For the treatment of relapsed or refractory aggressive B-cell lymphomas, chimeric antigen receptor–modified T-cell therapy is becoming more widely used. Still, little is known about outcomes for patients who receive CAR-modified T-cell therapy beyond 2 years.
For the treatment of relapsed or refractory aggressive B-cell lymphomas, chimeric antigen receptor (CAR)–modified T-cell therapy is becoming more widely used. Still, little is known about outcomes for patients who receive CAR-modified T-cell therapy beyond 2 years.1
Previously, a case series published in the New England Journal of Medicine (NEJM) provided 3-year follow-up data on the use of tisagenlecleucel (formerly CTL019; Kymriah) cells in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).2 As a result of this treatment, 57% of patients in the study achieved a complete remission (CR) and recovery of B cells and immunoglobulins were observed in a select group of patients. The investigators led by Stephen J. Schuster, MD, of Abramson Cancer Center stated that more research was warranted for this treatment approach.
Further follow-up of 5 years was conducted on patients from the prior case series and published in a letter to the editor of NEJM.1 The results showed that patients who had responses to CAR-modified T cells at 1 year were able to sustain their responses through 5 years.
“For patients who maintained a remission for 1 year, we found the subsequent rate of relapse to be very low for both DLBCL and FL. We successfully used lymphodepletion regimens that were not restricted to cyclophosphamide/fludarabine. There were no late safety signals at 5 years, and we frequently saw recovery of humeral and cellular immunity. For tisagenlecleucel, we also found that loss of CD19 expression on tumor cells and loss of CAR T-cell persistence did not appear to contribute significantly to lymphoma relapses,” Elise A. Chong, MD, assistant professor of Medicine at the Hospital of the University of Pennsylvania and coauthor of the study told Targeted Oncology, in an interview.
For the 5-year follow-up analysis, 49 patients were enrolled, 32 of whom had DLBCL and 17 of whom had FL. The population dosed with CAR-modified T cells included 24 patients in the DLBCL cohort and 14 with FL cohort. A total of 11 patients were not infused due to rapid disease progression, having an inadequate T-cell count or manufacturing failure, or withdrawal of consent.
At baseline, the infused DLBCL population had a median age of 55 years (range, 25-77. The DLBCL cohort was 29% female with 71% having advanced-stage disease. The median number of prior therapies in the DLBCL group was 5 (range, 1-10), and the median ECOG performance status for the group was 1 (range, 0-1). Baseline screening of the DLBCL population showed that 17% had bone marrow involvement, 67% had elevated lactate dehydrogenase (LDH) levels, and the patients scored a median of 2 (range, 1-4) on the International Prognostic Index. In terms of disease type, 33% of the DLBCL cohort had double-hit lymphoma and 92% had refractory large cell lymphoma. Forty-six percent of the DLBCL group had received prior autologous stem cell transplant (SCT) and 54% received bridging therapy.
In the FL cohort, the median age was 59 years (range, 43-72) and the population was 50% female. Eighty-six percent of patients with FL in the analysis had advanced-stage disease and the patients received a median of 5 (range, 2-10) prior therapies. The majority of the FL cohort had a lower ECOG performance score and the median was 0 (range, 0-1). Screening of these patients revealed that 29% had bone marrow involvement and 64% had elevated LDH. On the Follicular Lymphoma International Prognostic Index (FLIPI), the cohort scored a median of 3 (range, 1-5). Histological information showed that 71% of the cohort had progression of disease at 24 months, 715 had double refractory FL, and 100% of the patients with FL were rituximab (Rituxan) refractory. Fourteen percent of the FL cohort previously underwent autologous SCT, 7% underwent allogeneic SCT, and 29% had bridging therapy.
At a median follow-up of 60.7 months, responses to CAR-modified T cells were achieved in 58% of patients, with complete responses in 46%. In patients with FL particularly, the rate of complete responses was 71%. The median duration of response (DOR) was 61.4 months (95% CI, 3.2 to not estimable [NE]) and 60% (95% CI, 27%-82%) maintained their response at 5 years.
The progression-free survival (PFS) observed in patients with DLBCL was 5.8 months (95% CI, 1.6-64.2). At 5 years, 31% (9% CI, 14%-51%) of the DLBCL cohort remained progression-free. Among patients with FL, the median PFS was 26.2 months (95% CI, 2.8 to NE). This analysis showed that 43% (95% CI, 18%-66%) of all patients with FL remained progression free at 5 years.
Use of a quantitative polymerase chain reaction assay showed that among patients who achieved a CR at 1 year, the CAR19 transgene was continuously detectable throughout the 5 years of follow-up in 50% of patients with a median duration of 39.4 months (range, 22.5-57.3). The assay also detected that in the 18 patients who relapsed within 1 year, 6% had loss of transgene persistence. In addition, of those who had relapsed beyond 1 year (n = 5), 3 had undetectable transgene levels.
Recovery of B cells was notably observed within 2 years in 69% of patients who achieved a CR beyond 1 year, and of those patients, 82% had detectable CAR19 transgene at the time of B-cell recovery. Normal IgM, IgA, and IgG levels at 5 years were observed in 69%, 56%, and 38% of patients respectively.
Of the patients who responded to therapy, 27% were started on intravenous immunoglobulin treatment.
Patients who were still in remission beyond 1 year showed normal CD3, CD4, and CD8 T-cell counts. The median time to CD3 T-cell recovery was 4.6 months (interquartile range [IQR], 3.9-4.9). Notably, there were secondary cancers found in 16% of patients, but no replication-competent lentivirus was detected in the patients.
In terms of long-term safety, cytopenias of grades 1 through 4 were reported in 94% of the treated patients and took a median of 56 days to resolve (IQR, 27-139) with cytopenia ongoing at 56.6 months in 1 patient. Anemia or grade 3 or higher was reported in 34% of patients with a median time of 9 days to resolve (IQR, 4-13), though all events were resolved at 8.1 months. Thrombocytopenia of grade 3 or higher was observed in 34% with a median time to resolution of 14 days (range, 13-27), but all events were resolved by 19.5 months.
Based on these 5-year efficacy results, Chong et al concluded that response to CAR-modified T cells can be sustained for 5 years in patients with relapsed /refractory aggressive B-cell lymphomas but there is still a chance of relapse. The research also signals the feasibility of alternative approaches to lymphodepletion, despite being a small single-center study.
In an interview, Chong was asked what future research on CAR-modified T cells should explore in terms of relapsed/refractory aggressive B-cell lymphomas. Chong stated, “Research in the future will assess the efficacy of CAR T cells in high-risk, first-line patients and in randomized trials of CAR T cells versus autologous SCT. In the third-line setting, for which anti-CD19 CAR T cells are approved, the question is how to increase the long-term responses. New CAR T-cell constructs, CAR T cells in combination with other therapies, and allogeneic CAR T cells are all very interesting approaches and may further improve on these results.”
1. Chong EA, Ruella M, Schuster SJ. Five-year outcomes for refractory b-cell lymphomas with CAR t-cell therapy. N Engl J Med. 2021;384(7):673-674. doi:10.1056/NEJMc2030164
2. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-Cell lymphomas. N Engl J Med. 2017;377(26):2545-2554. doi:10.1056/NEJMoa1708566