What is the efficacy of CAR-T (Chimeric Antigen Receptor T-cell) products in patients with POD24 (Progression of Disease within 24 months) follicular lymphoma?

From the Guidelines

CAR-T cell therapy is a highly effective treatment option for patients with follicular lymphoma who have progressive disease within 24 months of initial therapy (POD24), with complete response rates of 60-80% and overall response rates of 80-95%. The two FDA-approved CAR-T products for follicular lymphoma are axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) 1. In POD24 follicular lymphoma patients, these therapies have demonstrated significant efficacy, with axicabtagene ciloleucel showing progression-free survival rates of approximately 70% at 18 months in this high-risk population, while tisagenlecleucel has demonstrated similar durability 1.

Key Considerations for CAR-T Cell Therapy

• The treatment process involves leukapheresis to collect the patient's T cells, followed by lymphodepletion chemotherapy (typically fludarabine and cyclophosphamide) before CAR-T infusion 1.
• Patients require close monitoring for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which typically occur within the first 1-2 weeks after infusion 1.
• The ability of CAR-T cells to recognize CD19 on B-cell lymphoma cells allows for targeted killing independent of prior treatment resistance mechanisms 1.
• CAR-T cell therapy is particularly valuable for POD24 patients because this group traditionally has poor outcomes with conventional therapies, with median survival of 2-5 years 1.

Eligibility Criteria for CAR-T Cell Therapy

• Patient eligibility criteria for CAR-T cell therapy include age, performance status, life expectancy, and history of malignancy 1.
• The decision to proceed with CAR-T cell therapy should be based on a careful consideration of the risk-benefit ratio, taking into account factors such as high tumor burden, prior treatments, and immunosuppressive treatment 1.

Recent Studies and Guidelines

• Recent studies have demonstrated the efficacy and safety of CAR-T cell therapy in patients with relapsed/refractory multiple myeloma, with response rates of 73% and a complete response rate of 33% 1.
• The NCCN Guidelines for B-Cell Lymphomas have been updated to include recommendations for the treatment of relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma, including the use of CAR-T cell therapy 1.

From the FDA Drug Label

The efficacy of KYMRIAH was evaluated in a multicenter, single-arm, open-label trial (ELARA, Study 3; NCT03568461) that included patients who were refractory to or relapsed within 6 months after completion of two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent), relapsed during or within six months after completion of an anti-CD20 antibody maintenance therapy following at least two lines of therapy, or relapsed after autologous hematopoietic stem cell transplant (HSCT). 66% had progression within 24 months of initiating their first anti-CD20 combination therapy (POD24) Table 14. Response Rates in Patients with Relapsed or Refractory FL ResponsePrimary efficacy populationN = 90All leukapheresed patientsN = 98 Overall response rate (ORR), n (%)(95% CI) 77 (86%)(76.6,92.1)84 (86%)(77.2,92.0) Complete response rate (CRR)a,b, n (%)(95% CI)61 (68%)(57.1,77. 2)66 (67%)(57.1,76. 5) Table 15. Duration of Response in Patients with Relapsed or Refractory FL From N = 90 Overall DOR, monthsN = 77 Median (95% CI)a,b NE (15.6, NE)

The CAR-T product efficacy in POD24 follicular lymphoma is supported by the ELARA study, which showed an overall response rate (ORR) of 86% and a complete response rate (CRR) of 68% in patients with relapsed or refractory follicular lymphoma, including those with progression within 24 months of initiating their first anti-CD20 combination therapy (POD24). The median duration of response (DOR) was not estimable, but the percentage of event-free probability at 9 months was 75.2% and at 12 months was 70.8% 2.

• Key points:
  • Overall response rate: 86%
  • Complete response rate: 68%
  • Median duration of response: not estimable
  • Percentage of event-free probability at 9 months: 75.2%
  • Percentage of event-free probability at 12 months: 70.8%

From the Research

CAR-T Products Efficacy in POD24 Follicular

• The efficacy of CAR-T products in follicular lymphoma has been demonstrated in several studies 3, 4, 5, 6.
• Specifically, axicabtagene ciloleucel and tisagenlecleucel have shown high overall response rates (ORR) and complete response rates (CR) in patients with relapsed or refractory follicular lymphoma (FL) 3, 6.
• The ZUMA-5 study reported an ORR of 94% and a CR of 79% for axicabtagene ciloleucel, while the ELARA study reported an ORR of 86% and a CR of 69.1% for tisagenlecleucel 3.
• A systematic review and meta-analysis of three CAR-T cell products, including axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel, found that all three products showed promising results in patients with different pathological subtypes and clinical characteristics, with ORR of nearly 70% or above and CR of more than 50% 5.
• Tisagenlecleucel has demonstrated high efficacy in relapsed or refractory follicular lymphoma, with a manageable toxicity profile, and has been approved by the FDA for this indication 6.

Comparison of CAR-T Products

• A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel in relapsed or refractory diffuse large B cell lymphoma found that axicabtagene ciloleucel had a higher efficacy, but also a higher toxicity, compared to tisagenlecleucel 7.
• The study found that the best overall response rate/complete response rate was 80%/60% for axicabtagene ciloleucel, compared to 66%/42% for tisagenlecleucel, and that the 1-year progression-free survival and overall survival were also significantly improved with axicabtagene ciloleucel 7.

Toxicity Profile

• The toxicity profile of CAR-T products, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, is a significant consideration in their use 5, 7.
• The study comparing tisagenlecleucel and axicabtagene ciloleucel found that grade 1-2 cytokine release syndrome was significantly more frequent with axicabtagene ciloleucel, and that both grade 1-2 and grade ≥3 immune effector cell-associated neurotoxicity syndrome were significantly more frequent with axicabtagene ciloleucel 7.