Lori A. Leslie, MD

What do you hope to see from the ongoing ZUMA-2 analysis?

There are a few different cohorts ongoing in ZUMA-2 looking at brexucabtagene. We've got a cohort looking at BTK-naive patients, we have a cohort that's expanded access that allows bridging therapies and more of our real-world population, and then there's a cohort where you can get access to cells if they're out of specification.

I think these data along with data that's emerging from real world experience with brexucabtagene in mantle cell lymphoma, show us that what we see in clinical trials is translating to our real-world population. I'm hoping these data will help convert the accelerated approval into a full, long term FDA approval for this CAR T-cell product in patients with relapsed mantle cells. I think moving forward too, it will be investigated in earlier lines of therapy as we're doing with other CD19 CAR T-cell products across B-cell lymphomas.

Are there any studies or novel CAR T cells that you have your eye on right now?

There's a lot of other studies looking at CD19 CAR T cells across different B-cell malignancies. We've got ZUMA-2 which looked at indolent lymphomas and led to an approval in follicular lymphoma based on overall response rate of 94% and a complete response rate close to 80% in patients with relapsed/refractory disease. I think further follow up from ZUMA-5 [NCT03105336] will let us know if this is a potentially curative option for our patients with the more indolent lymphomas, they can have relapses 10, 20, even 30 years down the line.

We have CD19 CAR T approved in DLBCL and that is being investigated in earlier lines of therapy. Recently published in a 

 is the ZUMA-7 [NCT03391466] study that looked at CD19 CAR T-cell therapy axicabtagene ciloleucel

[axi-cel; Yescarta] as second line therapy compared to standard of care, high dose therapy and autologous stem cell transplantation. This was the first initiated and first to meet its primary efficacy analysis among many different studies in this space trying to transform second line DLBCL therapy, away from high dose chemo and consideration of autologous stem cell transplant, particularly for patients with chemo-sensitive disease and instead sparing patients the toxicity of high dose chemo and transplant and allowing them to go straight to CD19 CAR T-cell therapy in the second line setting.

We are taking the CD19 CAR T cells and adjusting the types of lymphoma where we can use them and the lines of therapy where we can use them. Moving forward, what's probably transforming this space the most are potentially CAR T-cell products that target different antigens on the tumor cell, but also dual targeting CAR T, so these targets CD19 and there are other CAR T products that target more than 1 tumor antigen. Instead of autologous products, there are allogeneic off the shelf or their cell therapy products that may be T cells, they may be NK cells. There are some other ways of conjugating an antibody to an effector T-cell to have a CAR T-like effect with a more simple and potentially less expensive manufacturing process. There are a lot of ways that this space is moving forward quite rapidly in a way that's incredibly hopeful and promising for our patients.

What are your thoughts on the current landscape for mantle cell lymphoma and how the future looks?

I would say it is a exciting time in cancer in general and lymphoma therapies are advancing at the most rapid rate we've seen since I've been in medicine. It's really a very promising time for our patients. Even as a lymphoma specialist, it's hard to stay up to date sometimes because things are changing so rapidly. I feel very hopeful, our patients have all the reasons to feel very hopeful, and as we harness the power of the immune system, I think things are only going to continue to get better.

Videos

In an interview with Targeted OncologyTM, Leslie, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, discussed the CAR T-cell product, brexucabtagene autoleucel, and its influence on both MCL and indolent lymphomas.

EP. 1: Exploring CAR T-Cell Therapy in Patients with Mantle Cell Lymphoma

Lori A. Leslie, MD, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, discusses the impact brexucabtagene autoleucel (formerly KTE-X19; Tecartus) has had on the treatment landscape for patients with relapsed or refractory mantle cell lymphoma (MCL).

The CD19 autologous T-cell product was approved for patients with relapsed/ refractory MCL who had been previously exposed to chemoimmunotherapy and bruton tyrosine kinase (BTK). The approval was based on the ZUMA-2 study (NCT02601313) within this patient population.

Findings showed the high-risk patient population to demonstrate high overall response rates which ranged above 90% and 67% of patients to achieve a complete response.

At a follow-up of 12.5 months, 78% of patients who responded remained in complete response showing a positive and promising change in the landscape for these patients.

Brexucabtagene autoleucel is a CD19 autologous T-cell product that is approved in relapsed/refractory mantle cell lymphoma. It has really helped start to change the treatment landscape for these patients. It was approved based on the ZUMA-2 study which looked at patients with relapsed refractory mantle cell lymphoma who had been exposed to chemoimmunotherapy and a bruton tyrosine kinase inhibitor. All patients had to be BTK exposed, and it was a really high-risk group of patients.

 About a third of patients had very advanced blastoid mantle cell lymphoma, 88% of the patients were actively relapsing through their BTK inhibitor, which we know is a high-risk patient population with poor outcomes that really don't respond well to subsequent line of therapy. In this high-risk population, there were very high overall response rates for a single infusion of brexucabtagene autoleucel CD19 CAR T-cell, the other name is KTE-X19, with an overall response rate above 90 at 93% and 67% of patients achieving a complete remission.

With mantle cell lymphoma, treatment is more of a marathon such that these patients can relapse later. With the follow up, which was at a median of just over a year, 12.5 months, very remarkably, 78% of patients who responded remained in complete response. This is a very promising therapy that's given a 1 and done type of approach for high-risk patient population and responses seem to be durable. It really has changed the landscape for these patients with mantle cell lymphoma.

Lori A. Leslie, MD, discusses the impact that brexucabtagene autoleucel had on the treatment landscape for patients with relapsed or refractory mantle cell lymphoma.

CD19 CAR T-Cell Agent Shows Promise for Patients With MCL

Lori A. Leslie, MD, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, discusses her recent presentation around chimeric antigen receptor (CAR) T-cell therapy for mantle cell lymphoma (MCL) and indolent lymphomas.

 So, I presented the updates on car T cell therapy in patients with mantle cell and indolent lymphoma, and currently mantle cell lymphoma. We have CD19 CAR T brexucabtagene

approved for relapsed refractory disease based on the ZUMA-2 study, showing an overall response rate of 93% and a complete response rate of 67%. In indolent lymphomas, we have CD19 CAR-T cell therapy approved for patients with relapsed refractory follicular lymphoma based on the ZUMA-5 study, and that shows an overall response rate of 94% a CR rate of almost 80% and durable response with the latest follow up.

Another thing that was highlighted in the presentation is that studies are ongoing with other CAR T products across mantle cell and follicular lymphoma. And 1 very interesting combination type of approach that's moving forward in mantle cell lymphoma is the combination of BTK inhibitor, particularly Ibrutinib with CD19 CAR T. Ibrutinib may enhance the activity of CD19 CAR T-cell therapy or CAR T-cell therapy in general, because it shifts the immune response towards a TH1 [or] T-helper 1 type response, which is involved in cytotoxic effector response against cancer that in combination with an impact on the immune microenvironment may help make CAR T-cell therapy more effective and potentially mitigate cytokine release.

 So, there's a lot of interesting things going on in the mantle and indolent lymphoma space to take our current CAR T products, hopefully expand where they can be used, move them into earlier line settings and move forward with rational combinations to make our therapies more effective and less toxic.

Lori A. Leslie, MD, discusses her recent presentation around chimeric antigen receptor T-cell therapy for mantle cell lymphoma and indolent lymphomas. 

CAR T-Cell Agents for MCL and Indolent Lymphoma

Lori A. Leslie, MD, lymphoma attending, John Theurer Cancer Center, discusses the approval of tazemetostat in the follicular lymphoma setting and the data that that led to its FDA approval.

Leslie says that tazemetostat is an oral EZH2 inhibitor. The first designation for this agent was in epithelioid sarcoma in January 2020. On June 18, 2020, tazemetostat was approved for use in patients with relapsed or refractory follicular lymphoma (FL).

Although there is activity with this agent in both 

 wild-type FL, the label is for patients with relapsed/refractory disease with an 

 mutation or who have no other appropriate options. Because of this indication, there's some room in terms of the label based on the data that led to the approval, according to Leslie.

The results used for the approval were from a multicenter phase 2 trial that looked at the use of this agent in 99 patients. Leslie explains that one cohort enrolled patients with 

-mutant relapsed/refractory FL, and the other was made up of patients with 

 wild-type disease. The dosing for tazemetostat was 800 mg twice a day until patients experienced disease progression or unacceptable toxicity.

In terms of the primary end point of the trial, the objective response rate in patients with 

-mutant disease was higher, at 69%, according to Leslie. Twelve percent of patients achieved complete remission. There was also activity with this drug in those with EZH2 wild-type disease; for this cohort, the objective response rate was 34%, with a complete remission rate of 4%.

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Lori A. Leslie, MD, discusses the approval of tazemetostat in the follicular lymphoma setting and the data that that led to its FDA approval.

Exploring the Tazemetostat Approval in R/R Follicular Lymphoma

Lori A. Leslie, MD, lymphoma attending, John Theurer Cancer Center, discusses the current treatment options for patients with mantle cell lymphoma (MCL).

MCL is a very complicated lymphoma, Leslie says. In the upfront setting, physicians should consider factors like age, comorbidities, and what is driving the lymphoma, such as a P53 abnormality. The treatment options in this setting include high-dose chemotherapy and autologous stem cell transplant.

For patients with MCL who are older and less fit, options include bendamustine/rituximab (Rituxan)-like regimens. In a rare subset of patients with MCL, the watch and wait approach could be appropriate, but this is less common in MCL than in other indolent lymphomas.

Overall, Leslie says that she encourages participation in clinical trials for MCL. There are many ongoing studies right now evaluating novel agents, BTK inhibitors, BCL2 inhibitors, combination regimens, and more.

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Lori A. Leslie, MD, discusses the current treatment options for patients with mantle cell lymphoma.

Expert Reviews Treatment Landscape for Patients With Mantle Cell Lymphoma

Lori A. Leslie, MD, a medical oncologist at the John Theurer Cancer Center, discusses options for patients with relapsed/refractory mantle cell lymphoma (MCL).

Leslie says that this setting is rapidly evolving in a good way with many new targeted therapies, including cellular therapy entering as a treatment option. Usually the most important choice when a patient comes in with relapsed/refractory disease depends on what they received in the frontline setting and the length of their remission. If she had a patient who had already received chemoimmunotherapy and transplant and had a 10-year remission, she would treat them differently than a patient who was given chemoimmunotherapy and relapsed while still on maintenance treatment.

For a patient with relapsed MCL, whether they are higher-risk or not, the standard of care is to consider targeted therapies. This includes Bruton kinase inhibitors (BTK), venetoclax (Venclexta), lenalidomide (Revlimid) with rituximab (Rituxan), and bortezomib (Velcade)-based therapies. Bortezomib is not as preferred now that BTK inhibitors are available, according to Leslie.

Patients who have experienced multiple relapses have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy; Leslie thinks this is one of the most exciting things in that space at the moment. The recent data looking at this type of agent in patients with relapsed MCL who are resistant or refractory to BTK inhibitors have shown a high overall response rate and about two-thirds of patients achieving complete responses that seem durable.

<< View more resources and information regarding mantle cell lymphoma

Lori A. Leslie, MD, discusses options for patients with relapsed/refractory mantle cell lymphoma.

Lori A. Leslie, MD | Authors

Articles

EP. 1: Exploring CAR T-Cell Therapy in Patients with Mantle Cell Lymphoma

CD19 CAR T-Cell Agent Shows Promise for Patients With MCL

CAR T-Cell Agents for MCL and Indolent Lymphoma

Exploring the Tazemetostat Approval in R/R Follicular Lymphoma

Expert Reviews Treatment Landscape for Patients With Mantle Cell Lymphoma

Discussing How to Treat Patients With Mantle Cell Lymphoma