CD19 CAR T Cell Therapy Yield High MRD-Negativity in R/R CLL
Factors including measurable residual disease and CAR T-cell expansion appear to predict duration of response following JCAR014 in those with relapsed or refractory chronic lymphocytic leukemia in a phase 1/2 trial.
CD19 CAR T-cell therapy, JCAR014 produced durable measurable residual disease (MRD)–negative responses in patients with pretreated, high-risk, ibrutinib (Imbruvica)–refractory relapsed or refractory chronic lymphocytic leukemia (CLL), according to 5-year follow-up findings from a phase 1/2 trial (NCT01865617).
With a median follow-up of 79.6 months (interquartile range [IQR], 60.5-87.5), the median duration of response (DOR) was 18.9 months (95% CI, 9.7-55.6) in those with a complete response (CR), incomplete CR (CRi), or partial response by 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) at day 28 assessment (n = 33). Additionally, 26% (95% CI, 15%-47%) of patients had ongoing responses at 6 years.
The median progression-free survival (PFS) was 8.9 months (95% CI, 3.0-19.9), and the 6-year PFS rate was 18% (95% CI, 10%-33%) in all infused patients (n = 49). The median overall survival (OS) in this population was 25.0 months (95% CI, 11.5-62.1), and the 6-year OS rate was 31% (95% CI, 20%-48%).
![“In conclusion, this was the longest follow-up of a relatively large patient cohort for defined 1:1 CD4/CD8 CAR T cell ratio CAR T cells for CLL,” Elise A. Chong, MD, an assistant professor of Medicine at the Hospital of the University of Pennsylvania, said in a presentation on these data during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. “Undetectable MRD at week 4 continues to be associated with [DOR].”](/_next/image?url=https%3A%2F%2Fcdn.sanity.io%2Fimages%2F0vv8moc6%2Fcancernetwork%2Fd097e1402db4994972c36840cb45aa315e20fc32-1200x1080.jpg%3Ffit%3Dcrop%26auto%3Dformat&w=3840&q=75 "“In conclusion, this was the longest follow-up of a relatively large patient cohort for defined 1:1 CD4/CD8 CAR T cell ratio CAR T cells for CLL,” Elise A. Chong, MD, an assistant professor of Medicine at the Hospital of the University of Pennsylvania, said in a presentation on these data during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. “Undetectable MRD at week 4 continues to be associated with [DOR].”")
“In conclusion, this was the longest follow-up of a relatively large patient cohort for defined 1:1 CD4/CD8 CAR T cell ratio CAR T cells for CLL,” Elise A. Chong, MD, an assistant professor of Medicine at the Hospital of the University of Pennsylvania, said in a presentation on these data during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. “Undetectable MRD at week 4 continues to be associated with [DOR].”
Based on MRD status detected through multicolor flow cytometry (MFC), the median DOR was 1.8 months (95% CI, 1.6-not available [NA]) for those with MRD-positive disease and 27.1 months (95% CI, 14.4-NA) for those with MRD-negative disease, with 32% of MFC MRD-negative patients experiencing an ongoing response. Based on MRD detected with next-generation sequencing (NGS), the median DOR in each respective group was 7.8 months (95% CI, 4.2-NA) and 53.4 months (95% CI, 27.1-NA), with 40% of patients in the MRD-negative cohort experiencing an ongoing response.
“In conclusion, this was the longest follow-up of a relatively large patient cohort for defined 1:1 CD4/CD8 CAR T cell ratio CAR T cells for CLL,” Elise A. Chong, MD, an assistant professor of Medicine at the Hospital of the University of Pennsylvania, said in a presentation on these data during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. “Undetectable MRD at week 4 continues to be associated with [DOR].”
Investigators of this phase 1/2 trial aimed to evaluate long-term outcomes of patients with relapsed/refractory CLL receiving defined-composition CD19 CAR T-cell product JCAR014 with or without concurrent ibrutinib.
Primary study’s end points included DOR, PFS, and OS, with factors associated with DOR serving as an exploratory end point. Investigators assessed response rates using 2018 iwCLL criteria.
Of 49 patients, the median age was 61 years (IQR, 55-67), and most were male (67%). Additionally, 94% of patients had high-risk cytogenetics at time of enrollment, and 20% had prior or current Richter transformation. Patients received a median of 5.0 (IQR, 4.0-7.0) prior therapy, and 96% had intolerance to or disease progression on treatment with ibrutinib.
Among 42 evaluable patients, the median bone marrow CLL burden was 60.0 (IQR, 12.5-70.0). Moreover, patients had a median serum lactate dehydrogenase concentration of 200.0 (IQR, 153.0-308.0), and 27% of patients had bulky disease.
Based on univariate analysis, factors associated with DOR in this trial included response at day 28 via PET/CT (Hazard ratio [HR], 0.17; 95% CI, 0.05-0.64) and MRD negativity at day 28 by MFC (HR, 0.03; 95% CI, 0.01-0.15; P < .001) and by NGS (HR, 0.25; 95% CI, 0.09-0.68; P = .006). Additionally, peak CD4-positive CAR T-cell expansion (HR, 0.49; 95% CI, 0.28-0.85; P = .011) and CD8-positive expansion (HR, 0.53; 95% CI, 0.33-0.85; P = .009) correlated with DOR, as did CAR T-cell persistence (HR, 0.65; 95% CI, 0.48-0.87; P = .004).
“CAR T cell persistence and peak expansion are also associated with [DOR], and multivariate analysis and additional details on persistence may be informative,” Chong said.
Reference
Liang EC, Hirayama AV, Kimble EL, et al. Five-year follow-up update of defined-composition CD19 CAR T-cell therapy for relapsed/refractory CLL. J Clin Oncol. 2023;41(suppl 16):7511. doi:10.1200/JCO.2023.41.16_suppl.7511
