CAR T-cell Coadministration Strengthens Responses in Childhood B-cell ALL

The coadministration of CD19 and CD22 CAR T-cell therapy elicited promising responses and event-free survival rates in pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), according to findings from a phase 2 trial (ChiCTR2000032211).

Of the 194 patients enrolled to the trial with refractory disease or hematologic relapse, 99.0% (n = 192) achieved complete remission (CR; 95% CI, 97.5%-100%) and were minimal residual disease (MRD) negative, with an overall 12-month event-free survival (EFS) rate of 73.5% (95% CI, 67.3%-80.3%). After censoring 78 patients for consolidative transplantation, the 12-month EFS rate was 69.2% (95% CI, 60.8%-78.8%). The 12-month overall survival (OS) rate was 87.7% (95% CI, 82.9%-92.9%).

“We hypothesized that coadministration of CD19- and CD22-targeted CAR T cells would improve efficacy on the basis of the fundamental treatment principle for ALL that combination therapy forestalls the development of drug resistance and a preclinical model showing that simultaneous targeting may reduce the risk of antigen loss,” lead study author Tianyi Wang, MD, of Shanghai Jiao Tong University School of Medicine in China, and colleagues, wrote. “Moreover, coadministration would avoid repeated lymphodepleting chemotherapy that eradicates CD19 CAR T cells.”

Between September 17, 2019, and December 31, 2021, this single-arm trial enrolled 225 evaluable patients aged 20 years or younger, 194 of whom had refractory disease or hematologic relapse. The median age of the patients with refractory leukemia or hematologic relapse was 7.6 years (interquartile range, 4.8-10.8; range, 0.8-19.6). The median time from trial enrollment to CAR T-cell infusion in these patients was 7 days (range, 6-12).

The recommended dose was determined through a preliminary safety run-in stage that was conducted in 30 patients, 27 of whom received the recommended dose. This cohort enrolled patients with refractory disease and hematologic relapse who were ineligible for allogeneic transplantation or did not achieve remission after at least 2 courses of remission induction.

This trial’s second cohort enrolled patients with refractory leukemia or hematologic relapse with unfavorable genotype, prior CD19-directed CAR T-cell therapy, persistent disease after at least 2 treatments for relapse, or prior allogeneic transplantation. The third cohort enrolled patients with isolated extramedullary relapse and MRD negativity.

The recommended dose for patients with hematologic relapse was 5.0 x 10⁶ CAR T cells/kg. Patients with isolated extramedullary relapse received a dose between 5.0 x 10⁶ CAR T cells/kg and 1 x 10⁷ CAR T cells/kg to enhance CAR T-cell proliferation in a setting of low antigen stimulation.

The median dose of combined CD19 and CD22 CAR T cells in the subset of patients with refractory leukemia or hematologic relapse was 5.6 x 10⁶/kg (interquartile range, 4.1 x 10⁶-7.6 x 10⁶). The median doses of CD19 and CD22 CAR T cells were 2.7 x 10⁶/kg (interquartile range, 1.9 x 10⁶-3.7 x 10⁶) and 2.8 x 10⁶/kg (interquartile range, 2.1 x 10⁶-4.0 x 10⁶), respectively.

The primary end points of this trial were the recommended phase 2 dose of CD19 and CD22 CAR T cells, CAR T-cell infusion–related adverse effects (AEs), CR at 28 days post infusion, and 12-month EFS and OS rates with or without consolidative transplantation.

Of the 78 patients treated for hematologic relapse who received consolidative allogeneic hematopoietic cell transplantation, 24 had KMT2A- or ZNF384-rearranged ALL and 54 received transplantation upon parental request. In these patients, the 12-month EFS rate was 85.0% (95% CI, 77.2%-93.6%).

Transplantation did not result in a significant difference in 12-month OS (P = .40). Patients who received transplantation had a 12-month OS rate of 91.3% (95% CI, 84.8%-98.3%) vs 85.0% (95% CI, 78.1%-92.6%) in those who did not receive transplantation.

At a median follow-up of 11.0 months (interquartile range, 6.2-18.0; range, 0.1-32.4) after CAR T-cell infusion, of the patients with refractory leukemia or hematologic relapse, 43 experienced relapse, 24 with CD19-positive/CD22-positive relapse, 16 with CD19-negative/CD22-positive relapse, 1 with CD19-negative/CD22-negative relapse, and 2 with unknown relapse characteristics. The cumulative risk for this patient subset was 22.2% (95% CI, 16.0%-28.4%).

All 181 patients who were analyzed by day 28 post infusion had B-cell aplasia in the peripheral blood or bone marrow. The median time to normal B-cell recovery was 74.0 days (interquartile range, 47.8-97.8). The cumulative incidence of B-cell aplasia loss by 6 months post infusion was 59.8% (95% CI, 50.4-69.2).

Patients who had persistent B-cell aplasia at and beyond 2 months post infusion experienced a steady EFS improvement. The respective EFS rates in these patients at 2, 3, 4, and at least 6 months after 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%. In total, 25 patients had persistent B-cell aplasia at 6 months post infusion, all of whom remained in remission at 12 months.

Of the 116 patients who received only CD19 and CD22 CAR T-cell coadministration and did not receive transplantation, MRD of less than 15% before CAR T-cell treatment (70.7% [95% CI, 60.6%-82.5%] vs 54.6% [95% CI, 39.9%-74.7%]; P = .04), M1 bone marrow status (76.3% [95% CI, 64.5%-90.1%] vs 58.3% [95% CI, 46.8%-72.5%]; P = .05), and persistent B-cell aplasia for at least 6 months (100% vs 47.2% [95% CI, 34.8%-64.0%]; P < .001) were associated with favorable 12-month EFS rates.

A multivariate analysis found that 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 x 10^–9; 95% CI, 7.40 x 10^–10-3.16 x 10^–9; P < .001) were associated with better EFS rates.

Per quantitative polymerase chain reaction in 76 patients, expansion occurred earlier for CD19 CAR T cells than for CD22 CAR T cells (peaked at mean ± SE: 7.3 ± 0.5 days vs 10.9 ± 0.9 days; P = .0013). CD19 CAR T cells also had more robust expansion for longer duration than CD22 CAR T cells. All 11 of the patients with CD19-positive/CD22-positive relapse who were tested had lost CD19 and CD22 CAR T-cell persistence at relapse. Of the 9 patients with CD19-negative/CD22-positive relapse who were tested, 4 lost CD19 CAR T-cell persistence, and all 9 lost CD22 CAR T cells at relapse. One patient with CD19-negative/CD22-negative relapse was tested; this patient did not lose CD19 CAR T-cell persistence at relapse but did lose CD22 CAR T-cell persistence.

In total, 31 patients were treated for isolated extramedullary relapse, with a median age of 7.6 years (interquartile range, 6.0-10.3; range, 1.4-15.5), a median time from enrollment to CAR T-cell infusion of 7 days (range, 6-11), and a median dose of combined CD19 and CD22 CAR T cells of 7.0 x 10⁶/kg (interquartile range, 5.3 x 10⁶-8.9 x 10⁶; range, 1.4 x 10⁶-14.0 x 10⁶). The median doses of CD19 CAR T cells and CD22 CAR T cells were 3.0 x 10⁶/kg (interquartile range, 2.2 x 10⁶-4.1 x 10⁶) and 3.4 x 10⁶/kg (interquartile range, 2.7 x 10⁶-4.8 x 10⁶), respectively. All patients achieved CR without local irradiation.

Of the patients with extramedullary relapse, 16 had at least 1 high-risk factor, including second or third relapse; on-therapy relapse; prior allogeneic transplantation or CD19 CAR T-cell therapy; or unfavorable genotypes.

Twenty patients had isolated testicular relapse, with a 12-month EFS rate of 95.0% (95% CI, 85.9%-100%). At a median follow-up of 13.3 months, 1 patient in this group developed hematologic relapse. The 12-month EFS rate for the 10 patients with isolated central nervous system (CNS) relapse was 68.6% (95% CI, 44.5%-100%). At median follow-up, 3 patients in this group had AEs in the form of CNS relapse (n = 2) and fatal neurotoxicity (n = 1). The 1 patient with combined CNS and testicular relapse remained in CR for 14.4 months.

In total, 88.0% (n = 198) of patients developed cytokine release syndrome (CRS), which was grade 3 or higher in 28.4% (n = 64) of patients and fatal in 1 patient. Additionally, 20.9% (n = 47) of patients developed CAR T-cell neurotoxicity, which was grade 3 or higher in 4.0% (n = 9) of patients and fatal in 2 patients, who received CAR T cells at 12.0 x 10⁶/kg and 5.6 x 10⁶/kg, respectively.

Grade 3 or 4 seizure occurred in 14.2% of patients and was more common in those with isolated or combined CNS leukemia (n = 10/42) vs other patients (n = 22/183). Grade 3 or 4 hypotension developed in 40.9% of patients. Corticosteroids were administered to 35.1% (n = 79) of patients, and tocilizumab was administered to 74.2% (n = 167) of patients. The peak levels of interferon-gamma and interleukin-6 were significantly higher in patients with grade 3 to 4 CRS than those with grade 0 to 2 CRS (P < .001).

“These preliminary results are encouraging, and CAR T-cell therapy could become a therapeutic option for patients with extramedullary relapse,” the study authors concluded.

Reference

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