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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.
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2.
Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma
Westin, J. R., Locke, F. L., Dickinson, M., Ghobadi, A., Elsawy, M., van Meerten, T., Miklos, D. B., Ulrickson, M. L., Perales, M. A., Farooq, U., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;:Of1-of12
Abstract
PURPOSE Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. PATIENTS AND METHODS Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2-3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). RESULTS Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and <65 years. CONCLUSIONS Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.
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3.
Clinical and Radiographic Predictors of Progression and Survival in Relapsed/Refractory Lymphoma Patients Receiving Anti-CD19 CAR T-cell Therapy
Jodon, G., Colton, M. D., Abbott, D., Cai, A., Haverkos, B., Morgan, R., Kamdar, M.
Clinical lymphoma, myeloma & leukemia. 2023;23(1):49-56
Abstract
INTRODUCTION Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory (R/R) B-cell lymphomas, though certain patients do not respond to treatment or relapse afterwards. The purpose of this study is to determine patient variables that are predictive of response to CAR-T therapy. METHODS We conducted a retrospective review of 59 R/R B-cell non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy. Risk factors for progression free survival (PFS) and overall survival (OS) were identified and multivariate logistic regression models for PFS and OS at 1 year were created using stepwise selection. The final multivariate logistic regression models were used to estimate the area under the receiver operating curve (AUROC). RESULTS At median follow up of 25.6 months, median overall survival was not reached, and median progression free survival was 5.7 months. Stage IV disease (odds ratio (OR) 9.335, P = .025) was identified as a predictive variable for progression at day 365 with an AUC of 0.7922 (P < .001). IPI (OR 2.828, P = .014), ALC ≥ 0.50 at collection (OR 0.183, P = .043), CRP ≥ 11 (OR 6.177, P = .019), and tocilizumab administration (OR 0.062, P = .005) as predictors for death at day 365 with an AUC 0.8626 (P < .001). CONCLUSION Clinical variables identify R/R lymphoma patients who are at risk for progression and poor overall survival after CAR T-cell therapy. IPI, CRP, ALC, and tocilizumab administration may be predictors of survival.
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4.
ASCT vs CART for Patients with Relapsed LBCL in PR: Role of TMTV
Strati, P., Pasvolsky, O., Feng, L., Xu, G., Tewari, S., Varghese, J., Ow, K., Santiago, M. S., Al Zaki, A., Jallouk, A., et al
Blood advances. 2023
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5.
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.
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6.
Efficacy of Salvage Treatments in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta-Analysis
Kim, J., Cho, J., Yoon, S. E., Kim, W. S., Kim, S. J.
Cancer research and treatment. 2023
Abstract
PURPOSE We intend to evaluate the efficacy of salvage treatments for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) through meta-analysis. MATERIALS AND METHODS R/R DLBCL trials were divided into two groups based on eligibility for autologous stem-cell transplantation (ASCT), and meta-analysis of each group was performed. Random effects models were used to estimate the 1-year progression-free survival (PFS) rate, and CAR T-cell therapy was used as reference treatment. RESULTS 26 ASCT-eligible cohorts from 17 studies comprising 2924 patients and 59 ASCT-ineligible cohorts from 53 studies comprising 3617 patients were included in the pooled analysis. In the ASCT-eligible group, the pooled 1-year PFS rate was 0.40 (95% confidence interval (CI) 0.15-0.65) for the CAR T-cell group and 0.34 (95% CI 0.30-0.37) for the group with chemotherapy followed by ASCT intention. The two treatments were not significantly different in meta-regression analysis. In the ASCT-ineligible group, the pooled 1-year PFS was 0.40 (95% CI 0.35-0.46) for CAR T-cell, and the highest primary outcome was 0.47 (95% CI 0.37-0.57) for the tafasitamab group. CAR T-cell therapy showed significantly better outcomes than chemotherapy and therapies based on ibrutinib, lenalidomide, and selinexor. However, loncastuximab, polatuzumab plus bendamustine and rituximab, and the tafasitamab group showed no different efficacy than CAR T-cell therapy after adjusting for median number of previous lines of treatment. . CONCLUSION Although several regimens were crudely grouped for classification, CAR T-cell therapy did not outperform chemotherapy followed by ASCT in the second-line setting or several recently developed agents in the ASCT-ineligible setting.
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7.
CAR T-Cell Therapy Has Comparable Efficacy to Autologous Transplantation in Older Adults with DLBCL in Partial Response
Akhtar, O. S., Cao, B., Wang, X., Torka, P., Al-Jumayli, M., Locke, F. L., Freeman, C. L.
Blood advances. 2023
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8.
Survival outcomes for patients with relapsed/refractory aggressive B cell lymphomas following receipt of high dose chemotherapy/autologous stem transplantation and/or chimeric antigen receptor-modified T cells
Landsburg, D. J., Nasta, S. D., Svoboda, J., Gerson, J. N., Schuster, S. J., Barta, S. K., Chong, E. A., Difilippo, H., Weber, E., Cunningham, K., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Patients diagnosed with relapsed/refractory (R/R) diffuse large B cell and high grade B cell lymphomas (DLBCL/HGBL) may achieve prolonged survival following receipt of high dose chemotherapy/autologous stem cell transplantation (HDC/ASCT) or CD19-directed chimeric antigen receptor-modified T cells (CART19). While early results from randomized clinical trials suggest that assignment to CART19 versus salvage immunochemotherapy as second-line therapy results in improved survival, analysis of a large series of patients who actually received HDC/ASCT or CART19 has yet to be performed, and may inform future research efforts to optimize risk-stratification of R/R DLBCL/HGBL patients who are candidates for either therapy. OBJECTIVE To understand clinicopathologic factors which predict for freedom from treatment failure (FFTF) for R/R DLBCL/HGBL patients following receipt of HDC/ASCT or CART19, and compare patterns of TF for R/R DLBCL/HGBL patients receiving either HDC/ASCT or CART19. STUDY DESIGN Patients age ≤75 with R/R DLBCL/HGBL who received HDC/ASCT demonstrating partial or complete metabolic response to salvage immunochemotherapy and/or CART19 in the standard-of-care setting at the University of Pennsylvania from 2013-21 were included. Survival analyses were performed from the time of infusion of either HDC/ASCT or CART19 as well landmark time points post-infusion for patients who achieved FFTF. RESULTS For 100 HDC/ASCT patients with median length of follow-up of 62.7 months, the estimated rate of 36 month FFTF and overall survival were 59% and 81%, respectively. For 109 CART19 patients with median length of follow-up of 37.6 months, the estimated rate of 36 month FFTF and overall survival were 24% and 48%, respectively. HDC/ASCT patients achieved significantly higher rates of estimated 36 month FFTF if achieving actual FFTF at 3, 6, 12 and 24 months. Additionally, the incidence of baseline characteristics that predicted for TF at 36 months for either HDC/ASCT or CART19 patients was either similar or significantly lower at for CART19 as compared to HDC/ASCT patients who achieved actual FFTF at 3, 6, 12 and 24 months. CONCLUSION Patients with R/R DLBCL/HGBL achieving response to salvage immunochemotherapy who receive HDC/ASCT experience a high rate of estimated FFTF regardless of harboring features predictive of resistance to salvage immunochemotherapy, which may be more durable than that of R/R DLBCL/HGBL patients receiving CART19. These findings support further investigation of disease characteristics, such as molecular features, which may predict response to salvage immunochemotherapy in patients fit for HDC/ASCT.
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9.
The nutritional impact of CD19-targeted CAR-T therapy versus BEAM chemotherapy for adult patients with lymphoma
Ahern, K., Pham, J., Sanderson, R., Correia De Farias, M., Walsh, K.
Journal of human nutrition and dietetics : the official journal of the British Dietetic Association. 2023
Abstract
BACKGROUND Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapy demonstrating durable remissions in patients with refractory or relapsing non-Hodgkin's B-cell lymphoma. Maintaining a patient's nutritional status has been demonstrated to improve outcomes in cancer treatment. However, no studies have investigated how CAR-T therapy affects nutritional status, nor compared its impact with other cancer treatments for this patient group. The primary aim of the present study was to investigate the effect of CAR-T therapy on the prevalence of nutrition impact symptoms (NIS) and nutritional status within 30 days post-treatment of patients with lymphoma compared to a conditioning regimen for autologous haematopoetic stem cell transplant (carmustine/BCNU, Etoposide, cytarabine/Ara-C, Melphalan [BEAM] auto-haematopoetic stem cell transplant [HSCT]). METHODS Clinical notes of patients with lymphoma who underwent either CAR-T therapy or BEAM auto-HSCT between 2018 and 2021 were reviewed. Data extracted included body weight measurements and NIS, including decreased appetite, nausea, vomiting, diarrhoea, constipation, mucositis, cytokine release syndrome (CRS) and neurotoxicity at baseline and 30 ± 7 days post-treatment. RESULTS In total, 129 adults with lymphoma (n = 88 CAR-T vs. n = 41 BEAM) were included. Nutritional status was assessed in both groups at baseline prior to treatment. Mean absolute weight change was significantly different between groups (3.05 kg in CAR-T, -5.9 kg in BEAM, p ≤ 0.001). This was also significant when weight loss was categorised into percentage weight loss (p = 0.01). CAR-T patients experienced a significantly lower prevalence of decreased appetite (52.3% vs. 97.6%) nausea (25% vs. 78%,) vomiting (10.2% vs. 53.7%), diarrhoea (43.2% vs. 96.7%) and mucositis (5.7% vs. 75.6%) combined across all levels of severity compared to BEAM chemotherapy (all p ≤ 0.01). CRS and neurotoxicity, which are specific side effects of CAR-T therapy, were moderately positively associated with weight loss. CONCLUSIONS Weight loss, percentage weight loss and NIS were significantly reduced in CAR-T compared to BEAM treatment. However, patients who experienced neurotoxicity during treatment did have significant weight loss.
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10.
Comparative effectiveness of salvage chemotherapy regimens and chimeric antigen T-cell receptor therapies in relapsed and refractory diffuse large B cell lymphoma: a network meta-analysis of clinical trials
Gong, I. Y., Aminilari, M., Landego, I., Hueniken, K., Zhou, Q., Kuruvilla, J., Hodgson, D. C.
Leukemia & lymphoma. 2023;:1-12
Abstract
The optimal salvage chemotherapy regimen (SC) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant remains unclear. Moreover, although chimeric antigen receptor T cell (CAR-T) therapies were recently approved for primary refractory DLBCL, head-to-head comparisons are lacking. We searched MEDLINE, EMBASE and CENTRAL to July 2022, for randomized trials that enrolled adult patients with R/R DLBCL and performed network meta-analyses (NMA) to assess the efficacy of SC and CAR-T therapies. NMA of SC (6 trials, 7 regimens, n = 1831) indicated that rituximab with gemcitabine, dexamethasone, cisplatin (R-GDP) improved OS and PFS over compared regimens. NMA of 3 CAR-T trials (n = 865) indicated that both axi-cel and liso-cel improved PFS over stand-of-care, with no difference in OS. Our results indicate that R-GDP may be preferred for R/R DLBCL over other SC compared. Longer follow-up is required for ongoing comparative survival analysis as data from CAR-T trials matures.