Five-Year Follow-Up of Standard-of-Care Axicabtagene Ciloleucel for Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium

Abstract

Purpose: Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy.

Methods: We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.9 months. Here, we report extended follow-up of this cohort to a median of 58 months, with a focus on late survivorship events.

Results: Among axi-cel-infused patients, progression-free survival at 5 years was 29% and overall survival (OS) at 5 years was 40%. The 5-year lymphoma-specific survival was 53% with infrequent late relapses. However, the 5-year nonrelapse mortality (NRM) was 16.2%, with over half of NRM events occurring beyond 2 years. Patients who were 60 years and older had a lower risk of relapse (P = .02), but a higher risk of NRM compared with patients younger than 60 years (NRM odds ratio, 4.5 [95% CI, 2.1 to 10.8]; P < .001). Late NRM was mainly due to infections and subsequent malignant neoplasms (SMNs). In total, SMNs occurred in 24 patients (9%), including therapy-related myeloid neoplasms (n = 15), solid tumors (n = 7), and unrelated lymphoid malignancies (n = 2).

Conclusion: In the standard-of-care setting, axi-cel exhibits outcomes consistent with those reported in clinical trials, with sustained, durable responses observed at the 5-year time point. However, late infections and the development of SMN are key survivorship issues that reduce long-term survival after CAR T-cell therapy, particularly in the elderly.

Figure 1.. 5-year outcomes following standard-of-care axi-cel for R/R DLBCL after 2 or more prior lines of therapy.

A-B. PFS (A) and OS (B) among patients infused with axi-cel (n=275). C. OS among patients leukapheresed with intention to treat with axi-cel (N=298). D-E. PFS (D) and OS (E) stratified by best overall response. F. Visualization of lymphoma response and clinical outcomes between infusion and last known evaluation. Abbreviations: CR, complete response. PR, partial response. SD, stable disease. NRM, non-relapse mortality.

Figure 1.. 5-year outcomes following standard-of-care axi-cel for R/R DLBCL after 2 or more prior lines of therapy.

A-B. PFS (A) and OS (B) among patients infused with axi-cel (n=275). C. OS among patients leukapheresed with intention to treat with axi-cel (N=298). D-E. PFS (D) and OS (E) stratified by best overall response. F. Visualization of lymphoma response and clinical outcomes between infusion and last known evaluation. Abbreviations: CR, complete response. PR, partial response. SD, stable disease. NRM, non-relapse mortality.

Figure 1.. 5-year outcomes following standard-of-care axi-cel for R/R DLBCL after 2 or more prior lines of therapy.

A-B. PFS (A) and OS (B) among patients infused with axi-cel (n=275). C. OS among patients leukapheresed with intention to treat with axi-cel (N=298). D-E. PFS (D) and OS (E) stratified by best overall response. F. Visualization of lymphoma response and clinical outcomes between infusion and last known evaluation. Abbreviations: CR, complete response. PR, partial response. SD, stable disease. NRM, non-relapse mortality.

Figure 2.. Non-relapse mortality and relapse after standard-of-care axi-cel.

A. Competing-risk curve indicating the cumulative incidence of death due to relapse and non-relapse mortality (NRM) over time. B. Density plot with incidence from time since infusion. Left panel, patients in remission with last known follow-up indicated. Middle panel, incidence of lymphoma relapse marked at the time of relapse after axi-cel. Right panel, incidence of deaths due to NRM. C. Disease-specific survival, censoring patients who died of NRM. D. Competing-risk curves indicating the cumulative incidence of death due to relapse and NRM. Left, age under 60 at the time of CAR T-cell apheresis. Right, age 60 and over. P-values by Gray’s test comparing patients age 60 and over to age under 60 for relapse and NRM.

Figure 2.. Non-relapse mortality and relapse after standard-of-care axi-cel.

A. Competing-risk curve indicating the cumulative incidence of death due to relapse and non-relapse mortality (NRM) over time. B. Density plot with incidence from time since infusion. Left panel, patients in remission with last known follow-up indicated. Middle panel, incidence of lymphoma relapse marked at the time of relapse after axi-cel. Right panel, incidence of deaths due to NRM. C. Disease-specific survival, censoring patients who died of NRM. D. Competing-risk curves indicating the cumulative incidence of death due to relapse and NRM. Left, age under 60 at the time of CAR T-cell apheresis. Right, age 60 and over. P-values by Gray’s test comparing patients age 60 and over to age under 60 for relapse and NRM.

Figure 2.. Non-relapse mortality and relapse after standard-of-care axi-cel.

A. Competing-risk curve indicating the cumulative incidence of death due to relapse and non-relapse mortality (NRM) over time. B. Density plot with incidence from time since infusion. Left panel, patients in remission with last known follow-up indicated. Middle panel, incidence of lymphoma relapse marked at the time of relapse after axi-cel. Right panel, incidence of deaths due to NRM. C. Disease-specific survival, censoring patients who died of NRM. D. Competing-risk curves indicating the cumulative incidence of death due to relapse and NRM. Left, age under 60 at the time of CAR T-cell apheresis. Right, age 60 and over. P-values by Gray’s test comparing patients age 60 and over to age under 60 for relapse and NRM.

Figure 3.. Immune reconstitution and infections after standard-of-care axi-cel.

A. Infection events (severe and non-severe) occurring between 6 months and 2 years after axi-cel. B. Incidence of cytopenias at 1 year (left) and 2 years (right) after axi-cel. Grading by CTCAE 5.0. Grade 3 is Hb<8 g/dl , or ANC between 500-1000/mm3, or Plt between 25-50,000/mm3. Grade 4 is ANC<500/mm3, or Plt <25,000/mm3. Each ring of the sunburst chart represents the cytopenia indicated. Each ray of the sunburst chart represents patient(s) with that unique combination of cytopenias. C-F. Plots comparing indicated immune parameters at baseline, 12 months, and 24 months after CAR T-cell therapy, among patients with available data. G. Comparison of patients who did or did not receive IVIG between 6- and 24-months after CAR T-cell therapy, based on baseline IgG levels. H. Cumulative incidence of infections occurring between 6 months and 2 years (outer circle) compared to incidence of neutropenia at 1- and 2-years (inner circle). Each ray of the sunburst plot indicates co-occurrence of neutropenia and infections within the same patient(s), and indicating that the majority of infections occurred in patients without neutropenia. I. Comparison of patients who went on to develop a therapy-associated myeloid neoplasm (tMN) and those that did not. Hemoglobin, absolute neutrophil counts, and platelets were obtained at the time of apheresis.

Figure 3.. Immune reconstitution and infections after standard-of-care axi-cel.

A. Infection events (severe and non-severe) occurring between 6 months and 2 years after axi-cel. B. Incidence of cytopenias at 1 year (left) and 2 years (right) after axi-cel. Grading by CTCAE 5.0. Grade 3 is Hb<8 g/dl , or ANC between 500-1000/mm3, or Plt between 25-50,000/mm3. Grade 4 is ANC<500/mm3, or Plt <25,000/mm3. Each ring of the sunburst chart represents the cytopenia indicated. Each ray of the sunburst chart represents patient(s) with that unique combination of cytopenias. C-F. Plots comparing indicated immune parameters at baseline, 12 months, and 24 months after CAR T-cell therapy, among patients with available data. G. Comparison of patients who did or did not receive IVIG between 6- and 24-months after CAR T-cell therapy, based on baseline IgG levels. H. Cumulative incidence of infections occurring between 6 months and 2 years (outer circle) compared to incidence of neutropenia at 1- and 2-years (inner circle). Each ray of the sunburst plot indicates co-occurrence of neutropenia and infections within the same patient(s), and indicating that the majority of infections occurred in patients without neutropenia. I. Comparison of patients who went on to develop a therapy-associated myeloid neoplasm (tMN) and those that did not. Hemoglobin, absolute neutrophil counts, and platelets were obtained at the time of apheresis.

Figure 3.. Immune reconstitution and infections after standard-of-care axi-cel.

A. Infection events (severe and non-severe) occurring between 6 months and 2 years after axi-cel. B. Incidence of cytopenias at 1 year (left) and 2 years (right) after axi-cel. Grading by CTCAE 5.0. Grade 3 is Hb<8 g/dl , or ANC between 500-1000/mm3, or Plt between 25-50,000/mm3. Grade 4 is ANC<500/mm3, or Plt <25,000/mm3. Each ring of the sunburst chart represents the cytopenia indicated. Each ray of the sunburst chart represents patient(s) with that unique combination of cytopenias. C-F. Plots comparing indicated immune parameters at baseline, 12 months, and 24 months after CAR T-cell therapy, among patients with available data. G. Comparison of patients who did or did not receive IVIG between 6- and 24-months after CAR T-cell therapy, based on baseline IgG levels. H. Cumulative incidence of infections occurring between 6 months and 2 years (outer circle) compared to incidence of neutropenia at 1- and 2-years (inner circle). Each ray of the sunburst plot indicates co-occurrence of neutropenia and infections within the same patient(s), and indicating that the majority of infections occurred in patients without neutropenia. I. Comparison of patients who went on to develop a therapy-associated myeloid neoplasm (tMN) and those that did not. Hemoglobin, absolute neutrophil counts, and platelets were obtained at the time of apheresis.

Figure 3.. Immune reconstitution and infections after standard-of-care axi-cel.

A. Infection events (severe and non-severe) occurring between 6 months and 2 years after axi-cel. B. Incidence of cytopenias at 1 year (left) and 2 years (right) after axi-cel. Grading by CTCAE 5.0. Grade 3 is Hb<8 g/dl , or ANC between 500-1000/mm3, or Plt between 25-50,000/mm3. Grade 4 is ANC<500/mm3, or Plt <25,000/mm3. Each ring of the sunburst chart represents the cytopenia indicated. Each ray of the sunburst chart represents patient(s) with that unique combination of cytopenias. C-F. Plots comparing indicated immune parameters at baseline, 12 months, and 24 months after CAR T-cell therapy, among patients with available data. G. Comparison of patients who did or did not receive IVIG between 6- and 24-months after CAR T-cell therapy, based on baseline IgG levels. H. Cumulative incidence of infections occurring between 6 months and 2 years (outer circle) compared to incidence of neutropenia at 1- and 2-years (inner circle). Each ray of the sunburst plot indicates co-occurrence of neutropenia and infections within the same patient(s), and indicating that the majority of infections occurred in patients without neutropenia. I. Comparison of patients who went on to develop a therapy-associated myeloid neoplasm (tMN) and those that did not. Hemoglobin, absolute neutrophil counts, and platelets were obtained at the time of apheresis.

Figure 3.. Immune reconstitution and infections after standard-of-care axi-cel.

A. Infection events (severe and non-severe) occurring between 6 months and 2 years after axi-cel. B. Incidence of cytopenias at 1 year (left) and 2 years (right) after axi-cel. Grading by CTCAE 5.0. Grade 3 is Hb<8 g/dl , or ANC between 500-1000/mm3, or Plt between 25-50,000/mm3. Grade 4 is ANC<500/mm3, or Plt <25,000/mm3. Each ring of the sunburst chart represents the cytopenia indicated. Each ray of the sunburst chart represents patient(s) with that unique combination of cytopenias. C-F. Plots comparing indicated immune parameters at baseline, 12 months, and 24 months after CAR T-cell therapy, among patients with available data. G. Comparison of patients who did or did not receive IVIG between 6- and 24-months after CAR T-cell therapy, based on baseline IgG levels. H. Cumulative incidence of infections occurring between 6 months and 2 years (outer circle) compared to incidence of neutropenia at 1- and 2-years (inner circle). Each ray of the sunburst plot indicates co-occurrence of neutropenia and infections within the same patient(s), and indicating that the majority of infections occurred in patients without neutropenia. I. Comparison of patients who went on to develop a therapy-associated myeloid neoplasm (tMN) and those that did not. Hemoglobin, absolute neutrophil counts, and platelets were obtained at the time of apheresis.

Figure 3.. Immune reconstitution and infections after standard-of-care axi-cel.

A. Infection events (severe and non-severe) occurring between 6 months and 2 years after axi-cel. B. Incidence of cytopenias at 1 year (left) and 2 years (right) after axi-cel. Grading by CTCAE 5.0. Grade 3 is Hb<8 g/dl , or ANC between 500-1000/mm3, or Plt between 25-50,000/mm3. Grade 4 is ANC<500/mm3, or Plt <25,000/mm3. Each ring of the sunburst chart represents the cytopenia indicated. Each ray of the sunburst chart represents patient(s) with that unique combination of cytopenias. C-F. Plots comparing indicated immune parameters at baseline, 12 months, and 24 months after CAR T-cell therapy, among patients with available data. G. Comparison of patients who did or did not receive IVIG between 6- and 24-months after CAR T-cell therapy, based on baseline IgG levels. H. Cumulative incidence of infections occurring between 6 months and 2 years (outer circle) compared to incidence of neutropenia at 1- and 2-years (inner circle). Each ray of the sunburst plot indicates co-occurrence of neutropenia and infections within the same patient(s), and indicating that the majority of infections occurred in patients without neutropenia. I. Comparison of patients who went on to develop a therapy-associated myeloid neoplasm (tMN) and those that did not. Hemoglobin, absolute neutrophil counts, and platelets were obtained at the time of apheresis.

Figure 3.. Immune reconstitution and infections after standard-of-care axi-cel.

A. Infection events (severe and non-severe) occurring between 6 months and 2 years after axi-cel. B. Incidence of cytopenias at 1 year (left) and 2 years (right) after axi-cel. Grading by CTCAE 5.0. Grade 3 is Hb<8 g/dl , or ANC between 500-1000/mm3, or Plt between 25-50,000/mm3. Grade 4 is ANC<500/mm3, or Plt <25,000/mm3. Each ring of the sunburst chart represents the cytopenia indicated. Each ray of the sunburst chart represents patient(s) with that unique combination of cytopenias. C-F. Plots comparing indicated immune parameters at baseline, 12 months, and 24 months after CAR T-cell therapy, among patients with available data. G. Comparison of patients who did or did not receive IVIG between 6- and 24-months after CAR T-cell therapy, based on baseline IgG levels. H. Cumulative incidence of infections occurring between 6 months and 2 years (outer circle) compared to incidence of neutropenia at 1- and 2-years (inner circle). Each ray of the sunburst plot indicates co-occurrence of neutropenia and infections within the same patient(s), and indicating that the majority of infections occurred in patients without neutropenia. I. Comparison of patients who went on to develop a therapy-associated myeloid neoplasm (tMN) and those that did not. Hemoglobin, absolute neutrophil counts, and platelets were obtained at the time of apheresis.

Figure 3.. Immune reconstitution and infections after standard-of-care axi-cel.

A. Infection events (severe and non-severe) occurring between 6 months and 2 years after axi-cel. B. Incidence of cytopenias at 1 year (left) and 2 years (right) after axi-cel. Grading by CTCAE 5.0. Grade 3 is Hb<8 g/dl , or ANC between 500-1000/mm3, or Plt between 25-50,000/mm3. Grade 4 is ANC<500/mm3, or Plt <25,000/mm3. Each ring of the sunburst chart represents the cytopenia indicated. Each ray of the sunburst chart represents patient(s) with that unique combination of cytopenias. C-F. Plots comparing indicated immune parameters at baseline, 12 months, and 24 months after CAR T-cell therapy, among patients with available data. G. Comparison of patients who did or did not receive IVIG between 6- and 24-months after CAR T-cell therapy, based on baseline IgG levels. H. Cumulative incidence of infections occurring between 6 months and 2 years (outer circle) compared to incidence of neutropenia at 1- and 2-years (inner circle). Each ray of the sunburst plot indicates co-occurrence of neutropenia and infections within the same patient(s), and indicating that the majority of infections occurred in patients without neutropenia. I. Comparison of patients who went on to develop a therapy-associated myeloid neoplasm (tMN) and those that did not. Hemoglobin, absolute neutrophil counts, and platelets were obtained at the time of apheresis.

Figure 3.. Immune reconstitution and infections after standard-of-care axi-cel.

A. Infection events (severe and non-severe) occurring between 6 months and 2 years after axi-cel. B. Incidence of cytopenias at 1 year (left) and 2 years (right) after axi-cel. Grading by CTCAE 5.0. Grade 3 is Hb<8 g/dl , or ANC between 500-1000/mm3, or Plt between 25-50,000/mm3. Grade 4 is ANC<500/mm3, or Plt <25,000/mm3. Each ring of the sunburst chart represents the cytopenia indicated. Each ray of the sunburst chart represents patient(s) with that unique combination of cytopenias. C-F. Plots comparing indicated immune parameters at baseline, 12 months, and 24 months after CAR T-cell therapy, among patients with available data. G. Comparison of patients who did or did not receive IVIG between 6- and 24-months after CAR T-cell therapy, based on baseline IgG levels. H. Cumulative incidence of infections occurring between 6 months and 2 years (outer circle) compared to incidence of neutropenia at 1- and 2-years (inner circle). Each ray of the sunburst plot indicates co-occurrence of neutropenia and infections within the same patient(s), and indicating that the majority of infections occurred in patients without neutropenia. I. Comparison of patients who went on to develop a therapy-associated myeloid neoplasm (tMN) and those that did not. Hemoglobin, absolute neutrophil counts, and platelets were obtained at the time of apheresis.