Correlative Analyses of Patient and Clinical Characteristics Associated with Efficacy in Tisagenlecleucel-Treated Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients in the Juliet Trial

Westin, Jason R.; Tam, Constantine S.; Borchmann, Peter; Jaeger, Ulrich; McGuirk, Joseph P.; Holte, Harald; Waller, Edmund K.; Jaglowski, Samantha; Bishop, Michael; Andreadis, Charalambos; Foley, Stephen Ronan; Fleury, Isabelle; Ho, P. Joy; Mielke, Stephan; Teshima, Takanori; Schuster, Stephen J.; Bachanová, Veronika; Maziarz, Richard T.; Besien, Koen van; Izutsu, Koji; Kersten, Marie José; Magenau, John; Wagner‐Johnston, Nina D.; Katô, Kôji; Corradini, Paolo; Han, Xiuxin; Tiwari, Ranjan; Agoulnik, Sergei; Eldjerou, Lamis; Pacaud, Lida; Salles, Gilles

doi:10.1182/blood-2019-129107

Cited by 26 publications

(44 citation statements)

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“…The relationships between several biomarkers and efficacy of tisagenlecleucel were assessed in the overall JULIET study, and multivariate analyses identified that the high levels of LDH, a known marker of tumor burden and disease aggressiveness, at pre-infusion were associated with poor efficacy outcomes [12]. In our subgroup analysis, two non-responders and four responders also had high LDH levels at pre-infusion ( Table 1), showing that high levels of LDH at pre-infusion might not necessarily cause insufficient response in Japanese population.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of tisagenlecleucel in Japanese adult patients with relapsed/refractory diffuse large B-cell lymphoma

et al. 2020

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Background Tisagenlecleucel demonstrated a high rate of durable response in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in the pivotal global phase 2 JULIET study. Here, we report the efficacy and safety of tisagenlecleucel in the Japanese subgroup. Methods JULIET (NCT02445248) is a single-arm, open-label, multicenter, phase 2 study involving adult patients with r/r DLBCL who either relapsed after or were ineligible for autologous stem cell transplant. Primary endpoint was best overall response rate (ORR; complete response [CR] + partial response [PR]) as judged by an independent review committee. Results In Japan, of 17 patients enrolled, 9 were infused with tisagenlecleucel and completed ≥ 3 months of follow-up. Best ORR was 77.8% (7/9; 95% confidence interval, 40.0-97.2), with 5 patients (55.6%) in CR and 2 (22.2%) in PR. Cytokine release syndrome (CRS) occurred in 6 patients (66.7%), with grade 3 CRS in 2 patients (Penn grading scale). Two patients received tocilizumab. Two deaths (22.2%) occurred more than 30 days after tisagenlecleucel infusion due to disease progression, neither of which were related to tisagenlecleucel. Conclusion Tisagenlecleucel showed a high best ORR with a manageable safety profile, thus offering a new treatment option in selected Japanese patients with r/r DLBCL.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of tisagenlecleucel in Japanese adult patients with relapsed/refractory diffuse large B-cell lymphoma

et al. 2020

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“…Factors examined have included clinical and laboratory baseline characteristics, and the use and type of bridging therapy and lymphodepleting conditioning. When considering the 115 patients from both cohorts who were infused with tisa-cel and underwent follow-up for at least 3 months, the only baseline characteristic associated with a lower ORR in multivariate analysis was a high pre-infusion LDH level (defined as higher than twice the upper limit of normal), which is a known surrogate marker of disease burden and aggressivity (63). Of these patients, the ORR for the 11 who did not receive bridging therapy was higher than that of patients who did receive bridging therapy (82% vs. 49%), likely reflecting a lower tumor burden and less-aggressive disease in the former group (64).…”

Section: Tisa-cel For Aggressive B-cell Lymphoma Efficacy and Predictmentioning

confidence: 99%

CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences

Vitale

Strati

2020

Front. Oncol.

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Chimeric antigen receptor-modified (CAR) T cells targeting CD19 have revolutionized the treatment of relapsed or refractory aggressive B-cell lymphomas, and their use has increased the cure rate for these cancers from 10 to 40%. Two second-generation anti-CD19 CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for use in patients, and the approval of a third product, lisocabtagene maraleucel, is expected in 2020. The commercial availability of the first two products has facilitated the development of real-world experience in treating relapsed or refractory aggressive B-cell lymphomas, shed light on anti-CD19 CAR T-cell products' feasibility in trial-ineligible patients, and raised the need for strategies to mitigate the adverse effects associated with anti-CD19 CAR T-cell therapy, such as cytokine release syndrome, neurotoxicity, and cytopenia. In addition, promising clinical data supporting the use of anti-CD19 CAR T-cell therapy in patients with indolent B-cell lymphomas or chronic lymphocytic leukemia have recently become available, breaking the paradigm that these conditions are not curable. Multiple clinical CAR T-cell therapy-based trials are ongoing. These include studies comparing CAR T-cell therapy to autologous stem cell transplantation or investigating their use at earlier stages of disease, novel combinations, and novel constructs. Here we provide a thorough review on the use of the anti-CD19 CAR T-cell products axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel in patients with indolent or aggressive B-cell lymphoma or with chronic lymphocytic leukemia, and present novel CAR T cell-based approaches currently under investigation in these disease settings.

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“…In the JULIET trial, it has been reported that preinfusion elevated lactate dehydrogenase (LDH) was associated with poor outcome in patients receiving tisa-cel. 8 In clinical practice, treatment decisions are based on patient factors, including age, comorbidities, and the aggressiveness of the disease. Markers predicting adverse outcome include bulky disease, high IPI, and biological features, such as double/triple-hit cytogenetics or overexpression of MYC and BCL2 proteins.…”

Section: Introductionmentioning

confidence: 99%

Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma

Vercellino¹,

et al. 2020

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Chimeric antigen receptor (CAR) T-cell therapy has emerged as an option for relapsed/refractory aggressive B-cell lymphomas that have failed 2 lines of therapy. Failures usually occur early after infusion. The purpose of our study was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. With a median follow-up of 8.2 months, 55 patients failed treatment; 27 (49%) were early progressors. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 47.2% (95% confidence interval [CI], 38.0-58.6) and 67.0% (95% CI, 57-79), respectively. Univariate analyses for PFS and OS identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, stage III/IV disease, extranodal (EN) sites ≥2, elevated lactate dehydrogenase (LDH), increased C-reactive protein (CRP), high International Prognostic Index at TD and at TT, as well as increased CRP, bulky mass, and high TMTV at TT, as risk factors. Multivariate analyses for PFS, EP, and OS identified elevated LDH and EN sites ≥2 at TD and the same predictors at TT (ie, increased CRP, EN sites ≥2, and TMTV >80 mL). In summary, risk factors identified for early progression at TD and at TT were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).

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Correlative Analyses of Patient and Clinical Characteristics Associated with Efficacy in Tisagenlecleucel-Treated Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients in the Juliet Trial

Cited by 26 publications

References 0 publications

Efficacy and safety of tisagenlecleucel in Japanese adult patients with relapsed/refractory diffuse large B-cell lymphoma

Efficacy and safety of tisagenlecleucel in Japanese adult patients with relapsed/refractory diffuse large B-cell lymphoma

CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences

Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma

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