CAR-T safe, effective for patients with advanced ALL after allogeneic HSCT
Click Here to Manage Email Alerts
Ninety percent of patients with relapsed B-cell acute lymphoblastic leukemia after allogeneic stem cell transplantation had complete response to an investigational chimeric antigen receptor T-cell therapy, according to preliminary data.
The results of the CAR2.0 study — presented at the virtual ASH Annual Meeting and Exposition — showed 14 of the 18 patients who achieved complete response remained in remission as of the data cutoff date.
All patients in the multicenter, phase 1/phase 2 CAR2.0 study experienced disease progression following allogeneic HSCT. After progression, they received CD19-directed CAR T cells alone or in combination with other antigen-directed CAR T cells.
“CAR T-cell therapy has proved to be quite effective [for] patients with relapsed or refractory B-cell ALL,” Rui Zhang, MSc, of Shenzhen Geno-Immune Medical Institute in China, said during a presentation. “However, there has been limited study of CAR T-cell therapy in patients who have relapsed after receiving allogeneic hematopoietic stem cell transplantation.”
There are several important factors to consider regarding CAR T-cell therapy for patients with relapsed or refractory B-cell ALL who experienced disease relapse after allogeneic HSCT, Zhang said. Among them are whether rates of graft-versus-host disease would be higher, the optimal timing of CAR-T after HSCT and whether patients who had CAR-T after HSCT could achieve a durable response to therapy.
Patients in the CAR2.0 study underwent treatment with a 4SCAR-T regimen consisting of CD19-directed CAR T cells in a single dose or with a dose of fourth-generation genetically modified CAR T cells targeting alternative surface antigens, including CD22, CD38 and CD123.
4SCAR-T includes an inducible caspase-9 suicide gene system that acts as a “safety switch” to limit on-target, off-tumor toxicities, according to Zhang.
The 4SCAR-T manufacturing and administration process takes 5 to7 days, from apheresis to infusion with the genetically modified final product.
Each patient had their leukemia cells evaluated by immunohistochemical staining to determine the type of CAR T cells to be used based on the presence of target antigens.
The study’s primary outcome measurements included response rates, CAR T-cell expansion and persistence, and incidence of cytokine release syndrome (CRS) and GVHD.
At ASH, Zhang presented data from 20 patients (median age, 10.5 years; range, 2-41; 55% aged < 18 years; 50% male) who relapsed within 1.5 years after allogeneic HSCT and did not have active significant comorbidities. Notably, the majority of the cohort had low tumor burden; 15 patients (75%) had bone marrow blasts of less than 5% and only two patients had blasts of 50% or more.
Seven patients had GVHD before CAR T-cell therapy, including six patients aged younger than 18 years.
Eleven patients in the study received a single infusion of CD19-directed 4SCAR-T cells. The remaining nine patients had two infusions with CD19 4SCAR-T plus 4SCAR-T targeting CD22, CD38 or CD123.
Four patients had CAR T cells manufactured from their own T cells. The remaining 16 patients received allogeneic CAR T-cell therapy from donor T cells.
All study patients underwent lymphodepletion with cyclophosphamide and fludarabine before CAR T-cell infusion. Patients received a dose of 0.2 × 106 cells/kg to 5.8 × 106 cells/kg for each CAR T-cell infusion.
Results showed 18 patients (90%) had an initial complete response to therapy at 60 days after infusion as determined by flow cytometry. This included 10 patients aged younger than 18 years. The remaining two patients had no response to therapy.
Ten of the 11 patients who received a single CD19 CAR T-cell infusion had a minimal residual disease-negative complete response to therapy by day 60 after infusion as determined by flow cytometry.
Eight of the nine patients who received two CAR T-cell infusions achieved complete response to therapy.
Further study with more patients and longer follow-up is necessary to determine if there was a benefit to two CAR T-cell infusions compared with one infusion, Zhang said.
Fourteen patients (70%) remained in remission as of the data cutoff point, including six patients with a response lasting longer than 1 year. Four patients who had an initial response to therapy experienced disease progression.
None of the patients underwent a second HSCT after receiving CAR T cells.
Median RFS was 196.5 days (range, 0-1,452), and median OS was 197.5 days (range, 77-1,452).
4SCAR-T cells exhibited “a very good safety profile,” Zhang said, even among those with high disease burden.
Twelve patients had grade 1 CRS, including two patients with greater than 50% bone marrow blasts. The remaining eight patients did not have CRS.
Five of the 16 patients who received therapy prepared from donor T cells developed GVHD within 1 month of infusion, but they all responded well to therapy, according to researchers.
One of the key takeaways from the early data is that patient selection must include those without active comorbidities after HSCT, Zhang noted.
“4SCAR-T therapy is safe and effective for treating patients with relapsed B-cell ALL after HSCT,” she said. “The 4SCAR2.0 regimen may achieve prolonged remission without the need for a second HSCT.”
Collapse
Zhang R, et al. Abstract 162. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
Click Here to Manage Email Alerts