Efficacy and safety of sequential CD19 and CD22 CAR T-cell therapy for childhood R/R B-ALL

CD19-targeted chimeric antigen receptor (CAR) T-cell therapies have demonstrated promising outcomes in patients with relapsed or refractory (R/R) B-cell acute lymphocytic leukemia (B-ALL); however, 30%–50% of this patient population experience relapse. Bispecific CAR approaches that simultaneously target CD19 and CD22 are an effective treatment option and have successfully reduced antigen-escape-based relapse rates.

Below, we summarize the results of a phase II trial published by Pan et al. in Lancet Oncology, highlighting the safety and efficacy of sequential CD19-directed and CD22-directed CAR T-cell treatments in patients with R/R B-ALL.

Study design¹

This was a single center, single-arm, phase II trial that included:

• Patients aged 1–18 years with R/R B-ALL with CD19 and CD22 positivity >95%
• An Eastern Cooperative Oncology Group Performance Status of 0–2.

Before each CAR T-cell infusion, patients received fludarabine (30 mg/m² per day) and cyclophosphamide (250 mg/m² per day) intravenously on Days −5, −4, and −3 to reach lymphodepletion.

Patients were infused with fresh CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T cells immediately after manufacture, and once measurable residual disease (MRD)-negative complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) was reached, and all adverse events (AEs) were Grade 2 or better (except hematologic AEs).

Treatment cycles were defined as:

• Cycle 1 = the time from CD19-directed CAR T-cell infusion to before the second lymphodepletion.
• Cycle 2 = the time from CD22-directed CAR T-cell infusion to 30 days thereafter.

Endpoints

The primary endpoint was objective response rate, including MRD-negative CR and CRi 3 months after the infusion.

The secondary endpoints included:

• Event-free survival, defined as the time from first infusion to earliest relapse, treatment failure, or death from any cause
• Overall survival, defined as the time from first infusion to death from any cause
• Duration of remission, defined as the time from initial CR or CRi to recurrence or death from ALL.
• Disease-free survival, defined as the time from first infusion to earliest relapse or death from ALL
• Adverse events
• Pharmacokinetics, which included the expansion and persistence of CD19 and CD22 CAR T cells in the peripheral blood, and if needed in the cerebrospinal fluid and bone marrow
• B-cell count

Results

Overall, 81 patients were enrolled in this study. Patient characteristics are shown in Table 1.

Table 1. Patient characteristics*

At a median follow-up of 17.7 months, a total of 79 patients received sequential CAR T-cell therapy; two patients discontinued the study after CD19-directed CAR T-cell infusion; therefore, did not receive the CD22-directed CAR T-cells.

Overall, 81 patients received the target dose of CD19-directed CAR T cells (median 2.7 × 10⁶ cells per kg [interquartile range, 1.1 × 10⁶ to 3.7 × 10⁶]) and CD22-directed CAR T cells (2.2 × 10⁶ cells per kg [interquartile range, 1.1 × 10⁶ to 3.8 × 10⁶]). Two patients received the target dose of CD19-directed but not of CD22-directed CAR T cells.

Response

• Of the 62 patients who received the target dose, 97% achieved MRD-negative CR or CRi (Figure 1A).

• Of the 81 patients who received at least the first infusion, 98% had MRD-negative CR or CRi 3 months after infusion (Figure 1B).
• Of the 79 patients who had remission at 3 months, 63 patients remained in remission and alive, and one remained in remission until death from graft-versus-host-disease post hematopoietic stem cell transplantation.

Figure 1. A 3-month response rate in patients who received target dose (n = 62) B 3-month response rate in all treated patients (N = 81)*

CR, complete remission; CRi, CR with incomplete hematological recovery; PR, partial remission.
*Adapted from Pan, et al.¹

Survival

• The 18 month-event free survival for patients who received the target dose was 79%.; this rate was similar for all treated patients.

• The 18-month overall survival was 96% for all patients.
• The 18-month disease-free survival and duration of remission with hematopoietic stem cell transplantation censoring for patients who received the target doses and for all treated patients were 80% and 79%, respectively.

Safety

All patients experienced AEs (Table 2), none required dose reductions or discontinuation due to toxicity, and no treatment-related deaths occurred. Severe cytokine release syndrome and neurotoxicity events occurred less frequently in Cycle 2 than in Cycle 1.

Table 2. Adverse events

Conclusion

In this phase II trial, sequential CD19-directed and CD22-directed CAR T-cell therapy induced deep and sustainable responses and demonstrated an acceptable toxicity profile in childhood R/R B-cell ALL. A further randomized controlled trial is being planned due to these findings.