CAR-T regimen ‘should be new standard’ for high-risk B-cell acute lymphoblastic leukemia
Click Here to Manage Email Alerts
Dual administration of CD19- and CD22-directed chimeric antigen receptor T cells conferred a 99% complete remission rate in younger patients with relapsed or high-risk B-cell acute lymphoblastic leukemia, phase 2 study results showed.
The research — published in Journal of Clinical Oncology — is the largest study of CAR T cells in younger patients with B-cell ALL to date and may represent a new standard of care for those with high-risk disease, the investigators noted.
Background
Administration of a single-target CAR T-cell therapy is the conventional approach in today’s standard practice, but single-agent treatment is not a conventional approach overall in present oncology practice, according to Ching-Hon Pui, MD, chair of the oncology department and co-leader of the hematological malignancies program at St. Jude Children’s Research Hospital.
"One drug — generally speaking — will not kill all cancer cells. There are typically some cells that are resistant to therapy,” he told Healio. "Therefore, we often need to use more than one drug, including drugs with different mechanisms of action to kill cells that are resistant to another therapy.”
Most CAR T-cell regimens, including commercially available therapies, use only one agent targeting a single antigen, Pui said. His group decided to evaluate simultaneous administration of CAR T cells targeting separate antigens to see if they would be more effective and durable.
Methodology
Pui and colleagues enrolled 225 evaluable patients aged 20 years or younger as part of a phase 2 multicenter study to evaluate the safety and efficacy of dual administration of CD19- and CD22-directed CAR T cells among those with refractory, high-risk hematologic or isolated extramedullary B-cell ALL.
The China-based study included patients treated at one of five urban centers between Sept. 17, 2019, and Dec. 31, 2021.
Investigators divided the study into three cohorts, including one safety run-group (n = 6) of patients with refractory B-cell ALL and hematologic relapse who did not achieve remission after two or more courses of remission induction therapy or who were ineligible for allogeneic hematopoietic stem cell transplantation. Cohort 2 included patients (n = 188) with refractory disease or isolated or combined hematologic disease relapse, whereas cohort 3 comprised patients (n = 31) with isolated extramedullary disease relapse.
The researchers determined 5 × 106 CAR T cells/kg to be the recommended phase 2 dose for patients with hematologic relapse, whereas a dose between 5 × 106 and 1 × 107 CAR T cells/kg served as the recommended phase 2 dose for patients with isolated extramedullary disease relapse.
Patients underwent preconditioning lymphodepleting chemotherapy followed by administration of separately cultured CD19- and CD22-directed CAR T cells given as a single infusion in a 1:1 ratio.
Complete remission rate at 28 days after infusion, EFS, OS and treatment-related adverse events served as the study’s primary endpoints.
Key findings
A total 192 of 194 patients (99%) with refractory B-cell ALL or hematologic disease relapse had complete remission of disease after therapy. All patients who had a complete response achieved negative minimal residual disease status upon evaluation.
Investigators reported an overall 12-month EFS rate of 73.5% (95% CI, 67.3-80.3).
Twenty patients with isolated testicular disease relapse had a 12-month EFS rate of 95% (95% CI, 85.9-100), whereas 10 patients with isolated central nervous system disease relapse had a 12-month EFS rate of 68.6% (95% CI, 44.5-100).
Researchers noted a 12-month OS rate of 87.7% (95% CI, 82.9-92.9). Forty-three patients experienced disease relapse, including 24 patients with CD19/CD22-positive relapse.
Multivariate analysis demonstrated a significant association between improved EFS and consolidative HSCT (HR =0.24; 95% CI, 0.1-1.22) and B-cell aplasia lasting 6 months or longer after CAR T-cell infusion (HR = 1.88 × 10–9; 95% CI, 7.4 × 10–10 to 3.16 × 10–9).
Three patients died of treatment-related adverse events during the study.
Most patients (88%) developed cytokine release syndrome, with 64 patients (28.4%) experiencing grade 3 or higher CRS. Treatment-related neurotoxicity occurred in 47 patients (20.9%), including nine patients (4%) who experienced grade 3 or higher events.
Clinical implications
The key takeaway from the results is that combination treatment with multiantigen targeting of CAR T cells is more effective than commercially available CAR T cells that target CD19 alone, Pui said.
"We can definitely improve treatment outcomes for patients with relapsed or refractory disease,” he told Healio. “A high proportion of these patients can be cured.”
While his own group has no plans to translate these results into a commercial product, other research centers are pursuing such ventures with industry partners, Pui noted. His team's results, however, help solidify the rationale behind the multiantigen targeting approach for CAR-T, especially among those with high-risk disease.
Patients with extramedullary relapse — particularly testicular or CNS relapse — stand to benefit most from the dual-targeting approach, Pui added, because it would offer them a choice beyond radiation therapy — the current treatment standard in younger patients. It’s an approach he hopes will benefit children with B-cell ALL later in life, sparing them the long-term effects of radiation while improving their quality of life.
“We have discovered a way to cure a large proportion of these patients without the use of radiation,” he said. “I believe this should be the new standard of care for this disease.”
Collapse
Click Here to Manage Email Alerts