Tisagenlecleucel Climbs into Earlier Lines of Therapy for Pediatric R/R B-ALL

Rayne Helen Rouce, MD, BS

The autologous CD19-directed CAR T-cell therapy tisagenlecleucel (Kymriah) is being utilized in earlier lines of treatment for pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), according to data from a noninterventional, prospective study using the Center for International Blood & Marrow Transplant Research (CIBMTR) registry.¹

Findings presented at the 2024 SOHO Annual Meeting showed that there was an 11% decrease from 2018 to 2022 in patients receiving tisagenlecleucel in the third or later relapse. During the same time period, there was a 22% decrease in the rate of patients who underwent hematopoietic stem cell transplant (HSCT) prior to receiving the CAR T-cell therapy.

Furthermore, there was a 14% decrease from 2018 to 2022 in the rate of patients with high disease burden at the time of treatment, defined as a bone marrow blast percentage of at least 50%. In patients with a body weight of 50 kg or less, there was a 10% decrease in the rate of patients with high disease burden and a 15% decrease in those with intermediate disease burden—at least 5% to 50% bone marrow blasts—during this time period. For those with a body weight above 50 kg, there was an 18% decrease in the rate of patients with high disease burden.

“Incorporation of tisagenlecleucel into the treatment landscape of relapsed/refractory B-ALL has certainly reduced the use of HSCT, including in extremely high-risk and vulnerable populations, such as patients under 3 years [of age],” lead study author Rayne Helen Rouce, MD, BS, of the Baylor College of Medicine in Houston, Texas, stated during a presentation of the data.

In August 2017, the FDA approved tisagenlecleucel for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.²

Investigators conducted this noninterventional study to access the outcomes, safety, and treatment patterns for tisagenlecleucel since its approval. Data on the agent's use were collected between August 30, 2017, and May 4, 2023, as a part of the noninterventional, prospective, longitudinal study. These data were derived from the CIBMTR registry, and patients were treated in the United States, Canada, Korea, or Taiwan.

Efficacy outcomes were evaluated in patients with 12 or more months of follow-up and included best overall response (BOR) of complete remission (CR) or CR with incomplete hematologic recovery; minimal residual disease response; duration of response; event-free survival; recurrence-free survival (RFS); and overall survival (OS). Safety outcomes were evaluated in patients who completed 100-day assessments and included cytokine release syndrome (CRS); immune effector cell–associated neurotoxicity syndrome; prolonged neutropenia and thrombocytopenia; and death.

The median follow-up for efficacy was 33.3 months (interquartile range, 18.5-48.9). The overall infused set included 974 patients. From this infused set, patients were included in the efficacy set (n = 785) and the safety set (n = 911).

In the infused set, 287 patients were 18 years of age or older, and 687 were under 18 years of age, including 75 who were younger than 3 years of age. Baseline characteristics showed that patients had abnormal KMT2A rearrangements (≥18, 9.4%; <18, 15.6%; <3, 72.0%) and Philadelphia chromosome–positive ALL (7.7%; 5.2%; 0%). Bone marrow blast rates included 0% to less than 5% (21.6%; 20.5%; 17.3%), at least 5% to less than 50% (12.5%; 17.3%; 17.3%), and more than 50% (15.3%; 10.3%; 10.7%).

Across the 18 years of age or older, under 18 years of age, and under 3 years of age patient groups, 35.9%, 42.8%, and 41.3% had a morphologic CR, respectively; 22.0%, 22.3%, and 20% were MRD negative, respectively, and 11.5%, 16.3%, and 17.3% were MRD-positive, respectively. Of these respective patient groups, 10.8%, 10.5%, and 12.0% were primary refractory; 23.0%, 25.8%, and 37.3% were treated at first relapse; and 10.5%, 4.7%, and 2.7% were treated at their third relapse and beyond.

In total, 3.1% of patients 18 years of age or older and 6.7% in the under 18 years group had Down syndrome. Central nervous system involvement occurred at 9.1% and 8.3% in these groups, as well as at 18.7% in the under 3 years of age group. Across these 3 participant age groups, 6.3%, 3.6%, and 0% had prior cell therapy; 26.1%, 21.1%, and 16.0% had prior allogeneic HSCT; 26.8%, 15.9%, and 17.3% had prior blinatumomab (Blincyto); and 17.4%, 7.1%, and 9.3% had prior inotuzumab (Besponsa).

“There was an increase in patients treated in morphologic CR over time, which is particularly notable because the pivotal trials leading to FDA approval excluded patients who did not have morphologic disease,” Rouce said. The morphological CR rate increased by 17% from 2018 to 2022.

The rates of post-infusion HSCT also decreased since 2019 in patients under 3 years of age (22% decrease), patients between 3 and 18 years of age (7% decrease), and in patients at least 18 years of age (5%). Overall, 34.5% of patients received post-infusion HSCT.

Notably, 72.0% of patients under 3 years of age had a KMT2A rearrangement, and 43.4% of those underwent post-infusion HSCT. The reasons for post-infusion HSCT were not captured for most patients in all groups.

With censoring for post-infusion transplant (n = 679), the median RFS was 26.6 months (95% CI, 18.09-42.01); without censoring, the median RFS was 36.0 months (95% CI, 24.21–not estimable [NE]).

In evaluable patients (n = 785), the median OS was NE (95% CI, NE-NE) both with censoring for post-infusion HSCT and without censoring. The 36-month OS probability with and without censoring was 66% (95% CI, 61-71) and 62% (95% CI, 57-66), respectively.

“Long-term safety profiles remain favorable across age groups and largely consistent with previous reports, with expected relatively low incidence of high-grade CRS,” Rouce said. “Other adverse effects [AEs] like neurotoxicity, cytopenias, and infections were largely as expected across these age groups.”

Notably, grade 3 or higher CRS occurred in 16.2% of patients 18 years of age or older, 15.3% of patients younger than 18 years of age, and 7.2% of patients younger than 3 years of age; the rates of grade 3 or higher neurological events were 8.6%, 9.3%, and 10.1%, respectively.

“Studies exploring consolidative HSCT in patients who achieve remission after tisagenlecleucel should attempt to identify those at highest risk of relapse and assess whether HSCT in these patients could improve outcomes,” Rouce concluded.

References

1. Rouce RH, Baumeister SHC, Curran KJ, et al. Evolution of tisagenlecleucel use for the treatment of pediatric and young adult relapsed/refractory B-cell acute lymphoblastic leukemia: Center for International Blood & Marrow Transplant Research (CIBMTR) registry results. Presented at: 2024 SOHO Annual Meeting; September 4-7, 2023; Houston, TX. ALL-173.
2. FDA approval brings first gene therapy to the United States. FDA. August 30, 2017. Accessed September 4, 2024. https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states