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Page 8 of 14 Haydu et al. J Cancer Metastasis Treat 2021;7:36 https://dx.doi.org/10.20517/2394-4722.2021.39

[37]
have a positive interim PET after 2 cycles of standard frontline chemoimmunotherapy . For the 12
response-evaluable patients in a planned interim analysis, the ORR was 92% with a CR rate of 75%, and 75%
of patients had ongoing responses at data cut off. Interestingly, median peak CAR T-cell levels and cell
[10]
expansion were higher in ZUMA-12 patients compared to ZUMA-1 patients, which may reflect improved
CAR T health from exposure to fewer prior therapies. Although ZUMA-12 is not randomized and thus is
susceptible to selection bias, and the value of early interim PET in predicting outcomes in DLBCL remains
controversial although it may identify patients at increased risk of poorer outcomes , the initial results
[38]
from ZUMA-12 are promising and ultimately this and other studies, potentially with additional biomarkers
beyond interim PET, may help identify patients who benefit from an early intensification approach.

Follicular lymphoma and marginal zone lymphoma
FL typically has an indolent course although a small subset of patients will transform to an aggressive large
cell lymphoma which becomes life-threatening. Patients with tFL were eligible for the pivotal trials of CD19
CAR T-cells and response rates for tFL were generally on par with that seen in relapsed/refractory DLBCL.
In the ZUMA-1 trial, 16 of the 101 axi-cel-treated patients had tFL and in an updated analysis, there was an
ongoing response in 56% (9/16) of tFL patients at 24 months [10,18] . The TRANSCEND large B-cell cohort
included tFL (60/269; 22% of patients) as well as other transformed indolent lymphomas (iNHL) including
MZL (18/296; 7% of patients) . The ORRs in the 57 evaluable tFL patients and the 18 evaluable transformed
[9]
iNHL patients were 84.2% (48/57) and 61.1% (11/18), respectively. The TRANSCEND study also included a
small subset of patients with grade 3B FL (3/269; 1% of patients), which tends to behave more like an
aggressive lymphoma; 2 of these patients went on to receive liso-cel and both remain in a CR at 1 year.

In addition to axi-cel, other CAR T-cell products are under investigation in relapsed/refractory FL. In a
recently presented interim analysis of the ongoing phase 2 Elara trial of tisa-cel in relapsed/refractory FL,
52/97 tisa-cel treated patients were evaluable for efficacy, with an ORR of 83% in the ITT and 85% in the per
protocol populations, with CR rates of 65% and 71%, respectively . Of the 97 Elara patients evaluable for
[39]
safety, the rate of grade 3 or higher CRS or neurotoxicity was 0% and 2% respectively. ZUMA-5 and
[13]
[39]
Elara highlight the potential for CAR T therapy in relapsed/refractory FL and MZL and may ultimately
lead to additional FDA approvals for these diseases.

Chronic lymphocytic leukemia/small lymphocytic leukemia
CAR T-cell therapy has also been investigated in patients with relapsed/refractory CLL/SLL. CLL/SLL is an
indolent disease but patients with relapsed/refractory disease after BTKi and/or BCL2-directed therapy have
a poor prognosis with limited treatment options. Results from small series of relapsed/refractory CLL
patients treated with anti-CD19 CAR T-cell products have shown promising efficacy with tolerable side
effect profiles. For example, all 4 CLL patients treated with a CD28 co-stimulated CAR T product had a
response with 3 achieving a CR , while response rates for patients treated with 4-1BB co-stimulated
[40]
[41]
products in larger published series have ranged from 57% (8/14; 4 CR and 4 PR) to 74% (14/19; 4 CR and
10 PR) .
[42]
Currently, several clinical trials are evaluating the safety and efficacy of anti-CD19 CAR T approaches in
relapsed/refractory CLL. The ongoing, open-label, phase 1/2 TRANSCEND CLL 004 study (NCT03331198)
[43]
reported interim results for patients treated with liso-cel in the phase 1 cohort . Eligible patients had
received at least three prior regimens for standard risk disease or two prior regimens for high risk disease,
with high risk factors defined as 17p deletion, TP53 mutation, unmutated IGHV, or complex karyotype. All
patients had to have failed or been intolerant to a BTKi. The interim analysis included 23 safety-evaluable
and 22 efficacy-evaluable patients, and within this group, 83% of patients had high risk disease and all had
received prior BTKi. The ORR was 82% (18/22) with a CRR of 45% (10/22). At a median follow up of 18