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*

allo-SCT, allogeneic stem cell transplant; BM, bone marrow; R/R, relapsed/refractory. *Adapted from Wayne, et al.1
Characteristics, n (%) unless otherwise stated	2 × 106 (n = 4)	1 × 106, 68 mL (n = 11)	1 × 106, 40 mL (n = 9)	Overall (N = 24)
Age, median (range)	11.5 (8‒18)	12 (4‒17)	14 (3‒20)	14 (3‒20)
Sex
Male	2 (50)	8 (73)	5 (56)	15 (63)
Female	2 (50)	3 (27)	4 (44)	9 (38)
Lansky score
80	0	1 (9)	0	1 (4)
90	1 (25)	6 (55)	4 (44)	11 (46)
100	2 (50)	2 (18)	2 (22)	6 (25)
Karnofsky score
80	0	2 (18)	1 (11)	3 (13)
90	0	0	2 (22)	2 (8)
100	1 (25)	0	0	1 (4)
Number of prior regimens
≤2	2 (50)	5 (45)	7 (78)	14 (58)
≥3	2 (50)	6 (55)	2 (22)	10 (42)
Prior blinatumomab	0	5 (45)	3 (33)	8 (33)
Prior inotuzumab ozogamicin	0	1 (9)	0	1 (4)
Prior stem cell transplant	1 (25)	4 (36)	1 (11)	6 (25)
Refractory subgroup before enrollment
R/R to ≥ second-line therapy	2 (50)	3 (27)	6 (67)	11 (46)
R/R post allo-SCT	1 (25)	4 (36)	1 (11)	6 (25)
Primary refractory	1 (25)	4 (36)	2 (22)	7 (29)
BM blasts at screening, median (range), %	57 (41‒99)	28 (7‒98)	58 (6‒97)	44 (6‒99)
Preconditioning BM blasts, median (range), %	85 (49‒100)	6 (0‒89)	44 (1‒82)	37 (0‒100)

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*

AE, adverse event; CRS, cytokine release syndrome; NA, not applicable. *Adapted from Wayne, et al.1 †CRS was graded according to modified Lee criteria. ††Individual symptoms of the CRS and neurologic events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. §Duration was calculated for patients with resolved events. ‖Neurologic event was ongoing at time of death due to AE unrelated to KTE-X19.
Parameter, n (%) unless otherwise stated	2 × 106 (n = 4)	1 × 106, 68 mL (n = 11)	1 × 106, 40 mL (n = 9)	Overall (N = 24)
Cytokine release syndrome
Any grade CRS†	4 (100)	9 (82)	8 (89)	21 (88)
Grade 3	3 (75)	3 (27)	2 (22)	8 (33)
Grade 4	0	0	0	0
Grade 5	0	0	0	0
Most common any-grade symptoms††
Pyrexia	3 (75)	9 (82)	5 (56)	17 (71)
Hypotension	4 (100)	8 (73)	4 (44)	16 (67)
Median time to onset (range), days	2 (1‒4)	6 (3‒14)	7 (1‒9)	5 (1‒14)
Median duration of events, days§	10.5	7	8	7
Neurologic events
Any-grade neurologic events††	1 (25)	9 (82)	6 (67)	16 (67)
Grade 3	1 (25)	2 (18)	1 (11)	4 (17)
Grade 4	0	1 (9)	0	1 (4)
Grade 5	0	0	0	0
Most common any-grade events††
Confusion	0	4 (36)	2 (22)	6 (25)
Encephalopathy	1 (25)	1 (9)	2 (22)	4 (17)
Median time to onset (range), days	7 (7‒7)	9 (4‒14)	10 (3‒60)	9.5 (3‒60)
Median duration of events, days§	NA‖	8	11	8

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*

allo-SCT, allogeneic stem cell transplant; BM, bone marrow; CR, complete remission; CRh, CR with partial hematologic recovery; CRi, CR with incomplete hematologic recovery; MRD, minimal residual disease. *Adapted from Wayne, et al.1 †≤5% blasts by morphology in BM and any absolute neutrophil count and platelet values not meeting criteria for CR, CRi, or CRh. ††MRD negativity was assessed by flow cytometry with a sensitivity of 0.01%. MRD results after allogeneic stem cell transplant or new anti-cancer therapies are excluded.
Category, n (%)	2 × 106 (n = 4)	1 × 106, 68 mL (n = 11)	1 × 106, 40 mL (n = 9)	Overall (N = 24)
Overall CR + CRi	3 (75)	7 (64)	6 (67)	16 (67)
CR	0	3 (27)	4 (44)	7 (29)
CRi	3 (75)	4 (36)	2 (22)	9 (38)
CRh	0	1 (9)	0	1 (4)
Blast-free hypoplastic/aplastic BM†	0	0	1 (11)	1 (4)
No response	0	1 (9)	1 (11)	2 (8)
MRD negative††	3 (75)	8 (73)	7 (78)	18 (75)

• 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.