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The CAR T-cell product axicabtagene ciloleucel (axi-cel) has become established as a successful treatment for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). The efficacy and safety of axi-cel as a frontline treatment for high-risk LBCL is being investigated in the ZUMA-12 phase II clinical trial (NCT03761056). Interim study results have been previously reported by The Lymphoma Hub. Here, we summarize results from the primary analysis, published by Neelapu, et al., in Nature Medicine.1
The study is a multicenter, open-label, single-arm, phase II trial in adult patients with high-grade confirmed LBCL. High grade was defined as the presence of MYC and BCL2 and/or BCL6 translocations, or an International Prognostic Index ≥3 at any time prior to enrolment. Further information on the study design can be found here.
Table 1. Key patient baseline characteristics in ZUMA-12*
Baseline characteristic, n (%) |
N = 40 |
---|---|
Median age (range), years |
61 (23–86) |
≥65 years |
15 (38) |
Male |
27 (68) |
Disease stage III–IV |
38 (95) |
ECOG Performance Status ≥1 |
25 (63) |
One prior systemic line |
32 (100) |
Double- or triple-hit only |
6 (15) |
Double- or triple-hit and IPI ≥3 |
4 (10) |
IPI ≥3 only |
20 (50) |
Deauville score |
|
4 |
19 (48) |
5 |
21 (53) |
Alterations by FISH |
|
MYC |
19 (48) |
BCL2 |
15 (38) |
BCL6 |
10 (25) |
Previous systemic therapy |
|
R-CHOP |
19 (48) |
DA-EPOCH-R |
18 (45) |
Neither R-CHOP nor DA-EPOCH-R |
6 (15) |
DA-EPOCH-R, etoposide phosphate, prednisone, vincristine sulphate (Oncovin), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), and rituximab; ECOG, Eastern Cooperative Oncology Group; FISH, fluorescence in situ hybridization; IPI, International Prognostic Index; R-CHOP, rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (Oncovin) and prednisone. |
Table 2. Most common Grade ≥3 adverse events in patients receiving axi-cel*
Adverse event, n (%) |
N = 40 |
---|---|
Neutropenia |
5 (13) |
Reduced neutrophil count |
21 (53) |
Reduced white cell count |
17 (43) |
Anemia |
12 (30) |
Encephalopathy |
6 (15) |
Thrombocytopenia |
6 (15) |
Hypoxia |
5 (12) |
*Data from Neelapu, et al.1 |
Considering biomarkers and CAR T-cell levels:
No statistical significance was found between median peak levels of CAR T-cells in patients who relapsed/did not respond, and those who had an ongoing response to axi-cel. Several cytokines were found to be at least doubled in patients who experienced Grade ≥3 neurological events, including interleukin (IL)-5, macrophage inflammatory protein-1α (MIP-1α), interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), ferritin, tumor necrosis factor (TNF)-α, IL-10, IL-8, and programmed death-ligand 1 (PDL1) (p < 0.05).
The primary analysis of the ZUMA-12 phase II trial suggests that axi-cel has potential as a safe and effective option for the frontline treatment for high-grade LBCL. In the cohort of 37 efficacy-evaluable patients, objective response rate and complete response rate were 89% and 78%, respectively, and CAR T-cell expansion was observed in all participants. Safety data is comparable to other studies using axi-cel, with manageable adverse events and toxicities. Larger, randomized control studies are needed to replicate these results in large study populations and further compare efficacy and safety data with current standard-of-care treatment.
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