Barriers to CAR T-Cell Therapy for LBCL Challenge Physicians and Patients

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THE FDA APPROVALS of chimeric antigen receptor (CAR) T-cell therapies in hematologic malignancies have moved these novel options into standard treatment algorithms for diseases including large B-cell lymphoma (LBCL). However, various obstacles prevent CAR T-cell therapies from being used to their full potential despite strong efficacy data and expanded access.

For oncologists in the community setting, getting patients to CAR T-cell therapy is becoming a priority as the cellular therapies move earlier in the treatment paradigm. Two therapies have been approved as second-line therapy for patients with LBCL who are refractory to first-line chemoimmunotherapy or relapse within 12 months. In April 2022, axicabtagene ciloleucel (axi-cel; Yescarta) was approved based on the results of the phase 3 ZUMA-7 trial (NCT03391466).¹ Lisocabtagene maraleucel (liso-cel; Breyanzi) was approved in June 2022 for this indication based on the phase 3 TRANSFORM trial (NCT03575351) and is also indicated for all second-line patients who relapse and are not eligible for hematopoietic stem cell transplantation (HSCT).²

Prior to these approvals, CAR T-cell therapies were available to a smaller population who had received 2 or more lines of therapy. Additionally, the number of tertiary care centers able to perform CAR T-cell infusion were more limited. There are now over 200 accredited cellular therapy centers in the United States, according to the Foundation for the Accreditation of Cellular Therapy’s directory.³ As access has expanded, community physicians have gained experience with referring patients to receive these therapies, but they are seeing other barriers even though CAR T-cell infusion centers are within referral distance of their patients.

Long delays are still an issue for many patients who require CAR T-cell therapy, which can make it nonviable for those with aggressive disease who cannot afford to wait. In addition to the challenges of disease control, many physicians are seeing patients who decline treatment or experience hardships because of the logistics of getting cellular therapy.

“More and more of the issues are coming from the patient side,” Caron Jacobson, MD, MMSc, said while moderating a live, virtual Case-Based Roundtable event on B-cell lymphoma held by Targeted Oncology. “It’s about convincing the patient to go.… It’s becoming less and less about the medical issues.”

Jacobson is medical director of the Immune Effector Cell Therapy Program and senior physician at Dana-Farber Cancer Institute in Boston, Massachusetts and is an associate professor of medicine at Harvard Medical School.

At the event, Jacobson and other academic and community oncologists shared their experiences with the adoption of CAR T-cell therapy in LBCL. Participants in a second event moderated by Ajay K. Gopal, MD, medical director of clinical research for hematology, malignancies/hematology of Fred Hutch Cancer Center in Seattle, Washington, also outlined obstacles that came from both the provider and patient aspects of treatment, as well as disease-related factors.

PROVIDER-SIDE TIME DELAYS IMPACT PATIENTS

Hematologic oncologists have identified waiting periods before therapy can be given as 1 of the leading obstacles to using CAR T-cell therapy. These issues continue because of several bottlenecks in the process. When patients meet the criteria for CAR T-cell therapy, they are referred for evaluation. The next step is apheresis, which may be delayed by insurance approvals, and patients may also wait days or weeks for an apheresis appointment. Production of CAR T cells takes several more weeks, followed by an appointment for infusion.

Jacobson estimated that from the time patients receive consultation to cell collection is between 3 and 4 weeks, with another 3 to 4 weeks before the CAR T cells are ready for infusion.

During Gopal’s event, Amir Modarressi, MD, of Bellevue Medical Center in Washington, said the majority of his patients receive consultation for CAR T-cell therapy, but the process realistically takes 2 to 3 months from referral to treatment. Wen-Kai Weng, MD, PhD, another participant in Gopal’s event who uses CAR T-cell therapy at Stanford Health Care in California, said his institution tries to see patients as soon as possible and get them to apheresis within 2 to 3 weeks to accelerate the process.

The Sarah Cannon Transplant and Cellular Therapy Network (SCTCTN) published a retrospective review of 254 patients with non-Hodgkin lymphoma referred for CAR T-cell therapy across 5 centers up to September 5, 2022.⁴ The investigators found that the authorization, apheresis, and manufacturing steps generally result in a duration of greater than 3 months from referral to infusion. For eligible patients in 2022, the median time from referral to infusion was 98 days, with a median time from referral to apheresis of 61 days. This was a significant improvement from 140 days and 112 days, respectively, in 2021. The time from referral to consultation with a CAR T-cell specialist was not a significant contributor to delays, with a median of 3 days in 2022.

Another issue is that many patients have to travel long distances to reach CAR T-cell centers for consultation, apheresis, and infusion. Approximately one-third of patients who received CAR T-cell therapy between 2018 and 2020 lived over 2 hours away from the treatment center, according to an analysis of the Vizient Clinical Database.⁵ “A fair number of patients travel 100 or 200 miles away for evaluation and treatments for CAR T-[cell therapy],” Paul Unger, MD, of Champlain Valley Hematology Oncology in Vermont, said in Jacobson’s event. Unger explained that his practice tries to reduce unnecessary travel to the tertiary care center by collaborating on scans and bone marrow biopsies that can be done locally.

Although axi-cel and liso-cel require only a single infusion preceded by lymphodepleting chemotherapy, patients need to be monitored for 7 days at the CAR T-cell therapy center for signs of cytokine release syndrome and neurological toxicities, and remain within proximity of the care center for at least 4 weeks following infusion.^6,7 The median duration of hospital stay based on a United States database study was 12 days.⁸ Patients who live a long distance away may need local housing for this period, which can be expensive and interfere with daily life.

Patients may be ineligible or have treatment delayed because of clinical status, age, or comorbidities. “These patients do need to get their cardiac evaluation done, and some of them fail that, and that delays them,” said Ankur Mehta, MD, at Jacobson’s event. “All their basic workup prior to going on the CAR T-[cell therapy] can sometimes have challenges that derail quite a few.”

“These are people who have relapsed and generally are symptomatic from their disease. They have to be highly motivated.”

–Robert R. Koch, MD

PATIENT ISSUES MAKE CAR T-CELL THERAPY LESS APPEALING

Patients declining CAR T-cell therapy because of the burden it places on them is also a serious concern. Patients may not be motivated to go through the process knowing that it may require travel, financial issues, and complex logistics. In the SCTCTN retrospective review, of 98 patients who were screened but did not proceed to T cell collection, 8 were denied insurance coverage and 50 others declined because of reasons not related to disease progression, clinical status, or use of other treatment such as clinical trials.⁴

Those who are employed or have family obligations may be less able to take time away to receive CAR T-cell therapy. There is also a need for a caregiver to be present with the patient. “It is limiting for lots of people, especially because it means not only does the patient have to be out of work and not having income, but their caregiver does, too,” said Jacobson.

“There are huge socioeconomic issues that have to be overcome for most people if they are employed, if they’re on the margins. These are people who have relapsed and generally are symptomatic from their disease. They have to be highly motivated. And there are people who just are not capable, in terms of their motivation or their social services and economic support, to take this,” said Robert R. Koch, MD, of Tufts Medical Center in Boston, Massachusetts at Jacobson’s event.

Jacobson said patients who are otherwise healthy will not have access to skilled nursing care, but the toxicity of therapies is difficult to handle outside a hospital or home, such as in a hotel for patients who need to travel. Other participants at her event stressed the lack of social support for caregivers who help monitor patients at this time.

With these issues facing patients in addition to potential delays in the process, physicians in the Case-Based Roundtable events agreed that they lead some patients to avoid CAR T-cell therapy.

BRIDGING NECESSARY DUE TO DISEASE-RELATED FACTORS

Patients with LBCL are at risk of further disease progression and death when they are being considered for CAR T-cell therapy, making faster access crucial. The SCTCTN retrospective review found that at the time of consultation, 14 referred patients were not eligible because of disease progression and 7 because of declining clinical status. An additional 22 patients had T cells collected but did not receive infusion because of issues such as disease progression, clinical status, and manufacturing issues.⁴

When patients have high disease burden or aggressive disease, bridging therapy is needed in order to control disease long enough for patients to receive CAR T-cell infusion. In ZUMA-7, bridging therapy was limited to glucocorticoids, which 36% of patients received before axi-cel. In TRANSFORM, 63% of patients received bridging therapy with 1 cycle of standard-of-care (SOC) platinum-based chemotherapy before liso-cel.^9,10

In a review by the United States Lymphoma CAR T Consortium from 2020, a multivariate analysis of patients who were treated with axi-cel in the third line found bridging therapy was associated with inferior overall survival (HR, 1.7; 95% CI, 1.04-2.70; P = .03).¹¹ This did not distinguish among chemotherapy, radiation therapy, corticosteroids, and targeted therapies used, and it did not account for patients’ disease burden. “It could be that the patients who got bridging therapy had worse disease, and they were less likely to have a robust response,” said Jacobson when discussing how to interpret these data.

A large retrospective institutional cohort study of patients with LBCL treated with axi-cel or tisagenlecleucel [tisa-cel; Kymriah] between December 2017 and March 2021 did not show worse efficacy outcomes or tolerability concerns with bridging therapy, suggesting that bridging therapy can control aggressive and bulky disease without impairing CAR T-cell outcomes.¹²

“What we’re realizing is for patients who get bridging therapy, it’s not about whether they get bridging therapy or not; it’s more about whether they have a response to that bridging therapy,” said Jacobson. “Patients who have a response will do better with CAR T cells than patients who don’t.”

Using novel therapies in later lines as bridging therapy is a possibility, but they have their own obstacles. Participants in Gopal’s event observed that polatuzumab vedotin (Polivy) and rituximab (Rituxan) may be used in frontline regimens, limiting their use as bridging for refractory patients. Gopal said there is a “theoretical concern” that generally keeps him from using tafasitamab (Monjuvi) plus lenalidomide (Revlimid) before CAR T-cell therapy because both tafasitamab and the CAR T-cell therapies target CD19.

If patients do not receive CAR T-cell therapy, the ZUMA-7 and TRANSFORM trials showed that patients who get salvage therapy followed by autologous HSCT had relatively good outcomes. Gopal discussed a registry study that found favorable outcomes for HSCT vs axi-cel in patients who had a partial remission to salvage therapy.¹³ However, many patients cannot receive HSCT or do not respond to salvage therapy. Only 36% in the ZUMA-7 trial’s and 47% in the TRANSFORM trial’s SOC arms were able to receive high-dose chemotherapy with autologous HSCT.^9,10 Since it is not possible to anticipate who will respond to salvage therapy and receive the best alternative therapy, referring for CAR T-cell therapy instead of salvage therapy is the preferred approach for most patients.⁹

NEW APPROACHES TO CAR T-CELL THERAPY ADMINISTRATION

Although CAR T-cell therapy is one of the most promising options available for patients with LBCL, many patients face a major burden that makes treatment more difficult to receive or leads them to seek alternative treatment.

Hospital-based outpatient administration of CAR T-cell therapy is 1 approach to increasing availability of hospital resources. Investigators at Mayo Clinic in Rochester, Minnesota, reported this approach was feasible and safe with the help of remote monitoring tools.¹⁴

Producing autologous CAR T cells faster would shorten the time frame to treatment and reduce costs. A study of the FasT CAR-T platform for B-cell acute lymphoblastic leukemia (NCT03825718) showed promising efficacy for CAR T cells manufactured in a single day, and a phase 1 study of the T-Charge platform (NCT03960840) produced CD19 CAR T cells in under 2 days.¹⁵ Another approach, allogeneic CAR T-cell therapy using donor cells, would be available off the shelf with no apheresis needed, and several products are under investigation in early-phase studies such as ANTLER (NCT04637763), EXPAND (NCT05714345), and ALPHA2 (NCT04416984).

Coordination between referring physicians and CAR T-cell providers has dramatically improved timing and ease of access, but there are still significant limitations. Physicians referring for CAR T-cell therapy need to anticipate challenges that patients face beyond availability and eligibility concerns.

“Patient preferences is one of the factors that we can’t overcome—the patients and their families not wanting to uproot their lives or go through the process,” said Jacobson. “I do think we do try to offer as much as we can to make that to take that burden off the patients. But there are some things that are just insurmountable.”

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