Diffuse large B-cell lymphoma (DLBCL) patients who progress following immune-chemotherapy and transplantation typically have a poor prognosis. However, CD-19-directed CAR-T cell therapy has become a viable option for these patients, with a phase III study reporting a response rate of 64% at 2 years in 28 adult diffuse large B-cell lymphoma or follicular lymphoma patients who had no curative treatment options. These patients were infused with CTL019 cells (Tisagenlecleucel) (1.00×108 to 5.00×108 CTL019 cells) over a period of 1 to 4 days, following lymphodepleting chemotherapy. Now, long-term outcomes of these patients are reported, with an additional 3 years of follow-up.
At a median follow-up of 60.7 months, patients with DLBCL had overall response rate of 58%, with 46% achieving a complete response. The response observed in these patients was also durable, with a median duration of response of 61.4 months, with 60% of these patients having a sustained response at 5 years. The progression-free survival at 5 years in these patients was 31%. Patients with follicular lymphoma also had encouraging results. At the same median follow-up, an overall response rate of 79% was observed, 71% of which had a complete response. Again, the response was durable, with a median duration of response that was not reached and a sustained response at 5 years of 60%. At 5 years, 43% of these patients were progression-free.
The long-term persistence of CTL019 cells was also assessed, finding that the CAR19 transgene was detectable throughout follow-up in 50% of patients who had a complete remission that was sustained past 1 year. A further 33% of patients had transgene levels that could not be detected between 32.7 and 47.8 months, whilst the remaining patients had concentrations that alternated between detectable and undetectable levels. Interestingly, of the 18 patients who relapsed within 1 year of infusion, only 1 patient had a loss of transgene detection. A further 5 patients relapsed beyond 1 year, 3 of which had undetectable transgene levels.
From a clinical perspective, CAR-T cell therapy performed favourably in these patients, with all cytopenias resolving within 56 days following infusion. Furthermore, 69% of patients who were in complete remission beyond 1 year, had recovery of B cells at 2 years, with 82% having detectable levels of the CAR19 transgene at the time of B-cell recovery. At 5 years, 56% of patients had normal IgA levels, 38% had normal IgG levels and 69% had normal IgM levels. Intravenous immunoglobulins were required in 27% of patients who had a response. All patients who remained in remission past 1 year recovered CD3, CD4 and CD8 T-cell counts to normal levels, although secondary cancers did occur in 16% of patients. No cases of replication-competent lentivirus were reported.
Conclusion
This long-term follow-up demonstrates the durability of CAR-T cell therapy in DLBCL/follicular lymphoma, with the majority of responses observed at 1 year being sustained at 5 years, although this was not without late relapse in a small number of patients. Furthermore, no unexpected late safety concerns were reported and cellular and humoral immunity was restored in the majority of patients.
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