0
selected
-
1.
Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
Locke, F. L., Filosto, S., Chou, J., Vardhanabhuti, S., Perbost, R., Dreger, P., Hill, B. T., Lee, C., Zinzani, P. L., Kröger, N., et al
Nature medicine. 2024
Abstract
The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10(-9) for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10(-9) for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
-
2.
Long-Term Survivors After Failure of CAR-T Cell Therapy for Large B-Cell Lymphoma: A Role for Allogeneic Hematopoietic Cell Transplantation? A GLA/DRST Analysis
Derigs, P., Bethge, W. A., Krämer, I., Holtick, U., von Tresckow, B., Ayuk, F., Penack, O., Vucinic, V., von Bonin, M., Baldus, C., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND The outcome of patients with large B-cell lymphoma (LBCL) who relapse or progress after CD19-directed CAR-T cell therapy administered as salvage therapy beyond the second treatment line is poor. However, a minority of patients become long-term survivors despite CAR-T failure. The German Lymphoma Alliance (GLA) has proposed a hierarchical management algorithm for CAR-T failure in LBCL, aiming at allogeneic hematopoietic cell transplantation (alloHCT) as definite therapy in eligible patients. PURPOSE The purpose of this study was to investigate characteristics, relapse patterns and management strategies in long-term survivors after CAR-T failure with particular focus on feasibility and outcome of alloHCT. STUDY DESIGN Retrospective analysis of all evaluable patients with relapse/progression event (REL) observed in a previous reported GLA sample (Bethge et al, Blood 2022) between November 2018 and May 2021. RESULTS REL occurred in 214 of 356 patients (60%) having undergone CAR-T for LBCL in the previous GLA study. For 143 of these 214 patients (67%) an evaluable dataset was available. 26 of 143 patients (18%) survived 12 months or longer from REL, 109 (76%) died within the first year after REL, and 8 patients (6%) were alive but had not reached the 12-months landmark. Long-term survivors had more favorable pre-CAR-T features, had a longer interval between CAR-T and REL, and had more often received a tumor biopsy post CAR-T failure, whereas the choice of the first salvage regimen had no impact. AlloHCT was feasible in 40 of 53 patients (75%) intended and resulted in a 12-month post-transplant overall survival of 36% in those patients who underwent transplant with sensitive or untreated REL. CONCLUSIONS AlloHCT after CAR-T failure in LBCL is feasible and may be an important contributor to long-term survival although selection bias has to be taken into account. Thus, alloHCT should be considered as a reasonable treatment option in eligible patients in this setting. Since the overall outlook after CAR-T failure nevertheless remains poor, novel effective therapeutic approaches are needed, either for allowing long-term disease control per se, or for improving the preconditions for successful alloHCT.
-
3.
Hematopoietic stem cell boost for persistent neutropenia after CAR-T cell therapy: a GLA/DRST study
Gagelmann, N., Wulf, G. G., Duell, J., Glass, B., Heteren, P. V., von Tresckow, B., Fischer, M., Penack, O., Ayuk, F. A., Einsele, H., et al
Blood advances. 2022
-
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
Hematotoxicity after chimeric antigen receptor (CAR)-T cell therapy is associated with infection and death but management remains unclear. We report results of 31 patients receiving hematopoietic stem cell boost (HSCB; 30 autologous, 1 allogeneic) for either sustained severe neutropenia of grade 4 (<0.5 x109/l), sustained moderate neutropenia (less than or equal to 1.5 x109/l) and high risk of infection, or neutrophil count less than or equal to 2.0 x109/l and active infection. Median time from CAR-T cell therapy to HSCB was 43 days and median absolute neutrophil count at time of HSCB was 0.2. Median duration of neutropenia prior to HSCB was 38 days (range, 7-151). Overall neutrophil response rate (recovery or improvement) was observed in 26 patients (84%) within a median of 9 days (95% confidence interval, 7-14). Time to response was significantly associated with the duration of prior neutropenia (p=0.007). All non-responders died within the first year after HSCB. One-year overall survival for all patients was 59% and significantly different for neutropenia ≤38 days (85%) versus neutropenia >38 days prior to HSCB (44%; p=0.029). In conclusion, early or prophylactic HSCB showed quick response and improved outcomes for sustained moderate to severe neutropenia after CAR-T.
PICO Summary
Population
Adults with persistent neutropenia after CAR-T cell therapy (n=31)
Intervention
Hematopoietic stem cell boost (HSCB; 30 autologous, 1 allogeneic)
Comparison
None
Outcome
Median time from CAR-T cell therapy to HSCB was 43 days and median absolute neutrophil count at time of HSCB was 0.2. Median duration of neutropenia prior to HSCB was 38 days (range, 7-151). Overall neutrophil response rate (recovery or improvement) was observed in 26 patients (84%) within a median of 9 days (95% confidence interval, 7-14). Time to response was significantly associated with the duration of prior neutropenia. All non-responders died within the first year after HSCB. One-year overall survival for all patients was 59% and significantly different for neutropenia ≤38 days (85%) versus neutropenia >38 days prior to HSCB (44%).
-
4.
CAR T cells or allogeneic transplantation as standard of care for advanced large B-cell lymphoma: an intent-to-treat comparison
Dreger, P., Dietrich, S., Schubert, M. L., Selberg, L., Bondong, A., Wegner, M., Stadtherr, P., Kimmich, C., Kosely, F., Schmitt, A., et al
Blood advances. 2020;4(24):6157-6168
-
-
-
Free full text
-
-
Editor's Choice
Abstract
CD19-directed chimeric antigen receptor (CAR) T-cell treatment has evolved as standard of care (SOC) for multiply relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, its potential benefit over allogeneic hematopoietic cell transplantation (alloHCT) remains unclear. We compared outcomes with both types of cellular immunotherapy (CI) by intention to treat (ITT). Eligble were all patients with R/R LBCL and institutional tumor board decision recommending SOC CAR T-cell treatment between July 2018 and February 2020, or alloHCT between January 2004 and February 2020. Primary end point was overall survival (OS) from indication. Altogether, 41 and 60 patients for whom CAR T cells and alloHCT were intended, respectively, were included. In both cohorts, virtually all patients had active disease at indication. CI was recommended as part of second-line therapy for 21 alloHCT patients but no CAR T-cell patients. Median OS from indication was 475 days with CAR T cells vs 285 days with alloHCT (P = .88) and 222 days for 39 patients for whom alloHCT beyond second line was recommended (P = .08). Of CAR T-cell and alloHCT patients, 73% and 65%, respectively, proceeded to CI. After CI, 12-month estimates for nonrelapse mortality, relapse incidence, progression-free survival, and OS for CAR T cells vs alloHCT were 3% vs 21% (P = .04), 59% vs 44% (P = .12), 39% vs 33% (P = .97), and 68% vs 54% (P = .32), respectively. In conclusion, CAR T-cell outcomes were not inferior to alloHCT outcomes, whether measured by ITT or from CI administration, supporting strategies preferring CAR T cells over alloHCT as first CI for multiply R/R LBCL.
PICO Summary
Population
Patients with multiply relapsed/refractory (R/R) large B-cell lymphoma (LBCL) (n=101)
Intervention
CD19-directed chimeric antigen receptor (CAR) T cell therapy (CI, n=41)
Comparison
Allogeneic haematopoietic stem cell transplantation (alloHCT, n=60)
Outcome
. In both cohorts, virtually all patients had active disease at indication. CI was recommended as part of second-line therapy for 21 alloHCT patients but no CAR T-cell patients. Median OS from indication was 475 days with CAR T cells vs 285 days with alloHCT and 222 days for 39 patients for whom alloHCT beyond second line was recommended. Of CAR T-cell and alloHCT patients, 73% and 65%, respectively, proceeded to CI. After CI, 12-month estimates for nonrelapse mortality, relapse incidence, progression-free survival, and OS for CAR T cells vs alloHCT were 3% vs 21%, 59% vs 44%, 39% vs 33%, and 68% vs 54%, respectively.