21 research outputs found
Long-term outcomes of patients with large B-cell lymphoma treated with axicabtagene ciloleucel and prophylactic corticosteroids
ZUMA-1 safety management cohort 6 investigated the impact of prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs) following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Prior analyses of cohort 6 with limited follow-up demonstrated no Grade ≥3 CRS, a low rate of NEs, and high response rates, without negatively impacting axi-cel pharmacokinetics. Herein, long-term outcomes of cohort 6 (N = 40) are reported (median follow-up, 26.9 months). Since the 1-year analysis (Oluwole, et al. Blood. 2022;138[suppl 1]:2832), no new CRS was reported. Two new NEs occurred in two patients (Grade 2 dementia unrelated to axi-cel; Grade 5 axi-cel-related leukoencephalopathy). Six new infections and eight deaths (five progressive disease; one leukoencephalopathy; two COVID-19) occurred. Objective and complete response rates remained at 95% and 80%, respectively. Median duration of response and progression-free survival were reached at 25.9 and 26.8 months, respectively. Median overall survival has not yet been reached. Eighteen patients (45%) remained in ongoing response at data cutoff. With ≥2 years of follow-up, prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab continued to demonstrate CRS improvement without compromising efficacy outcomes, which remained high and durable
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Pre- and Post-Treatment Immune Contexture Correlates with Long Term Response in Large B Cell Lymphoma Patients Treated with Axicabtagene Ciloleucel (axi-cel)
Background: Axi-cel is a US and EU-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after 1 prior therapy as a result of ZUMA-7 (NCT. In ZUMA-1 (NCT02348216), the pivotal study which initially led to the approval of axi-cel in the 3L+ setting, the objective response rate was 83% (58% complete response rate; Locke et al. Lancet Oncol. 2019) and at 5 years follow up an OS rate of 42.6%, 5 years durable response and 5 years disease specific survival at 51% ( Neelapu et al. Blood 2023). T cell-related biology (Immunosign 21; Immunoscore®IC) measured pretreatment in the tumor microenvironment (TME) was associated with response to axi-cel ( Scholler et al., 2022). Increased density of activated PD-1+LAG-3+/−TIM-3−CD8+ T cells, measurable pretreatment, facilitates clinical response in pts post-axi-cel. This expanded analysis characterized the impact of axi-cel treatment on the TME immune contexture and examined associations between immune cell subsets and relapse. Methods: Baseline and post-infusion tumor biopsy samples were analyzed by multiplex immunohistochemistry ( Brightplex®). Four panels were developed and applied to assess T cell infiltration (CD3 CD8 FOXP3 TIM3 PD1 LAG3 TOX), regulatory T cell subtyping (CD3 CD8 GATA3 TBET RORg BCL6), T cell activation & exhaustion (CD3 CD8 TIM3 LAG3 PD1 GZMB KI67), macrophage (CD68 CD64 CD163 CD204 CD206 PDL1) and MDSC (CD3 CD11B CD68 CD14 CD15 LOX1 S100A9) subsets. Transcriptomic analysis was performed using nCounter® Pan Cancer panel. The association between T cell subtypes and macrophages cell subset density, and probability to relapse was evaluated. T test values were based on Brightplex analysis. Results: 34 tumor biopsies (16 at baseline, 18 post-infusion) from 26 pts were analyzed including 11 relapsed (6 CR/5 PR) and 15 durable response (15 CR). The baseline and post-infusion TME comprised all major macrophages, MDSC and T cell subsets, with diverse distribution across samples analyzed. Low proinflammatory M1 macrophage density was observed at baseline and post-infusion across patients. In relapsed patients, baseline tumors were enriched with a significantly higher proportion of protumoral M2 macrophage (p<0.0001). A shift of M1-M2 polarization was observed between baseline and post-infusion (Baseline 33%M1M2 / 65%M2, post infusion 76%M1M2 / 21%M2, p<0,0001) across the cohort. In contrast, in relapsed patients, M-MDSC cell density was significantly increased post treatment (p=0.0420). In addition, Innate lymphocyte cells subtype 2 (ILC2) cell density, previously described to be positively correlated with improved overall survival in CRC ( Huang et al. 2021 Cancers), was significantly decreased in relapsed patients post infusion (p=0.019).Post-infusion, durable response was associated with a significant increase in pan-Macrophages (p=0.0360) and cytotoxic T cell subset densities: CD8 naïve T cells (p=0.016); Activated Cytotoxic T cell (GZMB+)(p=0.0203); PD1+TIM3+LAG3- cytotoxic T cell (p=0.0117); CD8 regulatory T cell (FOXP3+)(p=0.012). Regarding T helper lineage, ongoing response was associated with a significant increase of: CD4 naïve T cells (p=0.021); T helper Th2 (p=0.020); cytotoxic T lymphocyte TC2 and TC1/TC2 cell densities (respectively p=0.0052 and 0.011).Additional characterization of the immune contexture and correlative analysis of cell subsets will be presented. Conclusion: These results suggest that baseline proportions of protumor M2 macrophages may predict disease relapse after axi-cel treatment. Following infusion, relapse is also associated with spatial enrichment of M-MDSC, whereas durable response is related to increases in T cell subpopulation densities inclusive of cytotoxic T cells, T helper, TC1/TC2 ratios and innate T-subpopulations. These findings suggest that axi-cel treatment drastically impacts tumor immune mobilization, infiltration and contexture, which correlates with long term response
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Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-cell Lymphoma
•ZUMA-1 Cohort 3 was an exploratory safety management study of axi-cel in LBCL•Tocilizumab and levetiracetam were assessed as prophylaxis against CRS and NEs•Grade ≥3 CRS events were reduced versus Cohorts 1 + 2, without impacting efficacy•Severe NEs were not abrogated with prophylactic tocilizumab in R/R LBCL•Grade ≥2 NEs were associated with elevated levels of key proinflammatory molecules
Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell–related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial.
ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel.
Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on Days –5 through –3 followed by a single infusion of axi-cel (2 × 106 cells/kg) on Day 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 hours after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines).
Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-month minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 months (95% CI, 5.4–not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid.
Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell–related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL
Impact of debulking therapy on the clinical outcomes of axicabtagene ciloleucel in the treatment of relapsed or refractory large B-cell lymphoma
Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, was approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the results from pivotal Cohorts 1+2 of ZUMA-1 (NCT02348216). ZUMA-1 was expanded to investigate safety management strategies aimed at reducing the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs). Prospective safety expansion Cohort 5 evaluated the impact of debulking therapy, including rituximab-containing immunochemotherapy regimens and radiotherapy, in axi-cel-treated patients; the CRS and NE management strategy paralleled those in Cohorts 1+2. Among the 50 patients in Cohort 5 who received axi-cel, 40% received ≥3 prior lines of chemotherapy, and 40% had disease that progressed while on the most recent chemotherapy. Forty-eight patients (96%) received debulking therapy, 14 (28%) radiotherapy only, and 34 (71%) systemic immunochemotherapy. Median decrease in tumor burden (per sum of product of diameters of target lesions) relative to screening was 17.4% with R-ICE/R-GDP, 4.3% with other debulking chemotherapies, and 6.3% with radiotherapy only. All patients were followed for ≥8 months. CRS was reported in 43 patients (86%), with 1 patient (2%) experiencing grade ≥3. NEs were reported in 28 patients (56%), with 6 (12%) experiencing grade ≥3. Cytopenias were the most frequent grade ≥3 adverse event (AE); 19 (38%) and 18 (36%) treated patients had any and grade ≥3 prolonged thrombocytopenia, respectively, and 25 (50%) and 24 (48%) patients had any and grade ≥3 prolonged neutropenia, respectively. Overall, patients who received debulking chemotherapy had higher incidences of serious treatment-emergent AEs than those who received radiotherapy only. At the 24-month analysis, objective response rate was 72%, and complete response rate was 56%. Median duration of response, progression-free survival, and overall survival were 25.8, 3.1, and 20.6 months, respectively. These results from exploratory Cohort 5 demonstrate the feasibility of debulking prior to axi-cel, and together with current real-world evidence, suggest that debulking regimens may help minimize the frequency and severity of CRS and NEs in patients with R/R LBCL. The incidence of other AEs observed in Cohort 5 suggest the risk/benefit profile was not improved via the debulking regimens studied here
Supplementary Figure S4 from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11
Axi-cel Product Characteristics and Phenotype</p
Supplementary Figure S5 from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11
Ex vivo Axi-cel Proliferation After Stimulation With Utomilumab</p
Supplementary Methods S1 from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11
SUPPLEMENTARY METHODS</p
Supplementary Table S2 from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11
Peak Concentration and AUC0–29 of Serum Utomilumab</p
Supplementary Table S1 from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11
Representativeness of Study Participants</p
Supplementary Figure S3 from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11
Patient Disposition</p