ZUMA-1 4-year follow-up: Polyclonal B-cell recovery and survival outcomes with axi-cel in R/R large B-cell lymphoma

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy with a CD28 transmembrane/co-stimulatory domain, approved for the treatment of relapsed/refractory (R/R) large B-cell lymphoma after ≥2 prior therapies. Approval was based on the phase I/II ZUMA-1 (NCT02348216) trial results.

Positive results from the 2-year analysis of the ZUMA-1 trial were previously reported on the Lymphoma Hub, where 83% of patients responded, 58% achieved a complete response, and 39% had ongoing responses after a median follow-up of 27.1 months.

Here, we report the survival outcomes and recovery of polyclonal B cells for ongoing responders with 4 years of follow-up from this phase II trial, as presented by Caron Jacobson during the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).¹

Patient disposition

• A total of 111 eligible patients were enrolled in the intent-to-treat population (ITT).
• Patients who went on to receive axi-cel treatment were categorized as the modified ITT population (MITT; n = 101).
• Patients with ongoing responses at ≥3 years of follow-up who had evaluable samples were included in the 4-year follow-up analysis.
• The median follow-up time was 51.1 months.

Results

Time to response (as previously reported in the 2-year follow-up), time to next anticancer therapy, and overall survival (OS) after ≥4 years of follow up are shown in Table 1. 

Table 1. Time to response, time to next therapy, median OS, and 4-year OS rates*

CR, complete response; ITT, intention to treat; KM, Kaplan Meier; MITT, modified intention to treat; OR, objective response; OS, overall survival. *Data from Jacobson et al.1 †Time from axi-cel infusion to initiation of new anticancer therapy, including CAR T-cell treatment and excluding stem cell transplantation, or death from any cause.
Response	ITT population (n = 111)	MITT population (n = 101)
Median time to OR, months (range)	1.7 (0.7–12.9)	1 (1–12)
Median time to CR, months (range)	1.9 (0.7–13.3)	1 (1–12)
Median time to next therapy, months (range)†	—	8.7 (0.3–53.8)
Median OS, months	17.4	25.8
KM estimate of 4-year OS rate, %	41	44

Safety

• Since study initiation, 59% of patients in the ITT population have died.
• Since the 2-year data cut-off date,
  • Eight deaths occurred, due to either progressive disease (n = 5), secondary malignancy (n = 1), cardiac arrest (n = 1), or unknown cause (n = 1).
  • No new axi-cel–related serious adverse events were reported.
  • Intravenous immunoglobulin therapy was received by four patients.
• At the 4-year data cut-off,
  • No new axi-cel–related secondary malignancies were reported.
  • There were no confirmed cases of replication-competent retrovirus.

CAR T-cell expansion and B-cell recovery

• Ongoing responders after 2 years had greater CAR T-cell expansion in the blood after 7–14 days of axi-cel infusion compared to patients who experienced relapse (p = 0.014) or no response (p = 0.0003).
• At 3 years after axi-cel treatment, all evaluable patients (n = 21) had detectable B cells in the blood; 67% had detectable CAR gene-marked cells and polyclonal B cells.
• 91% of patients with ongoing response at ≥3 years of follow-up (n = 21 out of 23) demonstrated polyclonal B-cell recovery as measured by the presence of kappa and lambda light chains on non-malignant CD19⁺ and/or CD20⁺ B cells. The median immunoglobulin kappa–lambda ratio was 1.6.
• Diversification of the B-cell population, including memory and naive B-cell immunophenotypes, indicated reconstitution of the B-cell repertoire.

Conclusion

In this long-term follow-up of the ZUMA-1 trial, axi-cel demonstrated deep and durable responses, with a 4-year OS rate of 44% among treated patients. The short time between enrolment and response, as previously observed, demonstrates the speed at which the therapy takes effect.

Moreover, patients with ongoing responses at ≥3 years of follow-up showed evidence of polyclonal B-cell restoration and clearance of functional CAR-T cells, which is a key component of the long-term safety of CD19-directed CAR T-cell therapy. This also supports the idea that persistence of functional CAR T cells is not necessary for deep and durable remission in large B-cell lymphoma.