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An expert panel hosted by
Customizing first-line BTK inhibitors for CLL
with Gilles Salles, Paolo Ghia, and Francesc Bosch
Wednesday, October 23, 2024
18:30-19:30 BST
This independent educational activity is supported by Pharmacyclics LLC, an AbbVie Company and Janssen Biotech. All content is developed independently by the faculty. The funder is allowed no influence on the content of this activity.
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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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