CAR T-Cell Therapy Debate in Leukemia/Lymphoma Subtypes
A Satellite Sessions event that took place at Fred Hutchinson Cancer Center and discussed treatments surrounding LCL and CLL.
Meet the experts
A Satellite Sessions event, hosted by CancerNetwork, took place at Fred Hutchinson Cancer Center and discussed treatments surrounding large-cell lymphoma (LCL) and chronic lymphocytic leukemia (CLL). Specifically, the panelists focused on considerations of chimeric antigen receptor (CAR) T-cell therapy, particularly axicabtagene ciloleucel (axi-cel; Yescarta) and lisocabtagene maraleucel (liso-cel; Breyanzi) treatments in comparison with each other. The use of bispecific antibodies in this space was also a conversation point.
Mazyar Shadman, MD, MPH, medical director at the Bezos Family Immunotherapy Clinic at Fred Hutchinson, led the panel. Also on the panel was Christina Poh, MD, a physician at Fred Hutch and assistant professor in the Division of Hematology and Oncology at the University of Washington School of Medicine; Hannah Alo, NP, a nurse practitioner; Lisa C. Getzendaner, MHS, PA-C, a physician assistant at Fred Hutch and a teaching associate in the Division of Hematology and Oncology at the University of Washington School of Medicine; Solomon A. Graf, MD, an associate professor in the Division of Hematology and Oncology at the University of Washington; Manoj P. Menon, MD, MPH, an associate professor in the Vaccine and Infectious Disease Division and the Clinical Research Division at Fred Hutch; Kurt Norman, MD, MS, a physician at Fred Hutch and clinical assistant professor in the Division of Hematology and Oncology at the University of Washington School of Medicine; Chaitra
S. Ujjani, MD, a physician and associate professor in the Clinical Research Division at Fred Hutch and associate professorin the Division of Hematology and Oncology at the University of Washington School of Medicine;and Brian Till, MD, an associate professor in the Translational Science and Therapeutics Division at Fred Hutch.
Axi-Cel vs Liso-Cel Discussion
Shadman / What do you think about axi-cel and liso-cel, knowing their safety profiles? If you have a patient with early relapse, do you discuss the product at all? Do you have any preferences, when you refer patients to us, about which product we use?
Menon / I don’t have a particular preference. I would defer to you.
Shadman / With our lymphoma group, when you refer your patient, is this patient coming from outside Fred Hutch? For internal patients, do you normally have these data?
Poh / I’m not necessarily telling my patients about the different CAR [chimeric antigen receptor] types. I’m just telling them they’re going to go see somebody and talk about CAR T-cell therapy, but when it comes to axi-cel and liso-cel, I leave it up to you to decide which one to give our patients.
Based on the data, it seems like liso-cel is safer and less toxic, but the study design is a little different, and my question, when looking at the data that you just presented, is [whether] the patients who were in the phase 3 TRANSFORM trial [NCT03575351] had less disease before CAR T-cell therapy because they got bridging [therapy]?1 Maybe that’s why they have fewer adverse effects [AEs].
Shadman / So, in TRANSFORM, many patients didn’t need to have measurable disease before CAR T-cell therapy. They had to have measurable disease at randomization, but if they [received] bridging therapy and had a complete response [CR], they stayed on the study.
But would that [change eligibility criteria] because the intention-to-treat population is from randomization and not necessarily from the CAR T treatment? You could argue that investigators felt more comfortable putting patients who had bulkier [disease] on TRANSFORM because they knew those patients had the option of getting bridging therapy vs selecting patients who [had] less bulky [disease].
Alo / In the phase 2 PILOT trial [NCT03483103], did patients get debulking chemotherapy?
Shadman / That trial was intended for patients who were not transplant eligible by comorbidity and got CAR T-cell therapy instead. I’m sure they could get the same bridging therapy.
The [investigators in the] phase 3 ZUMA-7 trial [NCT03391466] just published a paper in Blood showing that the metabolic tumor volume (MTV), pre–CAR T-cell therapy, predicts your outcome.2 Which is not surprising but is interesting because that’s always been confounded by bridging therapy. Is it because of MTV or is it because they got bridging therapy? ZUMA-7 did not allow for bridging therapy. It’s purely the impact of disease burden, which does predict the outcome.
With bispecific antibodies now, are there patients who make you wonder [whether] you can get [clearance] from insurance? For your primary refractory patients, have you offered a non–CAR T option in the past year?
Menon / There were some social reasons why the patient couldn’t turn to either CAR T cells or transplant.
Poh / Sometimes we have rare patients who are Jehovah’s Witnesses or live super far away and have no interest in coming to Seattle. These are the patients whom we just givebispecifics [to] and hope they get them inthe community setting.
Shadman / If somebody’s a CAR T-cell therapy candidate, would you still try to get them to CAR?
Poh / Correct.
Difference in Quality
Alo / I don’t discuss the products [with my patients], and I agree that liso-cel seems to have the better safety profile, but it seems like there’s something different in the quality of the product you’re getting from liso-cel or axi-cel.
Shadman / The FDA sets quality control criteria, and it’s different for each company. You don’t get to know what those [specifications] are. If they meet the bar, then they get released and we get them [for treatment]. They say, “Here’s a valid product.” If we get the product, that means they met the [specifications], essentially. There are other things you could look at on a research level, like the exhaustion markers. Those could be different, but that’s not the information we get.
Graf / Liso-cel, historically, had a higher out-of-specification rate, and patients sometimes go on the protocols that we have for that. They have changed the bar recently.
Getzendaner / It’s interesting because, last spring, at least one-third were coming back out of specification. Then something changed because we didn’t change the number of cases, but we’ve had no out-of-specification products for probably
2.5 months. My [feeling], however, is when we push that collection right on top of multiple therapies, those are the ones that come back out of specification.
When we push the CAR T collection on top of multiple therapies, I know...that it’s going to be close. [That] we’re going to get it out of specification on this one. They must have changed something.
Till / They presented data to the FDA that compared the patients who are in specification with the out-of-specification products, and there wasn’t much difference in terms of safety or efficacy, so they petitioned the FDA, and they changed the bar for those cutoffs. They raised them to a level where approximately 90% of patients were meeting it. I don’t know the exact cutoffs.
Product Availability
Shadman / How soon do we get the products, and what’s the slot availability for each product?
Poh / For axi-cel, the manufacturing time is about 2.5 to 3 weeks. For liso-cel, it’s closer to 4 or 5 weeks. There’s a slight difference there.
Getzendaner / We aren’t having trouble with slots. I haven’t had anybody come back and say that they can’t get a production slot for a week and a half. Getting a slot is not a problem. It’s more like 2.5 weeks vs 3.5 to 4 weeks [of wait time].
If the liso-cel is out of specification, we have to run the out-of-specification drill, and that extends things by another week and a half. We need to go through consent, and then the company’s got to have a meeting and then release it, and it’s a big hullabaloo. Usually, at that point, patients are hanging on by their fingernails. We don’t want to treat them again, because we don’t want to delay [their treatment]. Those are the tough cases.
How Is the Decision Made?
Norman / Did they look at MTV? Because that’s a fundamental question. Did patients on ZUMA-7 do better because it’s self-selected for someone who had less volume coming into the trial who wasn’t going to require bridging therapy, or was there equal disease bulk, and yet the CAR T-cell therapy just performed better?
Shadman / The Locke paper in Blood published a few months ago did exactly that.3 They looked at MTV predicting the progression-free survival in the ZUMA-7 study, and as there was no bridging in ZUMA-7, it did correlate with a lower disease volume.
Norman / Was there any comparison between ZUMA-7 and TRANSFORM when the patients were coming into CAR T? Was there more or less tumor bulk for those who got bridging [therapy] compared with the patients who were self-selected to just get dexamethasone?
Shadman / [Those] data with TRANSFORM do not exist. MTV will be very confounded by bridging therapy because patients did get bridging therapy. Let’s say you see that patients with low MTV did better, how do you know [whether] it’s MTV or [whether] it’s the cycle of [treatment] they got just before that?
Is [it] the disease kinetics or is it more treatment? It’s hard to know that from TRANSFORM, but they also haven’t presented it that way.
Getzendaner / We’ve also taken into account other psychosocial issues. You can’t just admit people [for treatment] now because you won’t get paid for the bed. Another reason to use axi-cel is if you don’t have any caregivers or if you have very limited caregivers because you can put patients in hospitals for about 14 days, which gets down your caregiver needs. We’ve done that.
Shadman / We talk about giving CAR T in the outpatient setting to improve access, but giving CAR T in the outpatient setting can also worsen access, because then you require a caregiver.
Outpatient Delivery of Tocilizumab
Shadman / Do you give tocilizumab [Actemra] in the outpatient [setting] for the first fever, or do you admit them?
Ujjani / Not unless they meet the criteria. You wouldn’t give the tocilizumab for a fever or grade 1 cytokine release syndrome [CRS].
Shadman / If the patient needs treatment, do you admit them?
Ujjani / Yes, we admit them.
Shadman / You don’t try outpatient treatment of CRS?
Ujjani / As we get a little bit more experienced with managing grade 1 CRS, we could keep them outpatient, but as of now, we’re going to admit everybody.
References
- Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6
- Westin JR, Oluwole OO, Kersten MJ, et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665
- Locke FL, Oluwole OO, Kuruvilla J, et al. Axicabtagene ciloleucel vs standard of care in second-line large B-cell lymphoma: outcomes by metabolic tumor volume. Blood. 2024;143(24):2464-2473. doi:10.1182/blood.2023021620
