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Interim results from ZUMA-12: Axi-cel as frontline treatment for high-risk LBCL

Jan 6, 2021

Patients with high-risk large B-cell lymphoma (LBCL) are mainly treated with rituximab-based chemoimmunotherapies that do not provide sufficient efficacy, as approximately 50% of these patients will not achieve long-term disease remission.1 The CD19 targeting CAR T product, axicabtagene ciloleucel (axi-cel), has shown great success in the relapsed/refractory (R/R) LBCL setting and has already been approved both in Europe and the US for the treatment of adult patients with R/R diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and primary mediastinal B-cell lymphoma (PMBCL) after ≥ 2 lines of prior therapy.1 The phase II trial, ZUMA-12 (NCT03761056), is currently assessing the efficacy and safety of axi-cel as frontline therapy for adults with high-risk LBCL. During the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition, the interim results from ZUMA-121 were presented by Sattva Neelapu and are hereby summarized.

Study design

  • A multicenter, open-label, single-arm, phase II trial in adult patients with high-grade confirmed LBCL with MYC and BCL2 and/or BCL6 translocations or an International Prognostic Index (IPI) ≥ 3 at any time prior enrolment. Eligible patients needed to have a positive positron interim emission tomography (PET; Deauville score of 4 or 5) scan after two cycles of anti-CD20 monoclonal antibody plus an anthracycline-containing regimen. The full study design of ZUMA-12 is shown in Figure 1
  • Prior to axi-cel infusion, on Days −5, −4, and −3, fludarabine (30 mg/m2), and cyclophosphamide (500 mg/m2) were administered as conditioning chemotherapy
  • Non-chemotherapy bridging therapy was optional
  • Axi-cel infusion was performed as a single intravenous dose of 2 × 106 CAR T cells/kg on Day 0
  • Primary endpoint was complete response (CR) rate as defined by the Lugano classification,2 while secondary outcomes included overall response rate (ORR), duration of response (DoR), event-free survival (EFS), overall survival (OS), progression-free survival (PFS), safety, and the number of circulating CAR T cells and cytokines

Figure 1. ZUMA-12 study design1

Axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; CR, complete response; DoR, duration of response; DS, Deauville score; ECOG PS, Eastern Cooperative Oncology Group performance score; EFS, event-free survival; IPI, International Prognostic Index; iv, intravenous; LBCL, large B-cell lymphoma; mAb, monoclonal antibody; ORR, overall response rate; OS, overall survival, PET, positron emission tomography; PFS, progression-free survival.


  • In total, 32 out of 37 enrolled patients received an axi-cel infusion. At data cutoff (August 25, 2020), 32 patients were evaluable for safety with a median follow-up of 9.5 months (range, 0.9–18) and 27 patients were included in the efficacy analysis with a median follow-up of 9.3 months (range, 0.9–18)
  • Key patient baseline characteristics are shown in Table 1

Table 1. Key patient baseline characteristics in ZUMA-121

ECOG PS, Eastern Cooperative Oncology Group performance score; FISH, fluorescence in situ hybridization; IPI, International Prognostic Index.

*Determined by FISH per investigator.

Baseline characteristic

N = 32



Median (range), years

61 (23–86)

≥ 65 years, n (%)

13 (41)

Male, n (%)

23 (72)

Disease stage III–IV, n (%)

28 (88)

ECOG PS ≥ 1, n (%)

21 (66)

One prior systemic line, n (%)

32 (100)

Double-/triple-hit*, n (%)

17 (53)

IPI ≥ 3, n (%)

23 (72)

Deauville score, n (%)



16 (50)


16 (50)


  • The following outcomes were reported:
    • ORR: 85%
    • CR: 74% (n = 20)
    • Partial response (PR): 11% (n = 3)
    • Stable disease (SD): 15%
    • None progressed
  • At data cutoff, 19 patients had ongoing responses (70%)
  • Median time to CR was 1 month (range, 0.9–6.4), similar to the median time to objective response (1 month [range, 0.9–3.1])
  • Five patients (19%) converted from PR (n = 4) or SD (n = 1) to CR
  • At a median follow-up of 9.5 months, median DoR, PFS, and OS were not reached
  • CAR T-cell expansion was higher in this trial when compared with ZUMA-1, with a median time to peak circulating CAR T cells of 8 days

With regards to safety:

  • The most common treatment-related Grade ≥ 3 adverse events were:
    • Encephalopathy (16%)
    • Alanine aminotransferase increase (9%)
    • Neutrophil count decrease (9%)
  • One death occurred during treatment due to COVID-19
  • All 32 patients developed cytokine release syndrome (CRS) while 22 (69%) experienced neurological events (NE). Details regarding grade, time to onset, duration, and management of these events are shown below in Table 2
  • The median levels of serum cytokines, including interleukin 6 (IL-6), IL-5, IL-8, interferon γ (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) among others, were associated with Grade ≥ 3 NE or CRS events

Table 2. CRS and NE events in ZUMA-121

CRS, cytokine release syndrome; NE, neurological events.

*The two unresolved NE events at data cutoff were Grade 1 tremor and Grade 1 memory impairment.


CRS (N = 32)

NE (N = 32)

Any Grade, n (%)

32 (100)

22 (69)

Grade ≥ 3, n (%)

3 (9)

8 (25)

Grade 4, n (%)

0 (0)

2 (6)

Grade 5, n (%)

0 (0)

0 (0)

Most commonly associated any-grade symptoms, n (%)

Pyrexia: 32 (100)

Chills: 8 (25)

Hypotension: 8 (25)

Encephalopathy: 10 (31)

Confusional state: 9 (28)

Management, n (%)




17 (53)

0 (0)


8 (25)

11 (34)

Median time to onset, days (range)

4 (1–10)

9 (2–44)

Median duration of events, days (range)

6 (1–13)

6 (1–54)

Patients with resolved events, n/N (%)

32/32 (100)

20/22 (91)*


 The phase II ZUMA-12 trial is the first to assess the use of CAR T cells as frontline treatment for high-grade LBCL. The interim data show promising response outcomes, with axi-cel infusion leading to an ORR of 85% and a CR rate of 74%. At data cutoff, 70% of patients had ongoing responses, indicating that these responses were durable. Lastly, axi-cel was well tolerated in this patient subset, with manageable CRS and NE toxicities. The authors also highlighted the higher CAR T expansion rates observed in ZUMA-12 compared with ZUMA-1, where axi-cel was used in the R/R setting, potentially indicating an improved CAR T cell fitness when axi-cel is used as first-line treatment. Further data are anticipated to validate these results.

  1. Neelapu SS, Dickinson M, Ulrickson ML, et al. Interim analysis of ZUMA-12: A phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients (Pts) with high-risk large B cell lymphoma (LBCL). Abstract 405. 62nd ASH Annual Meeting & Exposition; Dec 6, 2020; Virtual.
  2. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068. DOI: 10.1200/JCO.2013.54.8800