Article Highlights

• CAR T-cell therapy is gaining traction in relapsed/refractory lymphoma in older patients with aggressive disease.
• As a result of prospective trials investigating CAR T-cell therapy, there is potential that older patients with lymphoma can be spared multiple lines of chemotherapy and its resultant toxicities while still having long-term clinical benefit.
• Toxicities are still a major concern for older patients and those with comorbidities, but patients are likely to appreciate benefit of CAR T-cell therapy.

CAR T-cell therapy is rapidly gaining recognition as a promising treatment in patients with relapsed/refractory aggressive lymphomas, especially in those who have been previously exposed to multiple lines of therapy. There are two CD19-targeting CAR T regimens, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (t-cel), that are U.S. Food and Drug Administration (FDA)–approved for relapsed/refractory non-Hodgkin lymphoma (NHL) that has failed two previous lines of therapy. A third therapy, lisocabtagene maraleucel (liso-cel), is anticipated to gain FDA approval soon.

The ZUMA-1 phase II trial for axi-cel showed a best overall response rate (ORR) and complete response (CR) rate of 82% and 58%, respectively, in 101 evaluable patients who had either relapsed/refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B cell lymphoma (PMBCL), or transformed follicular lymphoma (tFL) and who had received at least two previous lines of therapy. At a median follow-up of 15.4 months, ongoing responses beyond 6.0 months were observed in 42% of patients, with a CR rate of 40%.¹

The JULIET phase II trial for t-cel showed a best ORR and CR rate of 52% and 40%, respectively, in 93 patients with relapsed/refractory DLBCL or tFL who had received at least two previous lines of therapy. At a median follow-up of 14 months, durable responses beyond 6 months were noted in 33% of patients, with 29% in CR.²

The ongoing TRANSCEND NHL-001 phase I study is investigating liso-cel in relapsed/refractory patients with NHL. In their planned DLBCL cohort, which included 49 patients with either de novo DLBCL or tFL, liso-cel demonstrated 84% and 61% for best ORR and CR, respectively, and an ongoing 52% CR rate at 6 months in their interim analysis.³ With prospective trials like TRANSFORM and ZUMA-7 investigating CAR T-cell therapy against standard of care for first relapse, there is potential that patients can be spared multiple lines of chemotherapy and its resultant toxicities while still having long-term clinical benefit. This would be especially beneficial to patients who might not be candidates for more aggressive salvage treatment and autologous stem cell transplant, as a result of their comorbid conditions.

Difficulties in Treating Older Patients

The median age of diagnosis for DLBCL, the most common subtype of aggressive lymphoma, is 65 years.⁴ Older patients with aggressive lymphomas are a group of special interest because this population tends to have increased comorbidities and geriatric symptoms, which can complicate their treatment with standard therapies. Furthermore, age greater than 60 is a poor prognostic factor when calculating the International Prognostic Index score for aggressive NHL.⁵

Treatment of relapsed/refractory disease in this group of patients can be especially difficult. Many are too frail to receive high-dose salvage chemotherapy and standard of care consolidative autologous stem cell transplant. Although there are more tolerable chemoimmunotherapy regimens incorporating novel agents, they generally have modest efficacy and short duration of response. For example, lenalidomide in combination with rituximab has an ORR of only 33% and CR of 22%, while ibrutinib with rituximab has an ORR and CR of 37% and 16%, respectively.^6,7 Both of these novel agents show a predilection for efficacy in the nongerminal center subtype of DLBCL.

CAR T-cell therapy, on the other hand, has the potential to provide more durable remissions in a substantial proportion of patients, and its efficacy is agnostic to DLBCL subtypes. Although it has its own set of toxicities that require attention and intervention, CAR T-cell therapy could be a viable treatment modality for this patient population given the general tolerability seen in clinical studies to date. Although actual published data in older patients (defined in the CAR T-cell trials as ³ 65 years of age) are relatively scant, it has been investigated in subgroup analysis within the aforementioned trials.

How Clinical Trials Inform Treatment

In ZUMA-1, the phase I portion had three patients older than 65, the oldest being 69; these patients received axi-cel for relapsed/refractory (r/r) DLBCL after the treatment failed two to four prior lines of therapy. Two of these older patients attained CR, with one of them having an ongoing CR at 24 months.⁸ In the phase II portion of ZUMA-1, the median age of all patients was 58 years. The overall number of treated patients over age 65 was 24 (out of 101); the oldest patient treated was 76. A subgroup analysis of patients ³ 65 showed a 92% ORR in comparison with 79% in patients < 65 years.¹

The JULIET phase I portion included patients with r/r DLBCL and follicular lymphoma at aged 25 to 77 years, but there was no further categorization of older patients and their response rates or safety outcomes.⁹ In the phase II part, which enrolled only patients with r/r DLBCL and tFL, there was an evaluated subsection of older patients with 25 patients being ³ 65 out of 111 total patients treated with t-cel. Subgroup analysis of these patients showed an ORR of 59% compared with 49% in patients < 65.² Further evaluation of how many older patients achieved CR or how many had sustained responses at the median follow-up timepoints are currently unknown for either study. Data from the TRANSCEND NHL-001 trial with liso-cel are not fully mature, so the proportion of elderly patients treated with liso-cel is not known.

A retrospective analysis was subsequently performed at The University of Texas MD Anderson Cancer Center, which included 61 patients with r/r DLBCL who had been treated with axi-cel at their institution, as either part of a clinical trial or institutional standard of care. These researchers were primarily studying safety outcomes and found that adverse events were similar in the older and younger patient populations.¹⁰ They compared the 44 patients < 65 with the 17 patients ³ 65 and found comparable ORR and CR rates by day 30 post–axi-cel infusion (76% and 47% vs. 75% and 48%, respectively).

Cytokine release syndrome (CRS), one of the most commonly observed toxicities associated with adoptive T-cell therapies, is characterized by high fever, hypoxia, hypotension, and/or multiorgan toxicity. CRS occurred in 83% and 91% of the older and younger patient groups, respectively, but the majority of events were grade 1 (defined as temperature > 38°C and/or grade 1 organ toxicity) or grade 2 (temperature > 38°C, hypotension responding to IV fluids or low dose vasopressors, FiO₂ < 40%, and/or grade 2 organ toxicity) as determined by the CARTOX system.^8,11 Grade 3 or higher CRS (defined as needing high dose or multiple vasopressors, FiO2 > 40%, grade 3/4 organ toxicity, or a combination of the three with or without a temperature > 38°C) was seen in 18% of older patients compared with 11% of the younger patients. Neurotoxicity is also frequently associated with T-cell therapies. The CARTOX guidelines, developed by MD Anderson, termed neurotoxicity in the setting of patients receiving CAR T-therapy as CAR-related encephalopathy syndrome (CRES), with common presenting symptoms being confusion, aphasias, and/or delirium with possible cerebral edema or seizures. CRES was noted in 58% and 71% of the older and younger patient groups, respectively, and the majority were grade 1 to 2 CRES. Twenty-nine percent of the older group had CRES grade 3 or higher compared with 39% of the younger group.¹⁰ The median hospitalization period was similar between the two groups (19 days for patients > 65 and 15 days for patients < 65).

Due to baseline comorbidities or neurologic issues, older patients may not tolerate severe CRS or CRES. However, in clinical practice and research protocols, there is now a trend to treat both toxicities more proactively at lower toxicity grades, which could allow safer CAR T-cell therapy implementation, especially in the geriatric population. In initial CAR T clinical trials, there was concern that premature administration of IL-6/IL-6 receptor antagonists and/or corticosteroids for CRS and neurotoxicity would impair CAR T-cell functionality and curtail their efficacy. The earlier CAR T-cell toxicity grading systems, such as the Lee Criteria and CARTOX, reflected this concern by recommending first general precautions and supportive care for patients receiving CAR T-cell therapy before using tocilizumab (an IL-6 receptor antagonist), and recommended steroid use only in the setting of tocilizumab failure.

Although no prospective clinical trials address the timing of these interventions, retrospective analyses indicate that earlier use of tocilizumab and corticosteroids do not appear to impact overall CAR-T antitumor response.^1-3 This shift toward quicker intervention is reflected in the latest effort to standardize the definitions and grading systems for CRS and neurotoxicity by the American Society for Blood and Marrow Transplantation (ASBMT), encouraging earlier algorithmic use of tocilizumab and steroids.¹²The lower threshold in giving tocilizumab and corticosteroids to patients receiving CAR-T therapies at grade 2 instead of higher grades would help abrogate unnecessary prolongation and escalation of these toxicities especially in older patients, who may be less able to withstand the adverse effects than younger patients (Tables 1 and 2). The earlier intervention of these agents could thus facilitate better tolerance of CAR T-cell therapy in older patients in the future.

Future Outlook of CAR T-Cell Therapy in Older Patients

Although results are promising for the potential treatment of older patients, there are significant questions that need to be addressed before CAR T-cell therapy can be universally recommended. First, data in older patients are sparse, primarily retrospective, and mostly available for only axi-cel. Second, we do not know the full extent of other hematologic/nonhematologic toxicities the older patient population may have experienced with axi-cel, or how treatment affected their functional status and quality of life. Older patients may not have the same physical reserve as younger patients to withstand higher grade CRS or CRES, which may lead to a longer and more difficult recovery period. Third, information is not available about how well older patients’ T lymphocytes were able to be procured in these trials and if there were issues with the number of T cells able to be isolated from leukapheresis to be able to manufacture CAR T cells adequately. This could impact the overall feasibility of CAR-T use in older patients.

All three CAR T constructs discussed here differ in significant ways in their structure, cellular composition, and clinical application, and have not been compared directly with each other in clinical trials. As such, no data are available to discern the superiority in efficacy and tolerance of one agent over another. In addition, we do not know the likelihood of long-term remission in older patients with any of the CD19. CAR T-cell constructs compared with younger patients, which could significantly affect the cost-effectiveness of CAR T-cell therapy within this patient population.

Lastly, although CAR T-cell therapy appears to be agnostic in efficacy outcomes with germinal center B cell (GCB) subtype versus activated B cell (ABC) subtype DLBCL, it would be beneficial to know if this remains the case in older patients as well, especially since the ABC subtype prevalence is increased in older patients and associated with poorer outcomes.^13,14 The majority of these questions can hopefully be answered as results from clinical trials continue to mature and retrospective analyses can be completed on the elderly patient groups to further devise a strategy to administer CAR T-cell therapy effectively.

Advancements during the last few decades with chemotherapy regimens and expanded options with novel agents have had a positive effect in treating older patients with aggressive lymphoma, especially in those who are frail and cannot withstand standard or high-dose chemotherapy. CAR T-cell therapy is a prominent step forward for this patient population. Efficacy seen in older patients appears to be equivalent to those seen in younger patients, and safety outcomes accrued from clinical trials thus far show CAR T-cell therapy to be tolerated quite well by the elderly. Based on present data, CAR T-cell therapy can positively be a viable option for an older patient with good functional status and relatively robust baseline health in the setting of r/r aggressive lymphoma. With cellular immunotherapy being a relatively new investigative field, there is much optimism in being able to improve on current findings and augmenting their clinical application in the future. Although some uncertainties requiring further research and inquiry remain, there is overall optimism and tremendous potential for the future in treating older patients with aggressive lymphomas with CAR T.