Advancements in cellular and immune-based therapies have changed the treatment landscape for relapsed aggressive B-cell lymphoma. The ZUMA-1 trial, in which patients with refractory large B-cell lymphoma received a single infusion of axi-cel, had previously reported a durable ongoing response rate of 39% at the 2-year analysis (median follow-up, 27.1 months; N = 101). Here at ASH 2020, we reported the results of a 4-year analysis of treated patients: at a minimum of 4 years of follow-up (median, 51.1 months), a median overall survival (OS) of 25.8 months was reached, and the 4-year OS rate was 44%, with no axi-cel–related secondary malignancies (abstract 1187). Importantly, on an intent-to-treat basis, the median OS was 17.4 months and the 4-year OS rate was 41%.

The correlative piece that we also reported is that patients in ongoing long-term remission are experiencing normal polyclonal B-cell recovery, implying that the CAR T cells are no longer functional, and the patients remain in remission. We know that upfront chemoimmunotherapy can be curative for many patients with large B-cell lymphoma, such as those with diffuse large B-cell lymphoma (DLBCL), and I believe that these findings suggest that CAR T-cell therapy, in the relapsed setting, may also have curative potential.

Aberrations in Myc and either BCL2 or BCL6, by genetic alterations or protein expression, are among those baseline large B-cell lymphoma features that predict inferior outcomes with standard frontline chemoimmunotherapy. Myc expression is a key part of our criteria for identifying double-hit or double-expressor lymphoma. In abstract 1194, Jaeger and colleagues investigated Myc status and tumor microenvironment characteristics as baseline variables in the JULIET trial. Patients with relapsed/refractory DLBCL in the JULIET trial were treated with tisa-cel, with durable responses and a manageable safety profile, as previously reported. In the present abstract (1194), Myc overexpression and/or an unfavorable immunosuppressive tumor microenvironment were associated with the decreased efficacy of tisa-cel in patients with DLBCL. Myc expression was assessed by immunohistochemistry, using baseline archival tumor biopsies (pre–CAR T-cell therapy). The authors also found that those with a low frequency of tumor-infiltrating CD3+ T cells had a shorter median progression-free survival and OS. High lactate dehydrogenase levels and the presence of myeloid cells within the tumor microenvironment were also linked to worse durable response rates. The potential association of Myc overexpression in tumor cells, with worse outcomes following CAR T-cell therapy, is a hypothesis-generating finding, as previous analyses of CAR T-cell therapies have suggested similar responses in double-hit and non–double-hit lymphoma.

Many clinical trials have investigated the combination of immune checkpoint inhibitors (ICIs) with CAR T-cell therapy in the treatment of lymphoma, and the addition of the ICIs do not appear to make a substantial difference in response. However, patients with aggressive B-cell lymphomas do, to some extent, respond to ICIs, and there may be interest in the safety of these agents when used in a more limited capacity in various settings. In abstract 3058, Chiappella and colleagues reported on a series of 16 patients with primary mediastinal B-cell lymphoma who received axi-cel, and many of them had prior ICI exposure. The outcomes in both ICI-exposed and non–ICI-exposed groups appeared to be similar, and ICI exposure did not appear to negatively affect the response rate or adverse events, although the number of patients in this analysis was quite small. While other agents that might be used in concert with cellular immunotherapies continue to be explored, my sense is that we need to continue to work to understand why CAR T-cell therapies do not work for every patient, and that is what will enable us to improve outcomes.

In summary, cellular immunotherapy for large B-cell lymphoma is a paradigm-changing treatment that offers long-term remissions for patients who previously were without other options. With the US Food and Drug Administration approvals of axi-cel and tisa-cel, we now have treatment options with durable responses for eligible patients who have access to treatment. In the future, we hope to achieve these types of results for more and more patients with aggressive B-cell lymphoma.