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Spotlight

This roundtable series looks at the use of CAR T-cell therapy for patients with large B-cell lymphoma and how this is expanding treatment options for these patients in the second-line setting, as discussed by key opinion leaders and participants at virtual live events.

Expanding Second-Line Therapy in B-cell Lymphoma with CAR T-Cell Therapy

A 67-year-old man presented with fatigue, back pain, and lymphadenopathy.​

 Hypertension is well controlled with medication​.

Left posterior cervical, 1.5-cm node; right anterior cervical node, 2.5 cm; left supraclavicular node, 2.0 cm​

 multiple enlarged mesenteric and retroperitoneal nodes, with the largest being 5.3 × 3.1 cm​

 confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal cent B-cell, double expressor lymphoma

: CD20, BCL-6, BCL-2 (50% of cells), MYC (> 40% of cells), Ki67 85%, MUM1​

 Lactate dehydrogenase elevated, complete blood count normal​

International prognostic indicator: high-intermediate risk

Rituximab (Rituxan), cyclophosphamide, hydroxydaunomycin, vincristine sulfate (Oncovin), and prednisone was initiated for 6 cycles.

Post-treatment PET scan demonstrated a complete response with a Deauville score of 2; patient was observed​ after.

The patient complained of fever, night sweats, and back pain. ​

A palpable lymph node in left groin was discovered on physical examination​.

new left inguinal lymph node, increase in size of residual nodes, as well as multiple metabolically active lesions in lymph nodes of the retroperitoneum, abdomen, and pelvis​.

Biopsy confirmed DLBCL, but next-generation sequencing was not performed.

The patient was referred to nearest transplant and cellular therapy center for evaluation.

TARGETED ONCOLOGY: How does the time of return with axicabtagene ciloleucel (axi-cel; Yescarta) compare to lisocabtagene maraleucel (liso-cel; Breyanzi) when treating patients with DLBCL?

[NCT03391466] is that they were potentially choosing better patients, because they did not allow bridging therapy on the study.

 I think some of that criticism is valid, but the other thing is that axi-cel comes back much quicker than the other chimeric antigen receptor T-cell therapies, in terms of manufacture time. On the trial, the average time of return was between 15 to 17 days, and now in reality, they've cut that down to 12 days. So, you get the product fast, [and during those] 12 days you probably...can hold [a patient who doesn't have severe disease] with radiation and steroids. For liso-cel…you're waiting 3 to 4 weeks for that product, but there's no way that you can hold somebody's disease that long on steroids.

Please describe the TRANSFORM trial (NCT0357531) set-up and results.

[The study] was a 1:1 randomization [comparing standard of care and liso-cel], where patients could get up to 3 cycles of salvage chemotherapy.

 The trial did allow crossover, so if you had less than a partial response on the transplant arm, you could go over to the CAR T-cell therapy arm. The primary end point was event-free survival [EFS]. [On this study], EFS and progression-free survival were improved with liso-cel over the standard of care.

What were the other notable outcomes from the trial?

The overall survival [OS] has not been shown to be statistically significant, and part of that's probably due to patient crossover, and even when they adjust for crossover, they are just at an HR [of approximately] 0.4.

 So, maybe with longer follow up, we'll see an OS benefit with liso-cel. If you look at the data, my guess is that [that OS benefit is] there, it's just that we aren't able to see it based on the way that this trial was designed.

In terms of outcomes, [there was a] complete response rate in the liso-cel arm of 68% [95% CI,63.7%-82.5%] vs 40% [95% CI, 33.2%-54.2%] in the standard of care arm [

 < .0001]. Again, OS was not shown to have benefit yet, but the overall response rate was quite high [with liso-cel compared with the standard-of-care arm] at 80% [95% CI, 78.3%-93.1%] vs 45% [95% CI, 38.3%-59.6%]. Patients who respond do have a very good overall duration of response as well.

What were the toxicities with this regimen?

The main non-CAR T-cell associated toxicity, in terms of cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS], was hematologic adverse events.

 In terms of CRS and ICANS, this is certainly a product that has less of an unique toxicity...and that's probably because of the 4-1BB costimulatory molecule, so you have a slower expansion, slower proliferation rate, and instead of that big spike, the CRS and ICAN events decreased [their grades] overall. So, any grade of CRS was seen in 49% [of patients], while [the rate of] events higher than grade 3 was very low. Any-grade events of ICANS [occurred at a rate of] 11%, while grade 3 or higher was about 4%.

1. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large b-cell lymphoma. 

. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133

2. Abramson JS, Johnston PB, Kamdar M, et al. Health-related quality of life with lisocabtagene maraleucel vs standard of care in relapsed or refractory LBCL. 

. 2022;6(23):5969-5979. doi:10.1182/bloodadvances.2022008106

3. Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. 

. 2023;141(14):1675-1684. doi:10.1182/blood.2022018730

During a Case-Based Roundtable® event, Sairah Ahmed, MD, discussed the data behind the use of lisocabtagene maraleucel for patients with diffuse large B-cell lymphoma in the second article of a 2-part series. 

Ahmed Discusses Why the Wait for Liso-Cel Is Worth It

A 67-year-old man presented with fatigue, back pain, and lymphadenopathy.

 multiple enlarged mesenteric and retroperitoneal nodes, with the largest being 5.3 × 3.1 cm​.

 confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal cent B-cell, double expressor lymphoma.

 Lactate dehydrogenase elevated, CBC normal​

Biopsy confirmed DLBCL, but next generation sequencing was not performed.

Targeted Oncology: What are the current options for a patient like this?

The current treatment landscape for [patients with] DLBCL has changed dramatically over the last 5 or 6 years. For the frontline setting, we often still use chemoimmunotherapy, but in the second-line setting, depending on the time of relapse, chimeric antigen receptor [CAR] T-cell therapy has been approved for both transplant eligible and ineligible patients.

After 12 months [of treatment], if someone has disease that relapses and they are transplant eligible, we still agree that transplant is certainly a viable option, and can potentially have a long-lasting curative effect. In terms of the third-line setting, there are a number of new agents, including CD19 targeting agents, CD79 targeting agents, checkpoint inhibitors, but more recently CD20 targeting bispecific [have emerged].

How do you approach sequencing these therapies for these patients?

The way that we sequence these drugs is very much dependent on the patient in front of us and their comorbidity status, and somewhat on how comfortable we are in utilizing some of these newer drugs. My colleagues…came up with an algorithm for second-line treatment [for patients with] large B-cell lymphoma, looking at where are we going to have the most efficacy with the treatment options that we have.

 We know that the vast majority of patients who have DLBCL are going to have early relapses, and that the majority of them will be eligible for CAR T-cell therapy and, potentially, 40% of those patients who receive second-line CAR T-cell therapy are going to have a durable remission, which would functionally be a cure.

What about for patients not eligible for CAR T-cell therapy?

For patients who are not eligible for CAR T-cell therapy, there are other options, but none of them, at this point in time, have been shown to be curative. Now, for patients who are eligible for transplant and have relapsed after 1 year, about 50% of them, based on historic data, are going to have a response to second-line treatment and therefore be able to proceed to autologous stem cell transplant, and about 50% of those patients will be cured of their disease.

Where does CAR T-cell therapy stand in the third-line setting?

Patients will potentially have the option for CAR T-cell therapy in the third-line setting, and again, that same 40% durable remission is still what we quote in [this later setting].

 In terms of being able to offer patients curative intent treatment, the advent of CAR T-cell therapy has given us one more time point at which we can potentially have the opportunity for [a curative therapy for these patients]…. There are also data to show that the patient can have a transplant before as well as after CAR T-cell therapy, and there are some patients who can still go on to allogeneic transplant after CAR T-cell therapy or other CAR T-cell therapies beyond just CD19 targeting [therapies].

1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 2.2024. Accessed May 23, 2024. 

2. Westin J, Sehn LH. CAR T cells as a second-line therapy for large B-cell lymphoma: a paradigm shift? 

. 2022;139(18):2737-2746. doi:10.1182/blood.2022015789

3. Testa U, Leone G, Pelosi E, et al. CAR-T cell therapy in large b cell lymphoma. 

. 2023;15(1):e2023066. doi:10.4084/MJHID.2023.066

4. Zurko J, Ramdial J, Shadman M, et al. Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma. 

. 2023;108(1):98-109. doi:10.3324/haematol.2022.281242

During a Case-Based Roundtable® event, Sairah Ahmed, MD, discussed how the burgeoning use of chimeric antigen receptor T-cell therapy presents a paradigm shift in treatment for patients with diffuse large B-cell lymphoma in the first article of a 2-part series. 

CAR T-Cell Therapy Presents a Paradigm Changing Option in DLBCL

Matthew Lunning, DO, FACP, discusses the use of CAR T-cell therapy lisocabtagene maraleucel in the second-line setting for patients with B-cell lymphoma.

CAR T-Cell Therapy Broadens Second-Line Treatment in LBCL

Matthew Lunning, DO, FACP, associate professor in the division of hematology/oncology, assistant vice chancellor of clinical research, and associate vice chair of research in the department of internal medicine at the University of Nebraska Medical Center, discusses the use of chimeric antigen receptor (CAR) T-cell therapies in the second-line setting for patients with B-cell lymphoma.

According to Lunning, CAR T-cell therapies have shown that regardless of the make-up of a patient’s disease they have strong outcomes. In particular, lisocabtagene maraleucel (liso-cel), an autologous, CD19-directed CAR T-cell therapy, has shown significant benefit for patients with early relapsed or refractory large B-cell lymphoma (LBCL). 

This recommendation comes from the phase 3 TRANSFORM (NCT03575351) study, which compared liso-cel with standard-of-care second-line therapy in patients with primary refractory or early relapsed LBCL. Patients were randomly assigned on a 1:1 basis to 100 × 106 CAR T-cells given intravenously compared with 3 cycles of salvage immunochemotherapy given intravenously followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation in responders.

Median event-free survival was significantly better for the patients in the liso-cel arm (n = 92) compared with standard of care (n = 92) at 10.1 months (95% CI, 6.1-not reached) vs 2.3 months (95% CI, 2.2-4.3), respectively (HR 0.35; 95% CI, 0.23-0.53, 

 < .0001). Lunning discussed how these better outcomes with CAR T-cell therapy make it important to get this therapy to patients as quickly as possible once their disease progresses to the second-line setting.

I think one of the things that we often think about at the beginning [of treatment] is do they have certain biologies, whether or not they have double-hit lymphomas, or those who have 

 [rearrangement], as well as BCL2 processes or those with high [international prognostic indictor] risk, or those patients who are either refractory or relapsed after their front-line therapy. I think one of the unique things that has come out amongst CAR T-cell therapy in general, and also when we dive deeper into the liso-cel data, is that CAR T-cells remain agnostic to these features, specifically around genetics, perhaps even having better outcomes…in general, comparatively to the control arm, which was second-line therapy and autologous stem cell transplant. Obviously, if [the patient is] relapsing vs refractory, there can be a spectrum of the disease activity. So, I think getting to the CAR T-cell [therapy] as quickly as possible in [this] primary refractory or even primary progressive patient population is incredibly important.

Matthew Lunning, DO, FACP, discusses the use of CAR T-cell therapy lisocabtagene maraleucel in the second-line setting for patients with B-cell lymphoma. 