Educational theme | Efficacy and safety of CAR T-cell therapy in older patients: A multicenter matched control cohort study

With a median age of 68 years, older patients make up the majority of diffuse large B-cell lymphoma (DLBCL) cases; however, data regarding the efficacy and safety of novel therapies in this population are limited. Therefore, the Lymphoma Hub is presenting an educational theme series on the treatment of older patients with lymphoma. Previously, the Lymphoma Hub published a summary of the results from the ZUMA-1 trial, which found that older patients with advanced B-cell non-Hodgkin lymphoma responded well to chimeric antigen receptor (CAR) T-cell therapy, similar to younger patients; the summary article can be found here.

At the 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, Ron Ram presented findings from a multicenter cohort study comparing the efficacy and safety of CAR T-cell therapy in older and younger patients with DLBCL.¹

Study design

• Retrospective multicenter matched control cohort study in Israel using real-life data of patients treated with CAR T-cell therapy.
• Patients diagnosed with DLBCL and who were ≥70 years of age were included in the older patient cohort (n = 41). Matched controls (n = 41) were <70 years of age and were selected based on Eastern Cooperative Oncology Group (ECOG) status and lactate dehydrogenase levels.
• The primary endpoints were response rate and progression-free survival.

Results

Baseline characteristics

• The baseline characteristics were comparable in both groups (Table 1), except for median age, which was 76.2 years in the older patient cohort and 55.4 years in the matched control group.
• A total of 49 patients were screened for the older patient cohort, and 87% (n = 41) received treatment with either axicabtagene ciloleucel (n = 8) or tisagenlecleucel (n = 33).
• The median time from enrollment to apheresis was 10 days (range, 4–26 days).
• The median number of apheresis cycles was 2 (range, 1.5–4) and it was similar in both groups.
• There was also a similar pattern of T-cell subgroups expressing exhaustion markers (human leukocyte antigen DR and programmed cell death protein 1).
• Interestingly, the two cohorts were also similar in respect to comorbidities.

Table 1. Baseline characteristics of both cohorts*

CAR-T, chimeric antigen receptor T-cell therapy; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; SD, standard deviation. *Adapted from Ram.1
	Cohort (n = 41)	Matched control (n = 41)	p value
Mean age, years (± SD)	76.2 (4.4)	55.4 (15)	<0.001
Sex, n (%)               Female	24 (61)	23 (54)	0.67
Therapy, n (%)               Tisagenlecleucel               Axicabtagene ciloleucel	33 (80.5) 8 (19.5)	34 (82.9) 7 (17.1)	0.78
ECOG performance status, n (%)               0               1               2               3	3 (7.3) 13 (31.7) 20 (48.8) 5 (12.2)	1 (2.4) 15 (36.6) 9 (22) 16 (39)	0.19
Specific comorbidities, n (%)               Ischemic heart disease               Hypertension               Diabetes mellitus               Smoker               Chronic kidney disease               Cerebrovascular disease               Dementia	10 (24) 14 (34) 7 (17) 3 (7.3) 4 (9.7) 3 (7.3) 1 (2.4)	7 (17) 8 (20) 9 (22) 4 (9.7) 2 (4.9) 1 (2.4) 1 (2.4)	0.41 0.14 0.58 0.69 0.39 0.61 0.61
Lines prior to CAR-T, n (%)               2               3               >3	22 (53.7) 13 (31.7) 6 (14.6)	20 (48.8) 11 (26.8) 10 (24.5)	0.45
High LDH prior to CAR-T, n (%)	18 (43.9)	18 (43.9)	1.0

Safety

• There was no difference in the incidence of cytokine release syndrome (p = 0.88) and immune effector cell-associated neurotoxicity syndrome (p = 0.48) between both cohorts (Table 2).
• Higher doses of tocilizumab (p = 0.48) and steroids (p = 0.26) were needed for older patients; however, this was not statistically significant.
• There was also no difference in both groups for infection (p = 0.30) and organ dysfunction (p = 1.0).
• There was a higher percentage of older patients with reactivation of human herpesvirus-6 (15% vs 4.3%); however, this was not statistically significant.

Table 2. Safety of CAR T-cell therapy in both cohorts*

CDI, clinically documented infection; CMV, cytomegalovirus; CRS, cytokine release syndrome; GCSF, granulocyte colony-stimulating factor; HHV-6, human herpesvirus-6; IgG, immunoglobulin G; ICANS, immune effector cell-associated neurotoxicity syndrome; MDI, microbiologically documented infection; SD, standard deviation. *Adapted from Ram.1
	Cohort (n = 41)	Matched control (n = 41)	p value
CRS, n (%)               0               1–2               3–4	13 (31.7) 24 (58.6) 4 (9.8)	13 (31.7) 25 (61) 3 (7.3)	0.88
ICANS, n (%)               0               1–2               3–4	29 (72.5) 10 (25) 1 (2.5)	34 (82.9) 5 (11.2) 2 (4.9)	0.48
Tocilizumab, doses/patient	1.5	0.9	0.48
Patient given steroids, n (%)	14 (32.5)	10 (24.4)	0.26
Need for GCSF on Day 14, n (%)	9 (22)	15 (36.9)	0.11
Early infections, n (%)               CDI               MDI	5 (12) 6 (14.8)	0 (0.0) 8 (19.5)	0.30
Organ dysfunction, n (%)               Congestive heart failure               Atrial fibrillation               Acute kidney injury	0 (0.0) 3 (7.3) 3 (7.3)	0 (0.0) 3 (7.3) 3 (7.3)	1.0
Days of hospitalization, mean (± SD)	23.4 (8)	24.6 (9.6)	0.55
Late pancytopenia, n (%)	9 (22)	11 (26.8)	0.39
IgG levels <4 gr/L, n (%)	5 (23.8)	5 (33)	0.39
Reactivation of CMV, n (%)	6 (18.8)	5 (15.2)	0.23
Reactivation of HHV-6, n (%)	3 (15)	1 (4.3)	0.09

Efficacy

• The response rate at 1 month was similar between the two groups. The complete response rate in older patients was ~45% compared with 55% in the younger cohort (p = 0.4). The partial response rate was 25% vs 20% and the progressive disease rate was 32% vs 28% (p = 0.54) in the older cohort vs the younger cohort, respectively.
• In the older cohort, progression-free survival was 39% at 6 months and 32% at 12 months. Furthermore, overall survival in the older cohort was 74% and 69% at 6 and 12 months, respectively. There were no statistically significant differences for survival in the older patients compared with the younger patients.
• Quality of life was measured in patients ≥70 years of age using EORTC QLQ-C30. At 1 month, disability and cancer-related symptoms increased and emotional wellbeing worsened. No change was observed in health perception and quality of life. However, at 3 months, improvements were observed for disability, cancer-related symptoms, emotional wellbeing, health perception, and quality of life.

Conclusion

Overall, this study demonstrated that CAR T-cell therapy induces response rates in older patients that are similar to those in younger patients, while it also showed a favorable safety profile. This suggests that CAR T-cell therapy is feasible in patients with DLBCL who are ≥70 years of age and that age should not be a limiting factor. However, a rehabilitation period after treatment is essential before patients experience improved quality of life.