CD19-DIRECTED CAR T CELL THERAPY (CTL019) FOR RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL AND FOLLICULAR LYMPHOMAS: FOUR YEAR OUTCOMES

2019 ◽  
Vol 37 ◽  
pp. 137-138 ◽  
Author(s):  
E.A. Chong ◽  
J. Svoboda ◽  
S.D. Nasta ◽  
D.J. Landsburg ◽  
N. Winchell ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Follicular Lymphomas ◽  
Large B Cell

scholarly journals Safety and efficacy of axicabtagene ciloleucel in refractory large B-cell lymphomas

2020 ◽  
Vol 11 ◽  
pp. 204062072090289 ◽  
Author(s):  
Peter A. Riedell ◽  
Michael R. Bishop
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Large B Cell

Aggressive large B-cell lymphomas represent a diverse population of diseases that are typically treated with anti-CD20 based immunochemotherapy. While this treatment is effective for a large proportion of patients, those that become refractory to induction therapy or experience disease relapse suffer an inferior overall prognosis, and novel treatment options are needed. Adoptive T-cell immunotherapy in the form of chimeric antigen receptor (CAR) T-cell therapy is one of the most revolutionary breakthroughs in the past several decades for the treatment of relapsed/refractory aggressive large B-cell lymphomas. Based on data from the pivotal ZUMA-1 study, axicabtagene ciloleucel (axi-cel) became the first-in-class anti-CD19 directed CAR T-cell therapy approved for patients with diffuse large B-cell lymphoma and other aggressive B-cell lymphoma variants. In this review, we provide an overview of CAR T-cell therapy, including its biology, manufacturing, and treatment course. In addition, we highlight the available efficacy data, review pertinent safety concerns, including cytokine release syndrome and neurologic toxicity, as well as provide an overview of emerging therapeutic strategies in the cellular therapy arena.

scholarly journals Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas

2021 ◽  
Vol 5 (13) ◽  
pp. 2707-2716
Author(s):  
Nora Liebers ◽  
Johannes Duell ◽  
Donnacha Fitzgerald ◽  
Andrea Kerkhoff ◽  
Daniel Noerenberg ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Overall Response ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Large B Cell

The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.

scholarly journals Axicabtagene ciloleucel for relapsed or refractory lymphoma after prior treatment with a different CD19-directed CAR T-cell therapy

2020 ◽  
Vol 4 (19) ◽  
pp. 4869-4872 ◽  
Author(s):  
Victor A. Chow ◽  
Ajay K. Gopal ◽  
Jordan Gauthier ◽  
Yolanda D. Tseng ◽  
Cameron J. Turtle ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Key Points ◽  
Car T ◽  
Refractory Lymphoma ◽  
Large B Cell

Key Points No meaningful responses were observed when axicabtagene ciloleucel was used for progression after a different CD19-directed CAR T cell. Further research is needed to understand how to sequence cell-based therapies for relapsed/refractory large B-cell lymphomas.

scholarly journals Outcomes of Patients with Large B-Cell Lymphomas and Progressive Disease Following CD19-Specific CAR T-Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 94-94 ◽  
Author(s):  
Victor A. Chow ◽  
Ajay K. Gopal ◽  
David G. Maloney ◽  
Cameron J. Turtle ◽  
Stephen D. Smith ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Research Funding ◽  
T Cell Therapy ◽  
Allogeneic Hsct ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Large B Cell

Abstract BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T-cell therapy has proven to be highly effective in patients with relapsed or refractory large B-cell lymphomas, yielding early complete response (CR) rates of ~40%, which are typically sustained. Unfortunately, most patients will not experience prolonged disease control. Despite this fact, little data exist defining the outcomes and impact of subsequent therapies for such individuals. Limited data also exist on the ability for such patients to pursue further clinical trials or allogeneic hematopoietic stem-cell transplant (HSCT). This project details the specific interventions and outcomes of this population to better inform the management of patients who suffer progressive disease (PD) after CD19-specific CAR T-cell therapy. METHODS: Adults with diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), and high-grade B-cell lymphomas (HGBCL) who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included in this analysis. Patients who received CAR T-cell therapy in conjunction with additional protocol-specified therapy were excluded. Those who exhibited PD or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined initial PD as patients who had evidence of disease progression on the initial response assessment. Delayed PD was defined as achieving a CR, partial response (PR), or stable disease (SD) on the initial response assessment, but eventually progressed or received subsequent anti-lymphoma therapy. Baseline characteristics and all data were retrieved from the electronic medical record up until date of death or date of last contact in our system, including subsequent interventions and outcomes. Primary endpoint of this analysis was overall survival (OS). RESULTS: Between October 2013 and May 2018, we identified 51 patients with PD following CD19-specific CAR T-cell therapy. Baseline characteristics are listed in the Table 1. Histologies included DLBCL (29), HGBCL (11), tFL (8) and PMBCL (3). Median age was 60 years (range 26-75), 65% were male, median prior regimens was 3 (range 1-8). Median time from CAR T infusion to PD was 42 days (range 11-609), with 27 (53%) patients exhibiting initial PD. Median follow up after time of progression was 4.2 months. Initial PD was associated with a higher risk of death (HR 2.376, 95% CI 1.19-4.75, p=0.0143, Figure 1). The median OS for those with initial PD and delayed PD was 5.1 months (95% CI 2.0-9.3) and 13.6 months (4.1-not reached) respectively. 39 (76%) patients received ≥ 1 subsequent therapies after PD. Initial therapies included: 2nd CAR T infusion (14), targeted therapy (10), chemotherapy +/- rituximab (7), other immunotherapy (3), radiotherapy (3), intrathecal chemotherapy (1) and allogeneic HSCT (1). 12 (24%) patients received no further therapy despite PD. Those who received ≥ 1 subsequent therapies after PD had a lower risk of death (HR 0.344, 95% CI 0.149-0.793, P=0.0122) compared to those who did not. There was no difference in survival if 2nd CAR T infusion was the next line therapy compared to others (p=0.449), targeted therapy compared to others (p=0.417), or chemotherapy compared to others (p=0.565). 5 (10%) patients enrolled onto a clinical trial as next line therapy. 4 (8%) patients eventually received an allogeneic HSCT after PD, 2 of whom are still alive. We identified 8 patients who were alive for ≥ 12 months after progression without evidence of lymphoma. Last line of therapy for these patients included allogeneic HSCT (2), subsequent CD19-specific CAR-T cell infusion (2), ibrutinib (2), lenalidomide/rituximab (1), and radiotherapy (1). CONCLUSIONS: Patients with PD post anti-CD19 CAR T-cell therapy, particularly those exhibiting initial PD, have poor long-term outcomes. Patients receiving at least one anti-lymphoma therapy after PD had improved overall survival, although no single approach appeared to confer a survival benefit. Few enrolled onto a clinical trial or received an allogeneic HSCT. These data reinforce the need to both further improve the durable CR rate after CAR T-cell therapy and to develop effective strategies for those not achieving a CR. Figure 1 Figure 1. Disclosures Gopal: Spectrum: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Brim: Consultancy; Janssen: Consultancy, Research Funding; Asana: Consultancy; Gilead: Consultancy, Research Funding; Aptevo: Consultancy; Incyte: Consultancy; Teva: Research Funding. Maloney:Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding. Turtle:Caribou Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Bluebird Bio: Consultancy; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptevo: Consultancy; Gilead: Consultancy. Smith:Genentech: Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Shadman:TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy; Verastem: Consultancy; Gilead Sciences: Research Funding; AbbVie: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Celgene: Research Funding. Cassaday:Seattle Genetics: Other: Spouse Employment, Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Lynch:Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding.

scholarly journals Outcomes of patients with large B‐cell lymphomas and progressive disease following CD19‐specific CAR T‐cell therapy

2019 ◽  
Vol 94 (8) ◽  
Author(s):  
Victor A. Chow ◽  
Ajay K. Gopal ◽  
David G. Maloney ◽  
Cameron J. Turtle ◽  
Stephen D. Smith ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Progressive Disease ◽  
B Cell Lymphomas ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Large B Cell

scholarly journals Efficacy and safety of CD22 chimeric antigen receptor (CAR) T cell therapy in patients with B cell malignancies: a protocol for a systematic review and meta-analysis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Komal Adeel ◽  
Nathan J. Fergusson ◽  
Risa Shorr ◽  
Harold Atkins ◽  
Kevin A. Hay
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
B Cell Malignancies ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Background Chimeric antigen receptor (CAR) T cell therapy has had great success in treating patients with relapsed or refractory B cell malignancies, with CD19-targeting therapies now approved in many countries. However, a subset of patients fails to respond or relapse after CD19 CAR T cell therapy, in part due to antigen loss, which has prompted the search for alternative antigen targets. CD22 is another antigen found on the surface of B cells. CARs targeting CD22 alone or in combination with other antigens have been investigated in several pre-clinical and clinical trials. Given the heterogeneity and small size of CAR T cell therapy clinical trials, systematic reviews are needed to evaluate their efficacy and safety. Here, we propose a systematic review of CAR T cell therapies targeting CD22, alone or in combination with other antigen targets, in B cell malignancies. Methods We will perform a systematic search of EMBASE, MEDLINE, Web of Science, Cochrane Register of Controlled Trials, clinicaltrials.gov, and the International Clinical Trials Registry Platform. Ongoing and completed clinical trials will be identified and cataloged. Interventional studies investigating CD22 CAR T cells, including various multi-antigen targeting approaches, in patients with relapsed or refractory B cell malignancies will be eligible for inclusion. Only full-text articles, conference abstracts, letters, and case reports will be considered. Our primary outcome will be a complete response, defined as absence of detectable cancer. Secondary outcomes will include adverse events, overall response, minimal residual disease, and relapse, among others. Quality assessment will be performed using a modified Institute of Health Economics tool designed for interventional single-arm studies. We will report a narrative synthesis of clinical studies, presented in tabular format. If appropriate, a meta-analysis will be performed using a random effects model to synthesize results. Discussion The results of the proposed review will help inform clinicians, patients, and other stakeholders of the risks and benefits of CD22 CAR T cell therapies. It will identify gaps or inconsistencies in outcome reporting and help to guide future clinical trials investigating CAR T cells. Systematic review registration PROSPERO registration number: CRD42020193027

scholarly journals Influence of TP53 Mutation on Survival of Diffuse Large B-Cell Lymphoma in the CAR T-Cell Era

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5592
Author(s):  
Edit Porpaczy ◽  
Philipp Wohlfarth ◽  
Oliver Königsbrügge ◽  
Werner Rabitsch ◽  
Cathrin Skrabs ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Tp53 Mutation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Refractory/relapsed diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The clinical behavior and genetic landscape of DLBCL is heterogeneous and still not fully understood. TP53 mutations in DLBCL have been identified as markers of poor prognosis and are often associated with therapeutic resistance. Chimeric antigen receptor T-cell therapy is an innovative therapeutic concept and represents a game-changing therapeutic option by supporting the patient’s own immune system to kill the tumor cells. We investigated the impact of TP53 mutations on the overall survival of refractory/relapsed DLBCL patients treated with comparable numbers of therapy lines. The minimum number of therapy lines was 2 (median 4), including either anti-CD19 CAR T-cell therapy or conventional salvage therapy. A total of 170 patients with DLBCL and high-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements (DHL/THL), diagnosed and treated in our hospital between 2000 and 2021, were included. Twenty-nine of them received CAR T-cell therapy. TP53 mutations were found in 10/29 (35%) and 31/141 (22%) of patients in the CAR T-cell and conventional groups, respectively. Among the 141 patients not treated with CAR T cells, TP53 mutation was an independent prognostic factor for overall survival (OS) (median 12 months with TP53 vs. not reached without TP53 mutation, p < 0.005), but in the CAR T cell treated group, this significance could not be shown (median OS 30 vs. 120 months, p = 0.263). The findings from this monocentric retrospective study indicate that TP53 mutation status does not seem to affect outcomes in DLBCL patients treated with CAR T-cell therapy. Detailed evaluation in large cohorts is warranted.

scholarly journals Fludarabine Exposure Predicts Outcome after CD19 CAR T Cell Therapy in Children and Young Adults with Acute Leukemia; An Exploratory, Observational Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3871-3871
Author(s):  
Linde Dekker ◽  
Friso Calkoen ◽  
Yilin Jiang ◽  
Hilly Blok ◽  
Maike Spoon ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Outcome ◽  
Cell Therapy ◽  
B Cell ◽  
T Cell Therapy ◽  
Free Survival ◽  
Cell Numbers ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract The addition of fludarabine to cyclophosphamide as lymphodepleting regimen prior to adoptive transfer of CD19 chimeric antigen receptor (CAR) T cells significantly improves CAR T cell expansion and correlates with longer B cell aplasia and a decreased probability of developing a CD19+ relapse (Gardner, 2017). Dosing of fludarabine is currently based on body surface area. We previously showed that this leads to a highly variable plasma exposure that correlates with clinical outcome after allogeneic hematopoietic cell transplantation (Langenhorst, 2019). We therefore hypothesized that optimal exposure of fludarabine might be of clinical importance in the CD19 CAR T setting. An observational cohort analysis was conducted with data from 26 consecutive patients receiving tisagenlecleucel as treatment for refractory/relapsed B cell acute lymphoblastic leukemia (B-ALL; table 1). Prior to CAR T cell infusion, patients received fludarabine on 4 consecutive days at a daily dosage of 30 mg/m 2 and cyclophosphamide on 2 consecutive days at a daily dosage of 500 mg/m 2. Fludarabine concentrations were measured longitudinally after fludarabine infusion using a liquid chromatography mass spectrometry method. The total exposure (Area Under the Curve (AUC 0−∞)) was subsequently determined using a fludarabine population pharmacokinetic model (Langenhorst, 2019). The study was performed in accordance with the Declaration of Helsinki. The primary outcome parameter was leukemia free survival, defined as the time between CAR19 T cell infusion and the moment of measurable leukemic blasts (&gt;5% or &gt;0.01% by two subsequent measurements). The effect of fludarabine on leukemia free survival and the secondary outcome measures CD19+ relapse and B cell aplasia were explored using martingale residuals and further identified by fitting univariable Cox Proportional Hazards models. In addition, Kaplan Meier and cumulative incidence curves were plotted and compared with log-rank tests. To compare CAR T cell numbers over time in peripheral blood, the AUCs were computed and compared between exposure groups with the Mann-Whitney test. Analyses were performed using R4.03 with packages pknca, survival and survminer. The fludarabine AUC 0−∞ was highly variable, resulting in a large range of 8.7-21.8 mg*h/L. Exposure of fludarabine was shown to be a predictor for leukemia free survival, B cell aplasia, and CD19+ relapse following CAR T cell infusion. Minimal event probability was observed at a cumulative fludarabine exposure ≥14 mg*h/L and underexposure was therefore defined as an AUC 0−∞ &lt;14 mg*h/L. In the underexposed group, leukemia free survival was lower (p&lt;0.001; Figure 1A) and the occurrence of CD19+ relapse was higher (p&lt;0.0001; figure 1B) compared to the group with an AUC 0−∞ ≥14 mg*h/L. Furthermore, the duration of B cell aplasia was shorter (p=0.009) and the AUCs of CAR T cell numbers lower (p=0.03) in the underexposed group. No significant differences in baseline characteristics were present between the two exposure groups. To our knowledge, this is the first study describing the effect of fludarabine exposure on outcome in a cohort of paediatric and young adults receiving CD19 CAR T cell therapy as treatment for B-ALL. These preliminary results suggest that optimizing fludarabine exposure may have a relevant impact on leukemia free survival following CAR T cell therapy. However, it should be noted that multivariate regression models are needed to show consistency of the relationship between fludarabine exposure and outcome. The limited number of patients did not allow for inclusion of potential covariates that may influence clinical outcome into the analysis. Therefore, our results need to be confirmed in a larger cohort. In conclusion, clinical outcome in patients receiving CAR19 T cell therapy might be improved by the optimization of fludarabine exposure in the lymphodepleting regimen. LD and FC contributed equally to this study. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document