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

[25]
events) . Similar to CRS rates, the lower rates of neurologic toxicity with tisa-cel and liso-cel may reflect
the kinetics associated with a 4-1BB co-stimulatory domain.

Neurologic toxicity is managed primarily with dexamethasone, which can improve symptoms and
accelerate the rate of recovery from ICANS and has become the predominant treatment for high-grade
neurotoxicity. Tocilizumab has shown only limited efficacy in treating ICANS [30-32] , perhaps because of poor
[33]
CNS penetration , and thus corticosteroids have remained the first line treatment for severe neurologic
toxicity, with tocilizumab given only for patients with concurrent CRS and neurotoxicity. Patients at high
risk of ICANS, or those with onset of ICANS symptoms, should also receive prophylactic antiepileptics such
as levetiracetam. Rare cases of cerebral edema are typically treated with high dose methylprednisolone.

Other CAR T-associated toxicities
Cytopenias, B-cell aplasia, and hypogammaglobulinemia also occur following CAR T treatment. B-cell
aplasia and hypogammaglobulinemia are attributed to on-target CD19 B-cell depletion, and notably most
patients enrolling on CAR T-cell trials are hypogammaglobulinemic at baseline due to extensive prior
lymphoma-directed therapies. Other cytopenias including neutropenia, lymphopenia, anemia, and
thrombocytopenia may be secondary to lymphodepleting chemotherapy but have also been reported in the
absence of conditioning and likely denote cytokine-mediated inflammatory marrow suppression .
[34]
Management of prolonged cytopenias is supportive until count recovery occurs. CD4 depletion may be
prolonged and consideration should be given to pneumocystis and viral prophylaxis until sufficient CD4
recovery is established. Infusion of intravenous immunoglobulin post-CAR T-cell therapy may be required
to prevent recurrent infections in the setting of hypogammaglobulinemia should patients experience severe
or recurrent infectious episodes.

ONGOING CAR T DEVELOPMENTS IN B-CELL NHLS
DLBCL and other large B-cell lymphomas
The pivotal trials of axi-cel, tisa-cel, and liso-cel enrolled relapsed/refractory patients treated with at least
two prior lines of therapy. Thus, patients were generally heavily pre-treated with potentially less fit T-cells
from which to generate CAR T-cells. Moreover, a small proportion of patients in these trials never made it
to CAR T-cell infusion due to progressive disease, reflective of the aggressive nature of these lymphomas. In
this context, growing interest to assess the efficacy and safety of CAR T-cells in the second line has led to
three large clinical trials comparing CAR T-cell therapy to ASCT at first relapse in DLBCL. ZUMA-7
[35]
(NCT03391466) , BELINDA (NCT03570892) , and TRANSFORM (NCT03575351) are randomized,
[36]
phase 3, open-label multicenter studies of anti-CD19 CAR T-cell therapy vs. standard of care (SOC) second
line treatment in relapsed/refractory DLBCL or other aggressive B-cell NHLs initially treated with standard
first line chemoimmunotherapy. In all three trials, patients are randomized 1:1 to CAR T-cell therapy or to
SOC. Patients in the SOC arm receive standard second line salvage chemoimmunotherapy per the treating
investigator’s choice (e.g., R-ICE, R-DHAP, R-GDP) and if responding proceed with high-dose
chemotherapy and ASCT. Crossover from SOC to CAR T is permitted for both BELINDA and
TRANSFORM in patients not responding to second line chemotherapy. Interim results from these studies
are eagerly anticipated.

Given that first line chemoimmunotherapy can cure a substantial fraction of patients with DLBCL, CAR T-
cell therapy has been primarily studied in relapsed/refractory disease. However, there may be a population
of patients at high risk of relapse who benefit from even earlier administration of CAR T-cells, although
identifying these patients in the upfront setting can be challenging. ZUMA-12 is an ongoing phase 2,
multicenter, open-label single arm study of axi-cel in patients with high risk large B-cell lymphoma who