Illuminating Optimal CAR T-Cell Therapies Across Large B-Cell Lymphoma Groups

CAR T-cell therapy has emerged as a viable treatment for patients with diffuse large B-cell lymphoma (DLBCL), offering significantly enhanced survival with manageable safety to optimize outcomes for this group. While the advantages are unmistakable, many considerations emerge when considering when and where to treat patients, especially those with relapsed/refractory disease, in the treatment landscape.

In a recent Satellite Sessions centered around the University of North Carolina (UNC) Health System, hematologic oncologists convened to elucidate the optimal conditions with which to deploy these agents, including for candidates vs non-candidates for CAR T-cell therapy, as well as based on a patient’s intention to undergo hematopoietic stem cell transplantation (HCT). The panel, led by Natalie Grover, MD, clinical director of the Cellular Therapy Program at UNC Lineberger Comprehensive Cancer Center, further deliberated about which line of therapy these agents should be deployed, as well as strategies for holding and bridging therapy prior to CAR T, informed by NCCN guidelines.

Moreover, the panel discussed how central nervous system (CNS) involvement impacts treatment selection for CAR T-cell therapy before diving into barriers to referral for these treatments. Finally, their discussion encompassed preferences for holding or bridging therapy.

In addition to Grover, UNC-based panelists included Christopher Dittus, DO, MPH, clinical director of the Lymphoma Program, Faculty Recruiter for Lymphoma, and a professor of medicine; Anne W. Beaven, MD, vice chief of operations and an associate professor of medicine; Deborah Stephens, DO, director of the Chronic Lymphocytic Leukemia (CLL) and Richter's Program, physician leader of the CLL and Lymphoma Research Program, and associate professor of medicine; and Megan Kathryn Sterlina, PA-C, hematology advanced practice practitioner (APP) manager and instructor at the UNC School of Medicine PA Program.

Additional panelists included Felicia Cao, MD, PhD, assistant professor of Medicine specializing in Cellular Therapy and Bone Marrow Transplant in the Division of Hematology; Daniel Reef, MD, FACP, hematology/oncology fellow; Bejal Kikani, MSN, FNP-BC, WHNP-BC, APP specializing in lymphoma; Laura Klos, PharmD, BCOP, CPP, clinical pharmacist practitioner in malignant hematology; Katharine Woodworth, PharmD, BCOP, oncology pharmacist; Stephanie O’Brien, MSN, RN, oncology sales specialist; and Stephanie Franco, MD, hematology/oncology fellow.

Who Should Receive CAR T-cell Therapy?

The discussion began with a question: who is not eligible for CAR T-cell therapy?

In concordance with the NCCN Guidelines for DLBCL in the second-line setting, the panelists noted that many of the patients they see are often eligible for the Category 1 recommendation, CAR T-cell therapy with either axicabtagene ciloleucel (axi-cel; Yescarta) or lisocabtagene maraleucel (liso-cel; Breyanzi), on a clinical trial with holding and bridging therapy pre- and post-pheresis, if they have relapsed disease after 12 months of prior treatment.

However, they also noted that select patients ultimately do not qualify for CAR T-cell therapy for a variety of reasons. One person who did not qualify for CAR T-cell therapy candidacy withing the 2 weeks following infusion had a personality disorder, according to Beaven. Another factor, Grover added, included the relative aggression of disease progression, but she suggested that they could be a candidate in a later line. They further touched upon patients who may not be able to undergo CAR T-collection due to reimbursement issues or cytopenias among those who might have to settle for bispecific-based options, such as polatuzumab vedotin-piiq (Polivy)-based combinations with chemotherapy or other targeted agents.

Furthermore, among patients whose disease has relapsed at greater than 12 months after last therapy line, the panelists noted that intention to undergo HCT impacted receipt of subsequent therapy. Among those with no intention to undergo HCT, liso-cel is listed as the preferred Category 2A option, followed by glofitamab-gxbm (Columvi) plus polatuzumab vedotin. By contrast, among those with an intention to undergo HCT, the preferred option is exclusively a rituximab (Rituxan)-based regimen with chemotherapy.

When Are Patients Referred for CAR T-Cell Therapy Evaluation at UNC?

When asked which setting they see most of their referrals from community, the general consensus was the second-line setting, or for disease that is primary refractory. However, Cao raised the question: are there patients who are HCT-evaluable, who are still referred for CAR T-therapy?

Dittus suggested that select patients may benefit, despite NCCN guidelines, such as for older patients who may be at a greater risk for complications that emerge during HCT. Moreover, he suggested that those who are far removed from HCT may also be candidates for CAR T-infusion.

Furthermore, Cao added that CAR T-cell therapy tends to be more convenient to provide. Dittus concurred, adding that patients may be apprehensive about the burden of HCT. Klos contributed by noting that HCT often results in longer hospital stays, whereas CAR T-cell therapy enables more outpatient treatment delivery.

“I see all the pros for it. It wasn’t going to surprise me to hear that, ‘Yes, [the transplanter] is still saying that we should just do CAR-T now for a second-line [therapy] even if it’s been more than 12 months.’ It wouldn’t surprise me if they were still doing CAR T and then we’ll [continue to transplant], just no injury,” Cao explained.

Regarding intravenous immunoglobulin (IVIG) therapy, Stephens suggested that CAR T-cell therapy, despite their use as a one-time treatment, may confer lifelong treatment with IVIGs.

Analyzing the ZUMA-7 Data: How it Impacted CAR T-Cell Therapy Feasibility in DLBCL

Grover then gave an overview of the phase 3 ZUMA-7 trial (NCT03391466), in which patients with confirmed LBCL relapsed/refractory to first-line treatment were randomly assigned 1:1 to axi-cel or standard of care (SOC).¹ She highlighted the significantly improve event-free survival (EFS) outcomes (HR, 0.4; P <.001) and overall survival (OS) outcomes (HR, 0.73; P <.03) with axi-cel for this transplant-eligible group, supplemented by findings for patients who are transplant-ineligible from the phase 2 ALYCANTE trial (NCT04531046).² However, Stephens added that the trial was conducted at a point when salvage therapies were different in a pre-bispecific era, suggesting that better comparators may be available today.

Next, the panelists discussed the implications of CAR T-cell therapy administration in the second-line line vs later line settings, homing in on long-term toxicities between HCT and CAR T-cell therapy in the primary relapsed/refractory setting. In accounting for higher grade toxicities, Grover noted a higher incidence of cytopenias, in addition to grade 3 or higher immune effector cell-associated neurotoxicity syndrome (ICANS), as well as 8 fatal AEs in the axi-cel arm. However, she expressed that a greater number of patients died from disease progression in the SOC arm, emphasizing the overall benefit of axi-cel despite increased second-line toxicity.

How has the Liso-cel Data TRANSFORMed Second-Line HCT-Eligible LBCL Practice?

In reviewing the phase 3 TRANSFORM trial (NCT03575351), Grover noted that that comparable efficacy was noted with liso-cel among a similar group of chemotherapy- and autologous stem cell transplantation (ASCT)-eligible patients, with significantly improved EFS outcomes vs SOC (HR, 0.356; 95% CI, 0.243-0.522).³ Although overall survival (OS) outcomes were not significant, they trended towards significance, with a median not reached (NR) with liso-cel after 4-year follow-up vs 29.9 months with SOC.

A higher rate of high-grade hematologic adverse effects (AEs), including neutropenia (82% vs 52%), anemia (52% vs 56%), and thrombocytopenia (50% vs 68%) were observed in both arms, with 1% of patients of patients experiencing grade 3 or higher CRS and 4% of patients experiencing grade 3 or higher neurological events in the liso-cel arm. She concluded in suggesting that the data could be convincing for an oncologist considering CAR T-cell therapy for patients in the second-line who are eligible for ASCT.

Stephens further expressed an important consideration, which supports the case for second-line CAR T-cell therapy administration:

“[M]ore therapy means likely [fewer] T-cells than this, too. If you’re considering CAR T-cell therapy, it makes sense to do it earlier rather than another type of therapy that might compromise your T-cell efficacy,” she explained.

Bridging and Holding Therapy: Optimizing Outcomes Before CAR T Administration

The panelists then deliberated over the optimal use of bridging and holding, or stabilizing, therapy leading up to CAR T-administration, for the sake of maintaining disease control without compromising CAR T-viability and reduce disease burden. Noting that NCCN guidelines exist for holding and bridging therapy, listing rituximab-based chemotherapy-containing regimens, in addition to polatuzumab vedotin/rituximab, and involved site radiotherapy (ISRT), Cao and Stephens cautioned against bendamustine as pre-collection therapy due to T-cell toxicity.

When to use Axi-cel Vs Liso-cel

When considering when to use axi-cel or liso-cel among young, healthy patients, many of the panelists suggested that liso-cel may offer the best benefit on the grounds of potential neurotoxicity with axi-cel. However, Cao and Stephens noted that institutional bias may play a role as well.

“There are some other places that also do mostly [liso-cel]. I was talking to someone, she’s at Seattle now, and she says they have done much more [liso-cel], but she [said] Stanford still [does] a lot of [axi-cel], so it’s definitely depends on the institution,” Stephens explained.

Another consideration for axi-cel stems from manufacturing issues with liso-cel, potentially resulting in treatment delays lasting weeks.

Moreover, Stephens initially suggested that younger patients who experienced a relapse after 12 months following treatment may benefit from transplantation, however some panelists debated about the optimal time to consider CAR T-cell therapy vs transplantation in the second-line setting. Particularly between years 1 and 2 post-treatment, Dittus suggested that CAR T-infusion in the second line could prevent secondary malignancies down the road.

“I’m at the point where I prefer to do CAR T. I mean, I’d have the conversation about transplant for sure...they can handle it better, but it also has a higher rate of [myelodysplastic syndromes (MDS)] and [acute myeloid leukemia (AML)] down the road,” Dittus explained. “If you could cure them potentially with CAR T, then they could always be transplanted down the road if they relapse again.”

For Dittus’s last point, the panelists discussed the viability of autologous HCT following CAR T, with some suggesting anecdotal success with despite an absence of data. The consensus for panelists, including Grover, for patients who are not refractory or sensitive to chemotherapy was allogenic HCT post-CAR T-cell therapy.

Considerations for CNS-involved LBCL

Regarding CNS-involved LBCL, Dittus suggested that certain factors may impact treatment selection, including the type of relapse – systemic vs CNS – and when it occurs:

“Traditionally, I’ve approached them as primary CNS, so then they would go to transplant with a thiotepa-based regimen. For secondary with systemic involvement, there's [phase 2] MARIETTA data [NCT02329080] for that [with CNS-directed chemoimmunotherapy].⁴ There are data to do high-dose methotrexate, and then [ifosfamide, carboplatin, and etoposide (ICE),] and then transplant. But that's usually for patients who present like that,” he explained. “If it’s relapsed, you’d make a good argument for going to CAR T in those cases, especially with the systemic relapse.”

Grover concurred, explaining that one patient developed CNS disease after CAR T collection. She had planned to treat them with a methotrexate-based therapy, and initiate CAR T-infusion once the CNS disease was controlled.

Examining Barriers to Access and Pretreatment Strategies for CAR T-Cell Therapy

The panelists discussed common barriers to access for CAR T-cell therapy, listing caregiver support, insurance authorization, and geographic and logistical barriers among the most frequent. Moreover, another common constraint is for securing apheresis slots, another insurance-related concern, with up to 2-month wait times.

Another consideration for patients who may not be eligible for or are unable to access CAR T-cell therapy in the second-line setting, is bispecific therapy followed by CAR T infusion. Sterlina suggested that patients may benefit from glofitamab as bridging or stabilizing therapy and that bispecifics until failure followed by CAR T-cell infusion could be feasible, with Stephens adding that bispecifics would be continued until failure if CAR T collection has not occurred.

Finally, Grover highlighted a single-arm feasibility trial of loncastuximab tesirine (Zynlonta) as a CD19-targeted bridging therapy, highlighting feasibility preclinically, but also keeping in mind potential targeting differences from CAR T.

References

1. Westin JR, Oluwole OO, Kersten MJ, et al. Survival with axicabtagene ciloleucel in large B-Cell lymphoma. N Engl J Med. 2023;389:148-157. doi:10.1056/NEJMoa2301665
2. Houot R, Bachy E, Cartron G, et al. Axicabtagene ciloleucel as second-line therapy in large B cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial. Nat Med. 2023;29:2593-2601. doi:10.1038/s41591-023-02572-5
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. Blood. 2023;141(14):1675-1684. doi:10.1182/blood.2022018730
4. Ferreri AJ, Doordujin JK, Re A, et al. MATRix–RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial. Lancet Haematol. 2021;8(2):110-121. doi:10.1016/S2352-3026(20)30366-5