KTE-X19 autologous anti-CD19 CAR T-cell therapy in patients with R/R B-ALL: Long-term phase I ZUMA-4 results

Despite the availability of novel therapies, clinical outcomes remain poor in the 10‒20% of pediatric and adolescent patients with B-cell acute lymphoblastic leukemia (B-ALL) who relapse after initial therapy. Two-year event-free survival (EFS) rates for this population have been reported at ≤41%, with a 1-year overall survival (OS) rate of approximately 36%, highlighting the need for additional options for the treatment of relapsed/refractory (R/R) B-ALL.

The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 is approved for the treatment of adults with R/R mantle cell lymphoma and is currently being evaluated for the treatment of children, adolescents, and adults with other B-cell malignancies. The phase I ZUMA-4 study (NCT02625480) is investigating KTE-X19 in pediatric and adolescent patients with R/R B-ALL, and the long-term results were presented by Alan S. Wayne at the 26th European Hematology Association (EHA) Annual Congress. Key findings are summarized herein.¹

Study design

ZUMA-4 is a multicenter, single-arm, open-label trial of KTE-X19 in children and adolescents (2‒21 years) with R/R B-ALL and >5% bone marrow blasts. Patients with Philadelphia chromosome-positive B-ALL were included.

After leukapheresis, bridging therapy was allowed at the investigator’s discretion. Following conditioning chemotherapy with fludarabine and cyclophosphamide, patients (N = 24) received either 2 × 10⁶ or 1 × 10⁶ CAR T cells/kg, with two product volumes investigated at the 1 × 10⁶ CAR T cells/kg dose level: 68 mL and 40 mL.

Patients in the 1 × 10⁶ CAR T cells/kg (40 mL) cohort received revised toxicity management:

• Tocilizumab was not administered for neurologic events if not in the context of cytokine release syndrome (CRS).
• Steroids were initiated for Grade 2 neurologic events (whereas they were previously given for Grade 3).

Endpoints

• The primary endpoint was the incidence of dose-limiting toxicities.
• Key secondary endpoints included complete remission (CR) and CR with incomplete hematologic recovery (CRi), duration of remission (DOR), relapse-free survival (RFS), overall survival (OS), and pharmacokinetics/pharmacodynamics (PK/PD).

Results

The median follow-up was 36.1 months as of September 2020, and 24 of 31 enrolled patients received KTE-X19. The median time from leukapheresis to KTE-X19 product release was 14 days for all treated patients.

Baseline characteristics

The median age across all treatment arms was 14 years (range, 3‒20), and 63% of patients were male. Baseline characteristics varied across treatment arms, as shown in Table 1.

Table 1. Baseline characteristics*

Dose-limiting toxicities and safety

• Three of the four patients who received 2 × 10⁶ cells/kg were evaluable, and there were no dose-limiting toxicities in these three patients.
• Grade ≥3 adverse events (AEs) occurred in 100% of patients; hypotension (50%) and anemia (42%) were the most common.
  • Grade ≥3 infections occurred in 42% of patients.
  • Serious AEs of any grade occurred in 71% of patients.
• There were eight (33%) patient deaths on study.
  • Six died due to disease progression.
  • Two died from AEs: one from disseminated mucormycosis and one from Escherichia sepsis.
  • Three of the patients who died received 2 × 10⁶ CAR T cells/kg, four received 1 × 10⁶ CAR T cells/kg (68 mL), and 1 received 1 × 10⁶ CAR T cells/kg (40 mL).

Regarding CRS and neurologic AEs:

• There were no Grade 4 or 5 CRS events reported, and only one Grade 4 neurologic event (brain edema) occurred (Table 2).
  • All CRS events resolved.
  • Neurologic events resolved in 14/16 patients. The two remaining patients had ongoing neurologic events at the time of death (one due to an AE considered to be unrelated to study treatment; progressive disease in the other patient).
• Overall, 42% of patients received steroids, 63% received tocilizumab, and 46% received vasopressors.
• Under revised toxicity management, overall safety was improved in patients who received 1 × 10⁶ CAR T cells/kg (40 mL) compared with those treated with 2 × 10⁶ CAR T cells/kg and 1 × 10⁶ CAR T cells/kg (68 mL).
  • Rates of Grade ≥3 CRS and neurologic events were lowest in the 1 × 10⁶ CAR T cells/kg (40 mL) cohort, and the median time to onset of these events appeared to be delayed in both the 1 × 10⁶ CAR T cells/kg cohorts compared with the 2 × 10⁶ CAR T cells/kg cohort.

Table 2. Cytokine release syndrome and neurologic AEs*

Remission rates

• CR/CRi across all doses was 38% among patients who had previously been treated with blinatumomab and 83% among patients who had received prior allogeneic stem cell transplant (allo-SCT). One patient had been previously treated with inotuzumab ozogamicin and achieved a CR after treatment with KTE-X19.
  • Fourteen of the 16 patients (87.5%) who achieved CR/CRi received subsequent allo-SCT after treatment with KTE-X19, with a median time to allo-SCT of 2.3 months.
  • Of the two patients who achieved CR/CRi and did not receive subsequent allo-SCT, one was lost to follow-up and one died as a result of progressive disease.
  • Overall CR rates (CR and CRi) for the dose groups are shown in Table 3.

Table 3. Remission rates and MRD status*

• In the 2 × 10⁶, 1 × 10⁶ (68 mL), and 1 × 10⁶ (40 mL) groups, median DOR was 4.14 months, 10.68 months, and not reached (NR), and median OS was 8 months, NR, and NR, respectively.

Conclusion

In this phase I trial, the CAR T-cell therapy KTE-X19 elicited no dose-limiting toxicities, and reported AEs were consistent with those known to be associated with CAR T-cell therapy. The 40 mL dose of 1 × 10⁶ CAR T cells/kg was shown to be the optimal formulation of KTE-X19 for the treatment of children and adolescents with R/R B-ALL, as this formulation was associated with an improved safety profile compared with the other dose formulations, while maintaining high rates of minimal residual disease negativity and CR + CRi rates in this patient population. Therefore, this dose was selected for the phase II ZUMA-4 trial, which is currently enrolling pediatric patients with R/R B-ALL (with expanded inclusion criteria) and patients with R/R B-cell non-Hodgkin lymphoma.