Clinical and Radiological Correlates of Neurotoxicity after Standard of Care Axicabtagene Ciloleucel in Patients with Relapsed/Refractory Large B-Cell Lymphoma

Tummala, Sudhakar; Nastoupil, Loretta J.; Westin, Jason R.; Fayad, Luis; Ahmed, Sairah; Fowler, Nathan; Hagemeister, F. B.; Lee, Hun Ju; Iyer, Swaminathan Padmanabhan; Nair, Ranjit; Parmar, Simrit; Rodriguez, Maria Alma; Samaniego, Felipe; Steiner, Raphaël; Wang, Michael L.; Pinnix, Chelsea C.; Adkins, Sherry; Claussen, Catherine M.; Martinez, Charles; Hawkins, Misha; Johnson, Nicole; George, Shirley St.; Neelapu, Sattva S.; Chi, Linda

doi:10.1182/blood-2019-125769

Cited by 12 publications

(10 citation statements)

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“…Response was independent of traditional baseline prognostic factors except for the baseline high tumor burden, which was indicated by either an elevated lactate dehydrogenase (LDH) level or high total metabolic tumor volume detected on a positron emission tomography (PET) scan (8). The use of axi-cel resulted in 11.5-fold higher odds of CR and a 73% reduction in the risk of death when compared with standard salvage regimens (9).…”

Section: Axi-cel For Aggressive B-cell Lymphoma Efficacy and Predictomentioning

confidence: 99%

“…Although the characteristics of CRS have been extensively described, CRS's clinical and radiological correlations with neurotoxicity were reported only recently (9). In a retrospective single-center study including 95 patients with relapsed or refractory large B-cell lymphoma treated with axi-cel, 65 patients experienced neurotoxicity.…”

Section: Crs Neurotoxicity and Persistent Cytopeniamentioning

confidence: 99%

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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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Section: Axi-cel For Aggressive B-cell Lymphoma Efficacy and Predictomentioning

confidence: 99%

Section: Crs Neurotoxicity and Persistent Cytopeniamentioning

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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“…A recent study looking at 25 patients (24 with NHL and 1 with B‐ALL) with CAR T‐cell‐related neurotoxicity demonstrated shorter overall survival for patients with grade 3‐4 ICANS 40 . In a large cohort of 95 patients with large B‐cell lymphoma treated with standard of care axicabtagene ciloleucel—ICANS was observed in 65 (68%) of patients 41 . The median day of onset was day 5 post infusion.…”

Section: Immune‐mediated Toxicity After Car T‐cell Therapymentioning

confidence: 99%

“…40 In a large cohort of 95 patients with large B-cell lymphoma treated with standard of care axicabtagene ciloleucel-ICANS was observed in 65 (68%) of patients. 41 The median day of onset was day 5 post infusion. While a CT scan, performed in 48 patients, only showed abnormalities in one (4%), in 26 evaluable MRI scans, 15 (58%) showed abnormal findings.…”

Section: Immune-med Iated Toxicit Y Af Ter C Ar T-cell Ther Apymentioning

confidence: 99%

Prolonged neurotoxicity in a lymphoma patient after CD19‐directed CAR T‐cell therapy: A case report and brief review of the literature

et al. 2020

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Cancer immunotherapy, particularly immune effector cellular therapy directed against tumor, is a major breakthrough in cancer treatment. The commercially approved chimeric antigen receptor (CAR) T-cell products aimed at CD19, a marker of B-cell differentiation, are being increasingly used. 1,2 Long-term response rates for CAR T-cell therapy for non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) are 45%-58% and 17%-50%, respectively, 2-6 and recent studies show promising results in other diseases, such as multiple myeloma and other B-cell malignancies. [7][8][9][10][11][12][13] Immune-directed therapies are becoming more common in cancer care, and the adverse events that result can be serious and at times life-threatening. In a recent study of more than 1000

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“…In addition to the above-mentioned studies, a number of other real-world studies evaluating the efficacy and safety of tisa-cel and axi-cel have been conducted all over the world [16,20,[22][23][24][25][41][42][43][44][45][46]. These studies will help provide further information on the treatment outcomes and clinical practice in the real-world setting.…”

Section: Real-world Evidencementioning

confidence: 99%

A Review of Two Regulatory Approved Anti-CD19 CAR T-Cell Therapies in Diffuse Large B-Cell Lymphoma: Why Are Indirect Treatment Comparisons Not Feasible?

Zhang

et al. 2020

Adv Ther

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Anti-CD19 chimeric antigen receptor (CAR) T-cell therapies can be effective for diffuse large B-cell lymphoma (DLBCL), a cancer with limited treatment options and poor outcomes, particularly for patients with relapsed or refractory (r/r) disease. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CAR T-cell therapies approved by regulatory bodies for certain patients with r/r DLBCL on the basis of demonstrated treatment effects in their pivotal single-arm trials, ZUMA-1 and JULIET, respectively. In the absence of head-to-head trials, the question of whether a valid indirect treatment comparison (ITC) between axi-cel and tisa-cel could be performed using existing evidence is of interest to patients, physicians, payers, and other stakeholders. This article addresses that question by summarizing the current evidence from clinical trials and realworld studies and discussing the challenges and limitations of potential analytical approaches associated with an ITC. Two ITC approaches attempting to adjust for cross-trial heterogeneity between ZUMA-1 and JULIET, matchingadjusted indirect comparison and regressionprediction model analysis, were evaluated. After evaluating the current clinical trial data and real-world evidence, and present and prior ITC analyses of axi-cel and tisa-cel, the authors conclude that a valid comparative analysis is not currently feasible. The substantial differences (e.g., timing of leukapheresis and enrollment, use of bridging chemotherapy [90% in JULIET vs. 0% in ZUMA-1], lymphodepleting regimens) between the two trials' designs and patient populations preclude a robust and reliable ITC. No other approaches are able to account for such differences. The current realworld data are still too immature to be used for ITCs. Thus, drawing conclusions from such ITCs should be avoided to prevent misinforming treatment choices or limiting patient access to effective treatment options. Additional data from ongoing or future real-world studies with appropriate statistical analyses are needed to provide insights into the comparative effectiveness and safety of these two treatments.

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Clinical and Radiological Correlates of Neurotoxicity after Standard of Care Axicabtagene Ciloleucel in Patients with Relapsed/Refractory Large B-Cell Lymphoma

Cited by 12 publications

References 0 publications

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

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

Prolonged neurotoxicity in a lymphoma patient after CD19‐directed CAR T‐cell therapy: A case report and brief review of the literature

A Review of Two Regulatory Approved Anti-CD19 CAR T-Cell Therapies in Diffuse Large B-Cell Lymphoma: Why Are Indirect Treatment Comparisons Not Feasible?

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