The prognosis of patients with large B-cell lymphoma refractory to first-line or second-line therapy is poor.1 SCHOLAR-1 was an international, retrospective study1 in which outcomes were assessed in patients with refractory large B-cell lymphoma, which was defined as progressive or stable disease as best response to first-line or second-line chemotherapy, or relapse less than 12 months after high-dose therapy with haemopoietic stem-cell transplantation. In this population, an estimated 26% (95% CI 21–31) of 523 patients had an objective response to standard-of-care therapy, and 7% (3–15) had a complete response; and median overall survival was 6·3 months (95% CI 5·9–7·0).
Research in context
Evidence before this study
We searched PubMed with the terms “CD19 chimeric antigen receptor” AND “lymphoma” AND (“clinical trial” OR “long term remission”) NOT “review” for clinical trials done in humans published in English up to Oct 1, 2018. Evidence of long-term durable responses after anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for high-grade B-cell lymphomas was scarce. We identified 11 citations that included response data for patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who were assessed for outcomes after treatment with anti-CD19 CAR T-cell therapy. Of these 11 citations, two included outcomes for anti-CD19 CAR T-cell therapy in conjunction with autologous stem-cell transplantation as a consolidation rather than as primary therapy for refractory diffuse large B-cell lymphoma, two included outcomes after treatment of B-cell malignancies with allogeneic donor-derived anti-CD19 CAR T cells after relapse post allogeneic stem-cell transplantation, and three were previous reports of the JULIET, TRANSCEND and ZUMA-1 trials assessing anti-CD19 CAR T cells as a salvage treatment for refractory patients with large B-cell lymphoma. The remaining four citations were small phase 1 studies or case series.
Added value of this study
There is an unmet need for therapies that can increase the proportion of patients with refractory large B-cell lymphoma who can achieve long-term responses. Our results show durable remissions, with ongoing responses in 39 (39%) of 101 patients who received axicabtagene ciloleucel. No late serious adverse events were attributed to axicabtagene ciloleucel. To our knowledge, ours is the first long-term analysis with more than 2 years of follow-up of a multicentre trial of anti-CD19 CAR T-cell therapy in patients with refractory large B-cell lymphoma. Axicabtagene ciloleucel can offer durable remissions to patients who otherwise lack treatment options.
Implications of all the available evidence
Our results showing durable responses lasting more than 2 years, combined with the available literature on long-term outcomes with conventional therapies in patients with diffuse large B-cell lymphoma, suggest that axicabtagene ciloleucel could potentially offer long-term responses for a substantial proportion of patients with refractory large B-cell lymphoma who otherwise are at high risk of disease progression with conventional chemotherapy. Axicabtagene ciloleucel had a manageable long-term safety profile, and late serious adverse events were rare. Other investigational and approved CD19 CAR T-cell therapies are available to patients and have shown similar anticancer activity, although with less follow-up. Additional follow-up and further studies are needed to fully characterise the differences in efficacy and safety between CAR T-cell therapies.
Chimeric antigen receptor (CAR) T-cell therapies targeting CD19 are a promising approach for the management of refractory large B-cell lymphoma.2, 3, 4, 5, 6 Axicabtagene ciloleucel is an autologous anti-CD19 CAR T-cell therapy generated by introducing the CAR construct into primary T cells with a replication-incompetent retroviral vector.7, 8 The CAR extracellular domain has a single-chain variable fragment targeting CD19, CD28 hinge and transmembrane domains, and intracellular signalling domains that consist of CD3ζ and CD28 for T-cell activation and costimulation, respectively.9 In the single-arm, multicentre, phase 1–2 ZUMA-1 study10 of axicabtagene ciloleucel, at a median follow-up of 15·4 months (IQR 13·7–17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma had an objective response, 63 (58%) had a complete response, and 45 (42%) were in remission.10 These results led to approval of axicabtagene ciloleucel in the USA and EU for treatment of patients with relapsed or refractory large B-cell lymphomas—including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, high-grade B-cell lymphoma, and transformed follicular lymphoma—as a third-line and higher therapy.11, 12 Another anti-CD19 CAR T-cell therapy, tisagenlecleucel, was approved for relapsed or refractory diffuse large B-cell lymphoma as a third-line and higher therapy shortly thereafter.13 There is great clinical interest in the long-term safety of, and durability of responses to, these treatments. In single-centre trials6, 14 with small study populations, durable responses as long as 56 months have been reported with CD28 costimulatory CD19 CAR constructs, and as long as 37·9 months with CD137 (4-1BB) costimulatory CD19 CAR constructs, with minimal late toxicities in patients with large B-cell lymphoma. Additionally, other multicentre trials of anti-CD19 CAR- T cell therapy in adult relapsed or refractory large B-cell lymphoma are ongoing.
The general structure of the three CD19 CAR T-cell therapies—axicabatgene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel—is similar in that all use the same single-chain variable fragment (FMC63) and use CD3 for intracellular signalling. However, they use different combinations of transmembrane and costimulatory domains. Axicabatagene ciloleucel uses CD28 for transmembrane and activation domains, tisagenlecleucel uses CD8 for the transmembrane domain and 4-1BB for costimulation, and lisocabtagene maraleucel uses a CD28 transmembrane domain and 4-1BB for costimulation.
In JULIET, the phase 2 trial of tisagenlecleucel, 48 (52%) of 93 treated patients with assessable activity achieved an objective response at a median follow-up of 14 months.5 Grade 3 or worse cytokine release syndrome occurred in 22% of 111 patients and neurological events were reported in 12%.5 In an interim analysis of TRANSCEND, the phase 1–2 trial of lisocabtagene maraleucel, with a median follow-up of 8 months, 80% of 73 patients with either diffuse large B-cell lymphoma not otherwise specified or high-grade B-cell lymphoma, the population selected for the registrational cohort, achieved an objective response. One (1%) of 73 patients had grade 3 or worse cytokine release syndrome and 11 (15%) had neurological events.4
Here, we report 2-year safety and activity results from ZUMA-1, and present data on persistence of CAR T cells and recovery of B cells in patients with refractory large B-cell lymphoma and an ongoing response to axicabtagene ciloleucel.