scholarly journals Proton Therapy as a Bridging Treatment in CAR T-Cell Therapy for Relapsed and Refractory Large B-Cell Lymphoma: Is There a Role?

2020 ◽  
Vol 7 (1) ◽  
pp. 13-20
Author(s):  
Omran Saifi ◽  
Mohamed A. Kharfan-Dabaja ◽  
Youssef H. Zeidan ◽  
Jennifer Peterson ◽  
William G. Rule ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Proton Therapy ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Since the relapse rate of DLBCL to frontline chemoimmunotherapy and salvage autologous hematopoietic cell transplant is high, CD19-directed chimeric antigen receptor (CAR) T-cell therapy was adopted. Given the time interval needed for CAR T cells to be manufactured (3-5 weeks) and the aggressiveness of these relapsed/refractory lymphomas, some patients do not make it to the CAR T-cell infusion phase. This calls for a bridging therapy to control, debulk, and sensitize the disease during this period. Radiation therapy can serve this purpose and has shown promising results in some studies. Proton therapy, compared to standard radiation therapy, in some locations, can reduce the radiation dose to the organs at risk, which may lead to fewer side effects for patients with lymphomas. Thus, we hypothesize that proton therapy may serve as a promising bridging strategy to CAR T-cell therapy for some patients.

scholarly journals Axicabtagene Ciloleucel: Clinical Data for the Use of CAR T-cell Therapy in Relapsed and Refractory Large B-cell Lymphoma

2020 ◽  
pp. 106002802094423
Author(s):  
Zachery Halford ◽  
Mary Kate Anderson ◽  
Lunawati L. Bennett
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Objective: To evaluate the literature for axicabtagene ciloleucel (axi-cel), a first-in-class chimeric antigen receptor (CAR) T-cell therapy, in the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Data Sources: We conducted a PubMed (inception to June 22, 2020) and ClinicalTrials.gov search using the following terms: CD19, chimeric antigen receptor, and lymphoma. Study Selection and Data Extraction: All retrospective and prospective studies evaluating the use of axi-cel in LBCL were reviewed. Data Synthesis: In the pivotal ZUMA-1 trial, axi-cel exhibited unprecedented overall and complete response rates of 83% and 58%, respectively. With a median follow-up of 27.1 months, 39% of patients had ongoing responses. Furthermore, postmarketing retrospective analyses found similar response rates in a more clinically diverse LBCL patient population. Novel CAR T-cell therapy elicits unique and potentially life-threatening toxicities that include cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Studies reported grade ≥3 CRS in 7% to 14% of patients and grade ≥3 ICANS in 31% to 55% of patients. Relevance to Patient Care and Clinical Practice: Axi-cel was the first US Food and Drug Administration–approved genetically engineered autologous CAR T-cell agent in r/r LBCL, representing an important milestone and paradigm shift in cancer treatment. Adoptive T-cell immunotherapy is a breakthrough treatment modality requiring careful patient selection, multidisciplinary collaboration, comprehensive patient counseling, and expert training to ensure optimal treatment. Conclusions: The initial and ongoing results with axi-cel are encouraging, but long-term safety and efficacy data are lacking. Additional studies are required to identify axi-cel’s ideal place in LBCL therapy.

scholarly journals P07.01 CD19 CAR T-cells for relapsed/refractory diffuse large B-cell Lymphoma: real-world data from LMU Munich

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A48.2-A49
Author(s):  
V Bücklein ◽  
V Blumenberg ◽  
C Schmidt ◽  
K Rejeski ◽  
M Ruzicka ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Heavily Pretreated

BackgroundThe anti-CD19 CAR T-cell products Axicabtagene Ciloleucel (Axi-cel) and Tisagenlecleucel have been approved by the EMA for the treatment of patients (pts) with relapse/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in August 2018. In clinical trials, both cell products induced ongoing complete responses in heavily pretreated patients. However, this activity was associated with significant toxicity. We evaluated the outcomes of DLBCL pts treated with Axi-cel and Tisagenlecleucel at the LMU Munich.Materials and MethodsCAR T cell product characteristics, toxicity and response rates of pts treated at our center between January and October 2019 were retrospectively assessed.ResultsAs of October 2019, 24 out of 34 r/r DLBCL pts (71%) with confirmed CAR T cell treatment indication were leukapheresed. Four apheresed pts died before CAR T cell therapy due to rapidly progressive disease. So far, 17 DLBCL pts have been treated. Median age was 60 years (range 19–74). ECOG was 0–1 in eleven, and 2–3 in six pts. Eight pts had undergone prior stem cell transplant (6 autologous, 2 allogeneic SCT). 13 pts received bridging chemotherapy between leukapheresis and CAR T cell transfusion. Only 6 (35%) of the 17 transfused pts would have met the inclusion criteria of the pivotal clinical trials (JULIET, ZUMA-1).CRS occurred in all pts (53% CRS °1, 29% °2 and 18% °3) with a median onset on day 2 (range days 0–7) and a median duration of 4 days (range 1–21). Tocilizumab was administered at least once in all pts. Ten pts (59%) experienced Immune Effector Cell associated Neurotoxicity Syndrome (ICANS, 30% °1, 10% °2, 30% °3, 20% °4 and 10% °5) with a median onset between day 7 and 8 and a median duration of 8 days (range 3–49). Cytopenia was significant following CAR T-cell treatment: all but one pts had neutropenia <500/µl for more than seven days.Response assessment four weeks after CAR T-cell transfusion was available for 15 pts.Objective response rate (ORR) at this early follow-up was 67%, with complete remission (CR) in four (27%) and partial remission (PR) in six pts (40%). Interestingly, ORR was higher in the four pts not receiving bridging chemotherapy between leukapheresis and CAR T-cell therapy than in pts in which bridging was applied (100% vs. 55%). Responders had significantly higher LDH levels at apheresis, start of lymphodepletion and CAR T-cell transfusion than non-responders.ConclusionsSince January 2019, the CAR T cell program has been successfully initiated at the LMU Munich, and 17 r/r DLBCL pts have been treated at our center to date. CAR T cells induced responses in heavily pretreated pts with response rates within the expected range. Toxicity was significant but manageable in most pts. Involvement of a multidisciplinary ImmunoTaskforce was a key element for adequate patient care. Preliminary data supports the hypothesis that low tumor dynamics are associated with favorable outcomes of CD19 CAR T cell therapy.Disclosure InformationV. Bücklein: None. V. Blumenberg: None. C. Schmidt: None. K. Rejeski: None. M. Ruzicka: None. N. Müller: None. A. Reischer: None. L. von Baumgarten: None. A. Völkl: None. B. Wagner: None. A. Humpe: None. J. Tischer: None. H. Stemmler: None. M. von Bergwelt: None. M. Subklewe: None.

scholarly journals Prognostic Impact of Corticosteroids on Efficacy of Chimeric Antigen Receptor T-cell Therapy in Large B-cell Lymphoma

Blood ◽  
2021 ◽  
Author(s):  
Paolo Strati ◽  
Sairah Ahmed ◽  
Fateeha Furqan ◽  
Luis E. Fayad ◽  
Hun Ju Lee ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Corticosteroid Treatment ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T

Corticosteroids are commonly used for the management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether their dose, duration, and timing may impact clinical efficacy. Here, we determined the impact of corticosteroids on clinical outcomes in patients with relapsed or refractory large B-cell lymphoma treated with standard of care anti-CD19 CAR T-cell therapy. Among 100 patients evaluated, 60 (60%) received corticosteroids for management of CAR T-cell therapy-associated toxicities. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803 mg) and the median duration of corticosteroid treatment was 9 days (range 1-30). Corticosteroid treatment was started between days 0 and 7 in 45 (75%) patients and beyond day 7 in 15 (25%). After a median follow-up of 10 months (95% CI 8-12 months), use of higher cumulative dose of corticosteroids was associated with significantly shorter progression-free survival. More importantly, higher cumulative dose of corticosteroids, and prolonged and early use after CAR T-cell infusion were associated with significantly shorter overall survival. These results suggest that corticosteroids should be used at the lowest dose and for the shortest duration and their initiation should be delayed whenever clinically feasible, while managing CAR T-cell therapy-associated toxicities.

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 Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma

2020 ◽  
Vol 4 (19) ◽  
pp. 4898-4911 ◽  
Author(s):  
Frederick L. Locke ◽  
John M. Rossi ◽  
Sattva S. Neelapu ◽  
Caron A. Jacobson ◽  
David B. Miklos ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Burden ◽  
Durable Response ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T

Abstract ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.

CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Author(s):  
John H Baird ◽  
Matthew Joshua Frank ◽  
Juliana Craig ◽  
Shabnum Patel ◽  
Jay Y Spiegel ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dose Escalation Study ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Large B Cell

The prognosis for patients with large B-cell lymphoma (LBCL) progressing after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first three consecutive patients with autologous CAR19-refractory LBCL treated with a single infusion of autologous 1×106 CAR+ T-cells/kg targeting CD22 (CAR22) as part of a phase I dose escalation study. CAR22 therapy was relatively well tolerated, without any observed non-hematologic adverse events higher than grade 2. Following infusion, all three patients achieved complete remission, with all responses ongoing at the time of last follow up (mean 7.8 months, range 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range 85.4-350 cells/µL), and persisted beyond three months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA (ctDNA) beyond six months post-infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients who have failed prior CAR T-cell therapies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT04088890)

scholarly journals Impact of Increasing Wait Times on Overall Mortality of Chimeric Antigen Receptor T-Cell Therapy in Large B-Cell Lymphoma: A Discrete Event Simulation Model

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Stephen Tully ◽  
Zeny Feng ◽  
Kelly Grindrod ◽  
Tom McFarlane ◽  
Kelvin K.W. Chan ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
Wait Times ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Large B Cell

PURPOSE The development of chimeric antigen receptor (CAR) T cells has transformed oncology treatment, with the potential to cure certain cancers. Although shown to be effective in selected populations and studies, CAR T-cell technology requires considerable health care resources, which may lead to additional wait times to access this type of treatment in future. The objective of our study was to estimate the potential impact of increasing wait times on CAR T-cell therapy effectiveness compared with standard chemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma. METHODS A health system–level discrete event simulation model was developed to project the potential impact of wait times on CAR T-cell therapy for patients with relapsed/refractory diffuse large B-cell lymphoma. Waiting queues and health states related to treatment and clinical progression were implemented. Using data from the literature, we evaluated nine scenarios of using CAR T-cell therapy with wait times ranging from 1 to 9 months. The outcome of interest was 1-year all-cause mortality. RESULTS Increasing the wait time of receiving CAR T-cell therapy from 1 to 9 months increased the predicted 1-year mortality rate from 36.1% to 76.3%. Baseline 1-year mortality was 34.0% in patients receiving CAR T-cell therapy with no wait times and 75.1% in patients treated with chemotherapy. This resulted in an increased relative mortality rate of 6.2% to 124.5% over a 1- to 9-month wait time compared with no wait time. CONCLUSION We found that modest delays in CAR T-cell therapy significantly hinder its effectiveness. Because CAR T-cell therapy offers a potential cure, it is expected that the uptake rate will be substantially increased once the therapy is regularly funded by a health care system. Wait times may be prolonged if system resource availability does not match the demand. Strategies must be developed to minimize the impact of delays and reduce complications during waiting.

Sign in / Sign up

Export Citation Format

Share Document