The average age of most patients at the time they are diagnosed with LBCL is 66, and patients over the age of 65 tend to have worse survival rates than younger patients. However, less than a quarter of the patients in the pivotal clinical trials leading to FDA approval of Yescarta and Kymriah were over the age of 65. The strict eligibility criteria of these randomized clinical trials tend to yield trial cohorts that are biased toward healthier older patients. Left out repeatedly are the patients most likely to receive this therapy in the real world: older patients, those with comorbidities, and those considered to be frail or vulnerable.
One single-institution study specifically addressed this issue by examining the real-world outcomes of older patients who were referred for Yescarta or Kymriah therapy between January 2018 and March 2019 . Forty-two patients aged 65 and over received a geriatric assessment before or on the day of hospital admission. Only 24 of the 42 ultimately received the CAR T-cell infusion; the other 18 either died or declined clinically and were deemed unfit for the treatment process. The geriatric assessment results and gender distribution were similar between the 2 sets of older patients. Twenty-five patients under the age of 65 received therapy during this period, and their baseline characteristics and clinical outcomes were compared to the older group. The older group had more comorbidities, but incidences of CRS, neurotoxicities, and ICU admissions were similar in both groups. Despite this study being limited by its small sample size, retrospective design, and selection bias, the results do show that older patients can benefit from CAR T-cell therapy. Furthermore, it supports that older patients should not be excluded from CAR T-cell therapy, provided that their care team meticulously manages toxicities.
In another report, researchers used the infrastructure of the Center for International Blood and Marrow Transplant Research database (CIBMTR) and presented Year 1 (of a planned 15-year follow-up) results on patients treated with Yescarta . This analysis included post-approval safety and efficacy data on 295 patients representing 43 US centers. The registry has a more substantial proportion of higher-risk patients (i.e., older, more inferior performance status, and higher incidence of transformed or double-hit lymphoma) compared to the ZUMA-1 clinical trials and the pivotal trial leading to the approval of Yescarta. Response outcomes and adverse event profiles of the registry group were similar to the ZUMA-1 group. Within the registry group, older patients (over 65) had similar clinical outcomes and adverse events, including rates or CRS, as younger patients (65 and under). A separate study looking at Medicare claims showed similar findings and concluded that older patients could be treated successfully with CAR T-cell therapy, resulting in lower healthcare costs, post-indexed care .
Additionally, the RWE scientific team at Cardinal Health reported real-world adverse events in older versus younger patients using the FDA Adverse Events Reporting System (FAERS) database and presented data specific to Yescarta and Kymriah neurotoxicities [5,6]. We found that 39% of the adverse event cases reported involved older patients. The older patient group had a higher incidence of neurotoxicity and atrial fibrillation, while the younger patient group had a higher incidence of CRS (eg, pyrexia and tachycardia). The younger patient group also had higher rates of hospitalization; this appears to be counter-intuitive and hence could provide greater insight into side-effect management. A second abstract focused on neurological adverse events associated with CAR T-cell therapy. Neurological adverse events are common in real-world CAR T-cell therapy administration; it is reported in 65% of adverse event cases. The types of neurological adverse events reported resembled those reported in the clinical trials and were associated with the agent used, age ≥ 65, as well as the simultaneous presence of CRS, cardiac, and psychiatric AEs.
There is increasing evidence from real-world data supporting the utilization and tolerability of Yescarta and Kymriah in patient populations beyond those included in the pivotal clinical trials. The efficacy and safety observed in older patients are not statistically different from younger patients. Longer follow-up is needed to assess the duration of response in patients treated in the real-world.