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Axi-cel, tisa-cel, and liso-cel have not been compared head-to-head, and probably never will be, but since all
have been shown to produce durable remissions in a significant proportion of treated patients, choice of
product for an individual patient may take into account additional factors including availability, processing
time, and side effect profiles (discussed below). Real-world experience with axi-cel and tisa-cel shows that
up to 62% of “real world” patients treated with a commercial product would not have met clinical trial
eligibility criteria, but encouragingly, outcomes are similar for these patients compared to patients treated
on the pivotal trials [21-24] .

Mantle cell lymphoma
Recently, the anti-CD19 CAR T product brexucabtagene autoleucel (brexu-cel, previously KTE-X19) was
FDA-approved (2020) for relapsed or refractory MCL [Table 1] based on the results from the phase 2 open-
label multicenter ZUMA-2 trial . Eligible patients were previously treated with anthracycline or
[12]
bendamustine, anti-CD20 monoclonal antibody, and BTKi (ibrutinib or acalabrutinib), and had disease that
was relapsed or considered refractory to up to five previous regimens. Although brexu-cel shares a CD28
costimulatory domain with axi-cel, the brexu-cel manufacturing process is unique from other FDA-
approved CAR T-cell products because circulating CD19-expressing malignant B-cells are removed during
production to help reduce tumor cell contamination and possible CAR T-cell activation and exhaustion.
Bridging therapy was permitted with investigator’s choice of steroid, BTKi (ibrutinib or acalabrutinib), or
steroid plus BTKi, and patients underwent lymphodepleting chemotherapy with fludarabine and
cyclophosphamide. Overall, brexu-cel was successfully manufactured for 71/74 patients and administered to
68 patients. Of the 60 treated patients with at least 7 months of follow-up, 93% responded, 67% completely.
At the time of data cutoff, a total of 57% of patients in the primary efficacy analysis and 78% of patients with
a CR remained in remission. The estimated 1-year PFS was 61% and the OS was 83%.

Liso-cel has also been studied in relapsed/refractory MCL, and an interim analysis of this cohort from the
[25]
TRANSCEND trial has been presented . Eligible patients had relapsed/refractory MCL after at least one
prior line of therapy and were treated with liso-cel at two different doses following lymphodepletion and
optional bridging therapy. At the time of data cutoff, 32 patients had received liso-cel [the majority of
patients (26/32) at the higher CAR+ T-cell dose]. Patients had received a median of three prior therapies,
including 28 patients (88%) who had received prior BTKi therapy and 11 patients (34%) considered BTKi-
refractory. Of the 32 patients, the ORR was 84%, with 59% of patients achieving a CR, and 74% of the 27
responders had an ongoing response at the time of analysis.

Follicular lymphoma
Follicular lympoma is an indolent disease with a favorable prognosis in the majority of patients; however,
FL which is refractory to both alkylating agents and rituximab, and FL that progresses within 24 months of
initial chemoimmunotherapy, are associated inferior OS . Initial studies of anti-CD19 CAR T approaches
[7]
in relapsed/refractory FL have demonstrated promising efficacy with CR rates ranging from 71%-88% [13,26,27] .
ZUMA-5 is the largest CAR T study to date in relapsed/refractory indolent NHL . In ZUMA-5, 146
[13]
patients received axi-cel (124 FL and 22 MZL patients). At a median follow-up of 17.5 months, the ORR was
94% for FL and 85% for MZL, with CR rates of 80% and 60%, respectively, and ongoing responses in 62% of
all patients. This study has led to the recent FDA approval (2021) of axi-cel in relapsed/refractory FL
[Table 1].

Managing CAR T-cell toxicities
The antigen targeting and immune activation that make CD19 CAR T-cells highly effective at eradicating
tumor cells are also responsible for the potential toxicities, which include cytokine release syndrome (CRS)
and a neurologic toxicity syndrome [immune effector cell associated neurologic syndrome (ICANS)]. The