Outcomes with tisagenlecleucel in non-Hodgkin lymphoma in real-world settings

Tisagenlecleucel (tisa-cel) is a second-generation CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of adult patients with non-Hodgkin lymphoma (NHL). Real-world data are essential to observe the efficacy and safety outcomes of tisa-cel in a patient population beyond clinical trials.

Marcelo C. Pasquini et al. conducted a noninterventional prospective study to investigate the efficacy and safety of tisa-cel in adult patients with R/R NHL who received the commercial product in a real-world setting. Patient data were collected from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry database. Study enrollment is still ongoing, and the results presented are with a data cut-off date of 23 January, 2020. The authors compared the results to those of the pivotal phase II JULIET trial (NCT02445248), which investigated the efficacy and safety of tisa-cel in adult patients with RR DLBCL.¹

Study design

Outcomes of interest included the following:

• Cytokine release syndrome (CRS), evaluated using the American Society of Transplant and Cellular Therapy (ASTCT) grading criteria based on the most severe clinical manifestation
• Immune effector cell-associated neurotoxicity syndrome, evaluated using the ASTCT criteria based on neurologic events associated with tisa-cel
• Subsequent primary malignancies
• Hematologic recovery
• Overall response rate
• Duration of response
• Event-free survival
• Progression-free survival
• Overall survival.

The analysis also included cell viability, defined by the percentage of viable T cells in the final product, and cell dose, defined by the total number of CAR⁺ viable T cells, as the final product release parameters (target dose range, 0.6 × 10⁸ to 6.0 × 10⁸ CAR⁺ viable T cells). The impact of these parameters on safety endpoints and best overall response was also assessed.

Patients

A total of 155 patients with a median age of 65.4 years (range, 18.45–88.99) were included in the analysis. The most frequently used lymphodepletion therapy was fludarabine and cyclophosphamide, and 9% of patients received bendamustine-based therapy. Baseline patient characteristics are provided in Table 1.

Table 1. Patient characteristics¹

Results

Comparative safety data are summarized in Table 2.

Table 2. Comparative safety outcomes¹

Two patients died due to disease progression; CRS was deemed a contributing factor.

The incidences of neutrophil recovery and platelet recovery at 28 days were 93% and 86%, respectively. Corresponding incidences at 100 days were 97%, and 89%, respectively. Subsequent primary malignancies occurred in six patients (3.9%) and comprised basal cell carcinoma (n = 1), genitourinary malignancy (n = 2), myelodysplastic syndrome (n = 1), B-cell acute lymphoblastic leukemia (n = 1), and cholangiocarcinoma (n = 1).

The comparison of efficacy outcomes is presented in Table 3.

Table 3. Comparative efficacy outcomes¹

Response rates in patients with double/triple hit lymphoma and those aged ≥ 65 years were comparable to rates seen in the overall population, 70.6%, and 61.7%, respectively.

The impact of final product characteristics

The median tisa-cel dose was 1.8 × 10⁸ CAR⁺ viable T cells, and the median cell viability was 83.8% (range, 61.4–94.9%). These values were lower than clinical trials. In total, 31% of patients received final product with cell viability < 80%, and 1.9% had < 70%.

When doses were doubled, the odds ratios for best overall response and CRS were estimated to be 1.31 (95% CI, 0.761–2.240) and 2.874 (95% CI, 1.508–5.478; p = 0.001), respectively, in the logistic regression analysis. The overall response rates for patients who received tisa-cel with a cell viability < 80% and ≥ 80% were 52%, and 65%, respectively.

Conclusion

This study is the largest series of patients treated with commercially available tisa-cel, and the first one including final product specification data. These findings indicate that the efficacy of tisa-cel in NHL (in terms of duration of response, event-free survival, progression-free survival, and overall survival) in the real-world setting is similar to that observed in a clinical trial. The authors acknowledged that more time is needed to collect information on long-term efficacy.

There were some differences in patient population between CIBMTR and the pivotal trial. The median age in the JULIET trial was 56 years, a greater number of patients had prior AHCT compared to CIBMTR data (49% vs 25.8%). In addition, bendamustine-based lymphodepletion therapy was more frequent (20% vs 9%).

The product viability in the pivotal trials using commercial tisa-cel was ≥ 70%. In this study, the viability of out of specification products ranged between 61% and 79%. According to the regulations by the U.S. Food and Drug Administration (FDA), the product viability must be ≥ 80%.

Efficacy and safety of tisa-cel were comparable between final products, with cell viabilities < 80% and ≥ 80%. There was a trend of increased CRS rate with dose increases.

This study highlights the need for more generalizable real-world data, complimentary to trial data, considering the differences between the real-world patient population and trial populations.