Coadministration of CD19 and CD22-Directed CAR T-cell Therapy Elicits Durable Remissions in Pediatric Patients With B-ALL
Coadministration CD19- and CD22-directed CAR T-cell therapy produced relatively durable remissions in children with high-risk hematologic or isolated extramedullary relapse of B-acute lymphoblastic leukemia.
Co-administering CD19- and CD22-directed CAR T-cell therapy produced relatively durable remissions in pediatric patients with high-risk hematologic or isolated extramedullary relapse of B-acute lymphoblastic leukemia (B-ALL), according to findings from a phase 2 study (ChiCTR2000032211) published in the Journal of Clinical Oncology. Of note, consolidative transplantation and persistent B-cell aplasia were linked to favorable outcomes, according to investigators.
Among 194 patients with refractory leukemia or hematologic relapse, 99.0% achieved complete remission and tested negative for minimal residual disease. The 12-month event-free survival (EFS) rate with the treatment was 73.5% (95% CI, 67.3%-80.3%), with 43 patients experiencing relapse.
For patients who also received transplantation (n = 78) and those who did not undergo transplantation (n = 116), the 12-month EFS rates were 85.0% (95% CI, 77.2%-93.6%) and 69.2% (95% CI, 60.8%-78.8%), respectively. Persistent B-cell aplasia lasting at least 6 months was reported for 25 patients, all of whom were in remission at 12 months.
A total of 31 patients were treated for extramedullary relapse on the study. Among 20 patients who had isolated testicular relapse, the 12-month EFS rate was 95.0% (95% CI, 85.9%-100%), and among patients with isolated central nervous system (CNS) relapse, the 12-month EFS rate was 68.6% (95% CI, 44.5%-100%).
Notably, the rate of cytokine release syndrome (CRS) was high (88.0%). The rate of CAR T-cell neurotoxicity was 20.9% (n = 47) and was responsible for 3 deaths.
“Coadministration of CD19- and CD22-chimeric antigen receptor T-cell therapy may be a promising therapeutic strategy for patients with relapsed or refractory B-acute lymphoblastic leukemia. However, longer follow-up is needed to determine the durability of the response,” Smita Bhatia, MD, MPH, director of the Institute for Cancer Outcomes and Survivorship in the UAB School of Medicine, as well as the vice chair for outcomes in the Department of Pediatrics and Senior Advisor for Cancer Outcomes Research at the O’Neal Comprehensive Cancer Center at UAB, commented in a review of the findings.
The trial enrolled a total of 232 patients, including 194 patients with refractory disease of hematologic relapse, and 31 with isolated extramedullary relapse. The median age of enrolled patients was 7.6 years and the median time from enrollment to infusion was 7 days.
The median combined dose between the 2 CAR T-cell therapies was 5.6 × 106/kg (IQR, 4.1-7.6 × 106; range, 1.3-13.0 × 106). The median doe of CD19-directed CAR T-cell therapy 2.7 × 106/kg (IQR, 1.9-3.7 × 106) and the median dose of CD22- directed CAR T-cell therapy was 2.8 × 106/kg (IQR, 2.1-4.0 × 106).
All 181 evaluable patients had developed B-cell aplasia in the peripheral blood or bone marrow by day 28 of post-infusion. The median time to normal B-cell recovery in either the blood or bone marrow was 74 days (IQR, 47.8-97.8 days; range, 27-371 days).
Overall, the cumulative incidence of B-cell aplasia loss by 6 months post infusion was 59.8% (95% CI, 50.4%-69.2%). For patients with persistent B-cell aplasia 2 months post-infusion, a steady improvement in EFS was observed—the EFS rates at 2, 3, 4, and greater than 6 months post-infusion were 77.0% (95% CI, 68.2%-87.0%), 88.7% (95% CI, 81.1%-97.1%), 97.4% (95% CI, 92.6%-100%), and 100%, respectively.
Investigators observed that both consolidative transplantation (HR, 0.24; 95% CI, 0.10-1.22; P = .07) and persistence of B-cell aplasia for at least 6 months post infusion (100% event-free; HR, 1.88 × 109; 95% CI, 7.40 × 10-10 –3.16 × 10-9; P < .001) demonstrated promising links to favorable outcomes this setting.
Seizure emerged as a notable adverse effect from treatment in addition to CRS and neurotoxicity. A total of 14.2% of patients experienced grade 3 or 4 seizure and was more common in those who presented with isolated or combined CNS leukemia compared with other patients. In addition, grade 3 or 4 hypotension occurred in 40.9% of patients.
To manage toxicities, 167 patients (74.2%) received tocilizumab (Actemra) and 79 (35.1%) received corticosteroids. Of note, the peak levels of IL-6 and interferon-gamma were significantly higher in patients with grade 3 or 4 CRS compared with those who had lower grade events (P < .001).
Wang T, Tang Y, Cai J, et al. Coadministration of CD19- and CD22-directed chimeric antigen receptor T-cell therapy in childhood B-cell acute lymphoblastic leukemia: a single-arm, multicenter, phase II trial. J Clin Oncol. Published online November 8, 2022. doi:10.1200/JCO.22.01214