In pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia, complete remissions were achieved in 99.0% of patients and their overall 12-month event-free survival was 73.5% with CD19-/CD22-chimeric antigen receptor therapy.
Pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), including those with isolated or combined extramedullary relapse, achieved relatively durable remission with CD19-/CD22-chimeric antigen receptor (CAR) T-cell therapy, according to findings from a phase 2, (ChiCTR2000032211).1
“We attributed our favorable results partly to the simultaneous administration of 2 different CAR T cells to enhance early eradication of leukemia clones, thereby impeding the development of resistance. Compared with 2 large CD19 CAR-T studies, this trial yielded a higher complete remission rate [99% vs 88% and 93.5%, respectively] and a lower relapse rate [22.2% vs36% and 31.5%, respectively], suggesting additional immune pressure via CD22 CAR T cells.” wrote authors of the study published in the Journal of Clinical Oncology, led by Tianyi Wang, MD, Department of Hematology/Oncology, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
This open-label, multicenter, phase 2 trial enrolled 225 evaluable patients aged ≤ 20 years between September 17, 2019, and December 31, 2021. We first conducted a safety run-in stage to determine the recommended dose. After an interim analysis of the first 30 patients treated (27 at the recommended dose) showing that the treatment was safe and effective, the study enrolled additional patients according to the study design.
In the first cohort of the study, patients with refractory leukemia and hematologic relapse who did not achieve remission after 2 or more courses of remission induction or were ineligible for allogeneic transplantation were enrolled. The second cohort enrolled patients with refractory disease or hematologic relapse with unfavorable genotype, persistent disease after ≥ 2 treatment regimens for relapse, prior CD19-CAR T therapy, or allogeneic transplantation. Lastly, the third cohort included patients with isolated extramedullary relapse and negative minimal residual disease (MRD) defined as <0.01% of leukemia cells in bone marrow by flow cytometry.
At the time of the safety run-in stage, 1 of 3 patients treated at the initial dose of 1 × 107 CAR T cells/kg developed a grade 4 neurotoxicity, but none of the patients experienced grade ≥ 3 toxicity at a de-escalated dose of 5.0 × 106 CAR T cells/kg. This was determined as the recommended dose for patients with hematologic relapse.
A dose between 5 × 106 and 1 × 107 CAR T cells/kg was used to treat isolated extramedullary relapse to enhance CAR T-cell proliferation in the setting of low antigen stimulation. After an interim analysis of the first 30 patients showed that the treatment was safe. Their event-free survival (EFS) was superior to that of 46 historical patients treated with CD19-CAR T cells.
Among those enrolled, CD3+ T lymphocytes were collected from peripheral blood (1-2 mL/kg) within 3 days of eligibility confirmation, and CAR T cells were manufactured at the Shanghai Children's Medical Center. Then, T cells were stimulated by anti-CD3/CD28 beads for 24-48 hours and were transduced with CD19-specific or CD22-specific CAR lentiviral vectors with 4-1BB costimulatory and CD3 zeta signaling domains. CD19- and CD22-specific CAR T cells were cultured separately and after 5-7 days in the culture, CD19- and CD22-CAR T cells were pooled together at a ratio of 1:1, washed, resuspended in saline solution with 2.5% human serum albumin, and transported to the participating medical center. Here, the patient received the infusion on day 0.
Investigators assessed the primary end points of determining the recommended phase 2 dose of combined CD19- and CD22-CAR T cells, CAR T-cell infusion–related adverse events (AEs), complete remission rate at day 28 post infusion, and EFS and overall survival (OS) at 12 months with or without consolidative transplantation.
A total of 232 patients were enrolled in the study and 225 were evaluable. This included 194 patients with refractory disease or hematologic relapse and 31 patients with isolated extramedullary relapse. At the time of enrollment, patients with refractory disease or hematologic relapse had a median age of 7.6 years (interquartile range [IQR], 4.8-10.8; range, 0.8-19.6 years). Median time from enrollment to infusion was 7 days (range, 6-12 days).
The median dose of combined CD19- and CD22-CAR T cells was 5.6 × 106/kg (IQR, 4.1-7.6 × 106; range, 1.3-13.0 × 106). For CD19-CAR T cells, the median dose was 2.7 × 106/kg (IQR, 1.9-3.7 × 106), and for CD22-CAR T cells, the median dose was 2.8 × 106/kg (IQR, 2.1-4.0 × 106). The median ratio of CD19-CAR T-cell dose to that of CD22-CAR T-cell dose was 0.94 (IQR, 0.78-1.19).
Data from the study showed that complete remission was achieved in 99.0% of the 194 patients with refractory leukemia or hematologic relapse, all of which were negative for MRD. The overall 12-month EFS among these patients was 73.5% (95% CI, 67.3-80.3).
Forty-three patients relapsed, including 24 CD19+/CD22+ relapse, 16 CD19–/CD22+, 1 CD19–/CD22–, and 2 unknown. Among the 78 patients treated with transplantation, the 12-month EFS was 85.0% (95% CI, 77.2-93.6) and 69.2% (95% CI, 60.8-78.8) for the 116 non transplanted patients (P = .03, time-dependent covariate Cox model). At 6 months, consolidative transplantation and persistent B-cell aplasia were associated with favorable outcomes. Further, all the 25 patients with persistent B-cell aplasia at 6 months remained in remission at 12 months.
For the 20 patients with isolated testicular relapse, the 12-month EFS was 95.0% (95% CI, 85.9-100). For the 10 patients with isolated cytokine release syndrome (CRS) relapse, the 12-month EFS was 68.6% (95% CI, 44.5-100). CRS was observed in 198 (88.0%) patients, and CAR T-cell neurotoxicity in 47 (20.9%), resulting in 3 deaths.
Consolidative transplantation was performed in 24 of 37 patients with KMT2A-rearranged or ZNF384-rearranged ALL. The clinical and biologic characteristics of patients who did or did not undergo consolidative transplantation were similar. However, none who received transplantation had B-cell aplasia for ≥ 6 months after infusion (P < .001. Those who received transplantation had better 12-month EFS compared with patients who did not (P = .03) at 85.0% (95% CI, 77.2-93.6) vs 69.2% (95% CI, 60.8-78.8) No significant difference in 12-month OS was observed between patients who did (91.3%; 95% CI, 84.8 to 98.3) or did not receive transplantation (85.0%; 95% CI, 78.1-92.6; P = .40).
Neurotoxicity occurred in 47 (20.9%) patients, was grade ≥ 3 in 9 (4.0%), and was fatal in 2 patients who were given 12.0 × 106 and 5.6 × 106 CAR-T cells/kg, respectively. Regarding grade 3 or 4 AEs, seizures developed in 14.2% of the patients and was more common in those presenting with isolated or combined CNS leukemia. A total of 40.9% of patients had grade 3 or 4 hypotension.
Tocilizumab (Actemra) was given to 167 patients (74.2%), and corticosteroids were administered to 79 (35.1%). Peak levels of interleukin-6 and interferon-gamma were higher in patients with grade 3-4 CRS vs patients with grade 0-2 (P < .001).
Overall, the coadministration of CD19- and CD22-CAR T-cell therapy has potential to be a promising treatment for patients with relapsed or refractory B-cell ALL. To confirm these data, longer follow-up is needed to determine the durability of the response.