Real-World Experience With CAR T Varies From Trials in DLBCL

Jennifer Amengual, MD

Real world experience with CAR T-cell therapy and bispecific antibodies in the treatment of patients with diffuse large B-cell lymphoma (DLBCL) may not approximate results seen in clinical trials, according to a presentation from the 42nd Annual Chemotherapy Foundation Symposium.¹

“CAR T-[cell therapy] is now approved for a number of [lymphoma] indications…[and with clinical trials, there are] a whole host of other possible B-cell and T-cell [lymphomas under evaluation]. So certainly, [we are] going to have more indications in the coming years,” Jennifer Amengual, MD, Herbert Irving Assistant Professor of Medicine, Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, said during a presentation at the symposium, adding, however, that challenges remain.

In particular, she included challenges such as access to care, the need for specialized centers, the possibility of hospitalizations, short- and long-term toxicities–including cytokine release syndrome (CRS), immune effector cell-associated toxicity, B-cell aplasia, hypogammaglobulinemia, infections, and prolonged cytopenias–as well as manufacturing time or failures, treatment delays, the need for bridging therapy, complicated step-up dosing, and multiple infusions.

“When thinking about treatment options for refractory DLBCL you consider: Is it safe to give an older patient CAR T-[cell therapy]?,” Amengual questioned. “I know that bi-specific [antibodies] are great, but how well do they perform in the real-world?”

Race/Ethnicity Considerations for CAR T-Cell Therapy

To provide context for oncologists, Amengual highlighted areas to consider when treating patients with CAR T-cell therapy across different racial and ethnic groups.

In a trial of real-world and clinical trial outcomes, Frederick Locke, MD, and colleagues evaluated outcomes from treatment with axicabtagene ciloleucel (axi-cel; Yescarta) among patients with relapsed/refractory LBCL, stratified by race and ethnicity.²

In total, 1290 patients in the real-world setting evaluation of axi-cel–including 106 and 169 patients from the ZUMA-1 (NCT02348216) and ZUMA-7 (NCT03391466) trials, respectively–were identified using the Center for International Blood and Marrow Transplant Research database, and stratified into non-Hispanic White, non-Hispanic Black (5.3%), non-Hispanic Asian (6.0%), and Hispanic (11.8%) subgroups.

Baseline demographics showed that non-Hispanic Black patients appeared to be younger than the other subgroups of patients, and there was no difference between groups when it came to sex, ECOG performance status, disease histology at diagnosis, as well as comorbidities. However, Amengual noted that there was a higher percentage of non-Hispanic Black patients who were ineligible (66%), vs eligible, for clinical trial participation. “Less than 50% of patients that were treated with CAR T in the real world would have been eligible for 1 of those clinical trials, which leads us to the desire to know: How do patients do in the real world?”

Locke et al found that non-Hispanic Black patients, compared with their non-Hispanic White counterparts, demonstrated a lower overall response rate (ORR; 54% vs 75%, respectively; odds ratio [OR], 0.37; 95% CI, 0.22-0.63) and complete response (CR) rates (46% vs 59%; OR, 0.57; 95% CI, 0.33-0.97). To compare against clinical trial results, in the ZUMA-1 and ZUMA-7 trials, the ORRs were 100% and 80%, respectively, while the CR rates were 100% and 70% among non-Hispanic Black patients.

“There's this dramatic difference seen in African Americans. And this is likely highlighted by [the fact] that there are very small numbers of African Americans that are enrolled in clinical studies,” Amengual explained. “[There were] 4 patients in ZUMA-1 and 10 patients in ZUMA-7 of African American descent. And so it's challenging [researchers] to relate these findings to the real world.”

Similarly, the non-Hispanic Black subgroup of patients experienced shorter progression-free survival (PFS) compared with non-Hispanic White patients (median PFS, 3.8 months vs 9.3 months, respectively; HR, 1.41; 95% CI, 1.04-1.90) and with non-Hispanic Asian patients (median PFS, 3.8 months vs 21.7 months; HR, 1.67; 95% CI, 1.08-2.59). Meanwhile, Hispanic patients demonstrated inferior overall survival (OS), at a median of 19.3 months, compared with the other subgroups of patients.

Conversely, non-Hispanic Asian patients showed a longer duration of response, compared with non-Hispanic White patients (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97).

Lastly, Amengual highlighted there no differences were observed across toxicities, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and prolonged cytopenias across the racial/ethnic subgroups.

“Really, the take home message here is, when thinking about designing clinical trials [and] really analyzing the results of trials, we need to be a little bit more inclusive, so that we can better relate these studies to [the real world] as a whole,” she said.

Real-World Outcomes of CAR T in Elderly Patients

An additional question that Amengual highlighted: Since most patients with DLBCL are older, and 30% are over the age of 75, how does CAR T-cell therapy fit in this population of patients?

According to a trial conducted by Dai Chihara, MD, PhD, and colleagues, CAR T-cell therapy was only utilized by a minority of older patients with DLBCL who received 2 or more prior lines of therapy as Medicare fee-for-service beneficiaries: 19% of those aged 65 to 69, 22% ranging in age from 70 to 74, and just 13% aged 75 or older.³

In the study, the majority of elderly patients lived in an urban or suburban area, with no major difference in baseline demographics, such as age, location, sex, comorbidity index, or bridging therapies.

“And importantly, most patients received CAR T [in the] inpatient [setting[, which is, I think, what's typically done across the country. And the length of stay across all these older patients is about 21 days, which I could say is not too much longer than what we see for younger patients,” Amengual explained. “Also looking at the cost and utilization of care, [the investigators] found that the cost was similar across these groups.”

Further, approximately one-third of patients reported having needed an emergency department (ED) visit (30.3%) or rehospitalization (28.7%). “[ED visits and rehospitalization should not limit access for these patients,” she added.

Lastly, CAR T-cell therapy among this patient population proved favorable. Among those aged 65-69, 70-74, 75 or older, and the entire patient population, the median event-free survival was 6.5 months, 12.6 months, 5.3 months, and 7.2 months, respectively, while the OS was 17.2 months, 20.1 months, 13.4 months, and 17.1 months.

“There's very favorable outcomes, and this should be considered more frequently,” Amengual said.

Glofitimab-Associated AEs

Despite the fact there is less real-world data around bi-specific antibodies, Amengual highlighted findings from 2 studies evaluating the use of glofitamab (Columvi) in Taiwan and Turkey.

In a real-world, multicenter study of glofitamab as a salvage treatment for patients with B-cell lymphoma in Taiwan, 34 patients with relapsed/refractory B-cell lymphoma were identified using the compassionate use program from 2021 to 2022.⁴ Among the patients, 26% were aged 65 or older and they all had at least 3 prior therapies.

“Really interestingly, there were only grade 3 or higher CRS. So the toxicity was quite similar to what we see in clinical studies,” Amengual explained. “And I would say these toxicities were manageable, and there were no [Immune effector cell-associated neurotoxicity syndrome] events.”

Further, real-world data from the study showed that the median PFS was 3.2 months, with a 1-year rate of 33%. In addition, the median OS was 8.4 months, with a 1-year rate of 40%. “Like all the other data for bi-specifics, those who are responders really have enrichment for a response. So those with a complete response have much more prolonged overall survival,” Amengual said.

Another real-world trial conducted in Turkey, also utilizing 43 patients from the compassionate use program, showed similar tolerability; however, there were several grade 5 events (febrile neutropenia, n = 2; COVID-19 infection, n = 4; and CRS, n = 1).⁵

The ORR was comprised of a 21% CR rate and 16% partial response rate, for a 6.3-month duration of response. Moreover, the median PFS and OS were 3.3 months and 8.8 months, respectively.

When comparing the real-world data to a phase 2 trial, Amengual noted that it was apparent this is a sicker population, given the compassionate use program. In addition, a slightly inferior response was observed.

“So I would say that this does closely resemble what we see in clinical trials, and I think it's very reassuring,” she concluded.

References

1. Amengual J. Real-World Evidence: Utilizing CAR T-Cell Therapies and Bispecific Antibodies in DLBCL. Presented at: 42nd Annual CFS®; November 13-15, 2024; New York, NY.
2. Locke F, Siddiqi T, Jacobson CA, et al. Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity. Blood. 2024;143(26):2722–2734. doi:10.1182/blood.2023023447
3. Chihara D, Liao L, Tkacz J, et al. Real-world experience of CAR T-cell therapy in older patients with relapsed/refractory diffuse large B-cell lymphoma. Blood. 2023;142(12):1047–1055. doi:10.1182/blood.2023020197
4. Hsu YT, Wu SJ, Kao HW, et al. Glofitamab as a salvage treatment for B-cell lymphomas in the real world: A multicenter study in Taiwan. Cancer. 2024;130(11):1972-1981. doi:10.1002/cncr.35217
5. Atesoglu EB, Gulbas Z, Uzay A, et al. Glofitamab in relapsed/refractory diffuse large B-cell lymphoma: Real-world data. Hematol Oncol. 2023;41(4):663-673. doi:10.1002/hon.3174