general answer would be no, but an ongoing study is exploring CAR T-cell therapy following fludarabine/cyclophosphamide as frontline therapy in patients with high risk large B-cell lymphoma (NCT03761056). The primary endpoint is the complete response rate per the Lugano classification by investigator. Results from that study will give us insight into the use of frontline CAR T-cell therapy, but then we will need a randomized trial to be able to say that CAR T-cell therapy is best in that patient population.

Michael R. Bishop, MD:
I agree. There will be a few other studies investigating different CAR T-cell therapies because of the interest in beginning CAR T-cell therapy earlier in treatment. I think the options for all of our patients keep getting better. In FL, I cannot say that we have too many great options.

Julie M. Vose, MD, MBA:
In patients with TP53-mutated MCL—not a large group of patients but certainly difficult to treat—we might consider CAR T-cell therapy earlier rather than later.

Kathleen Dorritie, MD:
I think patients with double-hit lymphoma—a group of fast-growing (aggressive) lymphomas characterized by MYC and BCL2 or BCL6 gene alteration—might be another group where frontline CAR T-cell therapy could be explored. Preliminary data from case reports show promising results in that patient population.

How would you choose between CAR T-cell therapy or mosunetuzumab for a patient with R/R FL?

Julie M. Vose, MD, MBA:
That is a challenging question because there are so many variables. My guess would be that the patient’s characteristics and what they previously have received would inform that decision. I do not think one option is necessarily better than the other. You also could sequence those 2 therapies as a strategy. I would not rule out one even if you are going to try the other.

Michael R. Bishop, MD:
I am partial to CAR T-cell therapy here because the results are very impressive, and it is a “one-and-done” therapy. Also, as Dr Vose said, you can come back to the other option if you need to. Patient preference is another consideration for me, but I certainly would not have any trouble bringing up CAR T-cell therapy during a conversation with the patient.

Julie M. Vose, MD, MBA:
Some patients like the CAR T-cell therapy option because of it being “one and done”—especially people who travel long distances to an oncology center. It is a little more involved than that, but you do not have to come back for multiple rounds of therapy.

Michael R. Bishop, MD:
A few patients may say, “No way.” The idea that they are in the hospital for 2 weeks is inconceivable. Other patients may say, “I just want to be done with my disease.”

Kathleen Dorritie, MD:
The CD20- and CD3-directed BiTE therapies mosunetuzumab, approved for use in R/R FL, and epcoritamab, approved for use in R/R DLBCL, both also require initial close observation. At our institution, we are admitting patients for epcoritamab step-up dosing because of the potential risk for CRS and ICANS. When having these discussions with patients about the requirement for hospital stays, they may say, “Well, if I’m going to be admitted, either way, I want the one-and-done approach.”

Can you compare CAR T-cell therapy with BiTE therapy in FL?

Michael R. Bishop, MD:
That is the elephant in the room. Now that we have both options, what do we plan to do with BiTE therapy?

Julie M. Vose, MD, MBA:
Without a randomized trial, how can we really compare the two? However, as I have said before, I think you may consider one vs the other based on different patient characteristics, as well as patient preferences for a one-and-done therapy vs another where they would need to come back multiple times. A few of the available therapies are given for a definite time period, and others are forever until relapse, so that can be a crucial decision point for a patient.

Michael R. Bishop, MD:
I would like to add a comment about this here. We do see that patients with complete remission with a BiTE-based therapy can have a very long duration of response, and some of the data are very impressive. It looks similar to CAR T-cell therapy, but patients do need to get to complete remission first. Unless my colleagues disagree, I think patients receiving CAR T-cell therapy are going to have a higher probability of achieving complete remission.

Julie M. Vose, MD, MBA:
I agree that it is a very individualized patient decision at that point.

Are there any strategies to enhance T-cell expansion and persistence and efficacy post CAR T-cell therapy?

Julie M. Vose, MD, MBA:
A few studies are looking at different options for improving T-cell expansion and CAR T-cell therapy persistence. One in particular (NCT04484012) is exploring BTK inhibitor use during the collection process and then post CAR T-cell therapy after engraftment. I think, personally, that this approach is the most promising, but several other studies with different agents are exploring this question too.

Kathleen Dorritie, MD:
I think one area that has been disappointing is incorporation of checkpoint blockade with CAR T-cell therapy. There is upregulation of PD 1 both on CAR T-cells and in the tumor microenvironment, so we were all hopeful that incorporating this strategy post CAR T-cell therapy or even around the time of infusion would prove beneficial. So far, however, the results have not been exciting. We have seen activity in specific subgroups—for example, in patients with primary mediastinal disease—who are expected to respond to checkpoint blockade.

Michael R. Bishop, MD:
I think it may have something to do with the CAR T-cell therapy itself. We have looked at the role of vaccinations in stimulating CD19 after it “goes away,” maybe because the CAR T-cell 4-1BB costimulatory domain may improve persistence. There is greater interest in exploring this in the myeloma community and they have great agents that they can use to explore this question (eg, lenalidomide). We use lenalidomide in FL and have observed some enhancement in T-cell function there. Overall, this is a great question because of a group of our patients who do not do as well between 6 and 12 months post CAR T-cell therapy.

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