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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.
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.
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 |
---|---|
Age |
|
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 (%) |
|
4 |
16 (50) |
5 |
16 (50) |
With regards to safety:
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. |
||
Parameter |
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 (%) |
|
|
Tocilizumab |
17 (53) |
0 (0) |
Steroids |
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.
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