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*

CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; HSCT, hematopoietic stem cell transplantation; IQR, interquartile range. *Adapted from Pan, et al.1 †Patients in ethnic minorities included two (2%) of Man, two (2%) of Yao, and one (1%) each of She, Bouyei, and Lahu. ‡This patient had disease in the testis, bilateral lower neck, mediastinum, abdominal cavity, and retroperitoneum. §One patient had disease in the right kidney and the other had disease in the left adrenal gland. ‖Baseline disease assessment was done at screening and before the first lymphodepleting chemotherapy. ¶Favorable and unfavorable risk features were defined according to the National Comprehensive Cancer Network Guidelines (version 1.2020) for pediatric acute lymphoblastic leukemia.
Characteristic, % (unless otherwise stated)	All treated patients (N = 81)
Median age, years (IQR)	8 (6–10)
Sex
Female	38
Male	62
Race
Asian	100
Ethnicity
Chinese Han	91
Chinese ethnic minorities†	9
Extramedullary disease
Any	19
Diffuse‡	1
Testicular	6
CNS	9
Other locations§	2
ECOG performance
0–1	98
2	2
Relapsed or refractory subgroup
Relapsed after last therapy	68
Refractory to last therapy	32
Number of previous lines of therapy
1	38
2	41
≥3	21
Previous HSCT
Yes	12
No	88
Baseline marrow blasts by morphology‖
<5%	42
≥5% to <50%	38
≥50%	20
Genetic features¶
Favorable	22
Unfavorable	11

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.

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

CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome. *Adapted from Pan, et al.1 †The worst grade of adverse events for each patient. ‡During Cycle 1, the median onset of CRS was 3 days (interquartile range, 1–6) and the median duration was 4 days (3–7). During Cycle 2, the median onset of CRS was 2 days (interquartile range 1–8) and median duration was 3 days (interquartile range 2–5). §The median time to onset of ICANS was 4 days (interquartile range 2–7) during Cycle 1 and 2 days (1–5) during Cycle 2, and the median duration was 3 days (interquartile range 1–4) during Cycle 1 and 2 days (interquartile range 1–3) during Cycle 2.
Adverse events, n (%)	Cycle 1 (N = 81)			Cycle 2 (N = 79)
	Grade 1–2	Grade 3	Grade 4	Grade 1–2	Grade 3	Grade 4
Any†	30%	40%	31%	32%	43%	25%
CRS‡	74%	15%	1%	68%	3%	3%
ICANS§	23%	4%	1%	16%	1%	0
Infection†	5%	4%	0	5%	5%	0
Hematologic†	41%	30%	30%	38%	38%	24%

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.