scholarly journals Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel–treated patients in the TRANSCEND NHL 001 trial

2021 ◽  
Vol 5 (6) ◽  
pp. 1695-1705
Author(s):  
Jeremy S. Abramson ◽  
Tanya Siddiqi ◽  
Jacob Garcia ◽  
Christine Dehner ◽  
Yeonhee Kim ◽  
...  
Keyword(s):  
Health Care ◽  
T Cell ◽  
B Cell Lymphoma ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
System Perspective ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Chimeric antigen receptor (CAR) T-cell therapies have demonstrated high response rates in patients with relapsed/refractory large B-cell lymphoma (LBCL); however, these therapies are associated with 2 CAR T cell–specific potentially severe adverse events (AEs): cytokine release syndrome (CRS) and neurological events (NEs). This study estimated the management costs associated with CRS/NEs among patients with relapsed/refractory LBCL using data from the pivotal TRANSCEND NHL 001 trial of lisocabtagene maraleucel, an investigational CD19-directed defined composition CAR T-cell product with a 4-1BB costimulation domain administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This retrospective analysis of patients from TRANSCEND with prospectively identified CRS and/or NE episodes examined relevant trial-observed health care resource utilization (HCRU) associated with toxicity management based on the severity of the event from the health care system perspective. Cost estimates for this analysis were taken from publicly available databases and published literature. Of 268 treated patients as of April 2019, 127 (47.4%) experienced all-grade CRS and/or NEs, which were predominantly grade ≤2 (77.2%). Median total AE management costs ranged from $1930 (grade 1 NE) to $177 343 (concurrent grade ≥3 CRS and NE). Key drivers of cost were facility expenses, including intensive care unit and other inpatient hospitalization lengths of stay. HCRU and costs were significantly greater among patients with grade ≥3 AEs (22.8%). Therefore, CAR T-cell therapies with a low incidence of severe CRS/NEs will likely reduce HCRU and costs associated with managing patients receiving CAR T-cell therapy. This clinical trial was registered at www.clinicaltrials.gov as #NCT02631044.

scholarly journals Clinical Presentation, Management and Biomarkers of Cytokine Release Syndrome after Anti-CD19 CART-Cell Therapy for r/r ALL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5625-5625
Author(s):  
Ping Li ◽  
Lili Zhou ◽  
Shiguang Ye ◽  
Shaoguang Li ◽  
Aibin Liang
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Clinical Presentation ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a novel treatment modality for B-cell malignancies. CD19-specific CAR-T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL). However, cytokine release syndrome (CRS) is the most common and severe toxicities of CAR T-cell therapy for ALL, and clinical experience is limited. Here, we describe the clinical presentation and management of 30 patients who presented with CRS following CAR-T cell therapy for relapsed/refractory ALL at our hospital. 12 of the 30 patients (40%) developed grade 1-2 CRS, 14 patients (46.7%) presented with grade 3-4 CRS and 2 patients (6.7%) died of grade 5 CRS. Compared with grade 1-2 CRS, grade 3-4 CRS correlated negatively with overall survival and progression-free survival (P =0.02). We found that higher ferritin levels and percentages of CD19 positive cells in blood lymphocytes cells at time of CAR-T cell infusion were associated with more severe CRS. Grade 3-4 neurotoxicity was frequently present in patients with grade ≧3 CRS. We also observed that the organ disfunctions occurred in sequence after fever onset during the period of CRS. Neurotoxicity, cardiovascular disfunction and cytopenia in some patients manifest as biphasic. Compared to use of tocilizumab for CRS ≧ grade 3, early intervention of tocilizumab for hyperpyrexia duration ≧ 6h alleviates the severity of CRS, and no patients died of severe CRS since this management approach was performed. As use of novel CAR-T cell therapy expands, the data from our clinical experience may help others anticipated the clinical course of organ function and manage CRS in CAR-T therapy. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Anakinra Targeting Cytokine Release Syndrome Associated with Chimeric Antigen Receptor T-Cell Therapies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2812-2812
Author(s):  
Sandy W. Wong ◽  
Shambavi Richard ◽  
Yi Lin ◽  
Deepu Madduri ◽  
Carolyn C. Jackson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Receptor Antagonist ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T

Abstract Introduction: Cytokine release syndrome (CRS) is a common toxicity associated with chimeric antigen receptor (CAR) T-cell therapies. Corticosteroids and steroid-sparing therapies such as tocilizumab, an interleukin-6 receptor antagonist, and anakinra, an interleukin-1 receptor antagonist, have been used to reduce the incidence and severity of these toxicities. Preclinical and clinical case studies of anakinra, administered subcutaneously or intravenously at various doses, have shown promising results in the management of CRS and systemic inflammatory responses resembling hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS). In CARTITUDE-1, CRS occurred in 95% of heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) receiving ciltacabtagene autoleucel (cilta-cel), a CAR T-cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies (Berdeja et al. Lancet 2021). Per protocol, tocilizumab was required to manage CRS with option to give steroids and/or anakinra per investigator discretion. Here, we report the institutional experiences of anakinra use in the management of CRS in patients who have received cilta-cel as part of the CARTITUDE-1 study. Methods: Eligible patients had MM and received ≥3 prior therapies or were refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody (Berdeja et al. Lancet 2021). After apheresis, bridging therapy was permitted. Patients received a single cilta-cel infusion (target dose: 0.75×10 6 CAR+ viable T cells/kg; range 0.5-1.0×10 6) 5-7 days after lymphodepletion (300 mg/m 2 cyclophosphamide, 30 mg/m 2 fludarabine daily for 3 days). Lee et al (Blood 2014) grading criteria for CRS were mapped to the ASTCT criteria for CRS. Post-hoc analysis of data revealed use of anakinra at some sites in patients who failed to respond to the initial management of CRS with tocilizumab +/- dexamethasone or in clinical settings where rise of ferritin and/or liver function tests were indicative for continued HLH/MAS-like manifestations (Kennedy et al. ASH 2020). Results: Of 97 patients in CARTITUDE-1, CRS occurred in 92 (95%) patients; 4% were grade 3/4. The median time to onset was 7 days (range 1-12) and median duration was 4 days (range 1-14). Supportive measures to treat CRS were administered to 91% of patients, most commonly tocilizumab (69%; 4 patients received ≥3 doses), corticosteroids (22%), and anakinra (18 patients, 19%). CRS resolved in 99% of patients. Anakinra was administered after initial tocilizumab and within the first 48 hours (range 0-6 days) of CRS onset for the majority of patients as part of effective management of CRS. Anakinra was administered at a dose of 100-200 mg every 8-12 hours over a median of 2.5 days (range 1-15 days). CRS uniformly resolved following anakinra use in CARTITUDE-1, apart from one patient who died from sepsis (grade 5 outcome) due to HLH/MAS considered related to treatment (Table). Conclusions: CRS events in cilta-cel-treated patients in CARTITUDE-1 were common, generally low-grade, and successfully managed with standard tocilizumab +/- dexamethasone. The use of anakinra should be considered in patients with persistent CRS/inflammatory symptoms despite tocilizumab use, and in particular in patients with HLH/MAS-like symptoms/phenotype occurring following CRS or in the absence of prior CRS. Figure 1 Figure 1. Disclosures Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Richard: Karyopharm, Janssen: Honoraria. Lin: Juno: Consultancy; Legend: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy. Madduri: Janssen: Current Employment. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Zudaire: Janssen: Current Employment. Romanov: Janssen: Current Employment. Trigg: Janssen: Current Employment. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Garrett: Legend Biotech USA: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Martin: Oncopeptides: Consultancy; Sanofi: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved

scholarly journals Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies

2020 ◽  
Vol 8 (2) ◽  
pp. e001159 ◽  
Author(s):  
Haneen Shalabi ◽  
Vandana Sachdev ◽  
Amita Kulshreshtha ◽  
Julia W Cohen ◽  
Bonnie Yates ◽  
...  
Keyword(s):  
Young Adults ◽  
T Cell ◽  
Cardiac Dysfunction ◽  
Cardiac Toxicity ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cell ◽  
Car T ◽  
Children And Young Adults ◽  
Grade 3

BackgroundChimeric antigen receptor (CAR) T-cell-associated cytokine release syndrome (CRS) may present with tachycardia, hemodynamic instability and reduced cardiac function. Pediatric CAR studies examining cardiac toxicity are limited.MethodsWe report on cardiac toxicity observed in children and young adults with hematologic malignancies enrolled in a CD19-28ζ CAR T-cell phase I trial (NCT01593696). All patients had a formal baseline echocardiogram. Real-time studies included echocardiograms on intensive care unit (ICU) transfer, and serial troponin and pro-B-type natriuretic peptide (pro-BNP) in the select patients.ResultsFrom July 2012 to March 2016, 52 patients, with a median age of 13.4 years (range 4.2–30.3) were treated. CRS developed in 37/52 (71%), which was grade 3–4 CRS in nine patients (17%). The median prior anthracycline exposure was 205 mg/m2 (range 70–620 mg/m2) in doxorubicin equivalents. The median baseline left ventricle ejection fraction (LVEF) and baseline LV global longitudinal strain (GLS) were 60% (range 50%–70%) and 16.8% (range 14.1%–23.5%, n=37) respectively. The majority, 78% (29/37), of patients had a reduced GLS <19% at baseline, and 6% (3/52) of patients had baseline LVEF <53%. ICU transfers occurred in 21 patients, with nine requiring vasoactive hemodynamic support and three necessitating >1 vasopressor. Six (12%) patients developed cardiac dysfunction (defined by >10% absolute decrease in LVEF or new-onset grade 2 or higher LV dysfunction, per CTCAE v4), among whom 4 had grade 3–4 CRS. Troponin elevations were seen in 4 of 13 patients, all of whom had low LVEF. Pro-BNP was elevated from baseline in 6/7 patients at the onset of CRS, with higher levels correlating with more severe CRS. Cardiac dysfunction fully resolved in all but two patients by day 28 post-CAR.ConclusionCardiac toxicity related to CD19-28ζ CAR T-cell-associated CRS was generally reversible by day 28 postinfusion. Implementation of more frequent monitoring with formal echocardiograms incorporating systemic analysis of changes in GLS, and cardiac biomarkers (troponin and proBNP) may help to earlier identify those patients at highest risk of severe cardiac systolic dysfunction, facilitating earlier interventions for CRS to potentially mitigate acute cardiac toxicity.

Health care resource utilization (HCRU) and total costs of care (TCOC) among patients (pts) with diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor (CAR) T-cell therapies in the United States: An analysis of four claims databases.

2020 ◽  
Vol 38 (29_suppl) ◽  
pp. 76-76
Author(s):  
Scott J. Keating ◽  
Tao Gu ◽  
Monika Parisi Jun ◽  
Corey Pelletier ◽  
Ali McBride
Keyword(s):  
Health Care ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
The United States ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

76 Background: Non-Hodgkin lymphoma comprises a heterogenous group of hematologic malignancies, including aggressive lymphomas such as DLBCL. Novel treatment modalities include CAR T cell therapies. Limited real-world data exist on HCRU and costs among pts treated with FDA-approved CAR T cell therapies. Methods: Pts with DLBCL treated with CAR T cell therapies were identified in 4 databases (IBM MarketScan, n = 60; Optum Clinformatics, n = 56; PharMetrics Plus, n = 75; and Humana, n = 14) from September 2017–H2 2019. Mean total, inpatient, outpatient, and pharmacy costs were calculated and adjusted to 2019 US dollars. HCRU and costs were stratified by adverse events (AEs) of interest—cytokine release syndrome (CRS) and neurological events (NEs)—identified through unvalidated “loose” and “strict” criteria. Results: A total of 205 pts were identified. Across databases, mean age ranged from 55.2–68.9 years, 63%−86% were male, and 88%−100% received CAR T cell therapy in the inpatient setting. In the 3 months after CAR+ T cell infusion, mean TCOC for all pts ranged from $353,642−$525,772 across databases (Table); mean TCOC were highest among pts who had CRS ($344,486−$730,224; strict CRS criteria). Mean inpatient length of stay (LOS) ranged from 17−21 days and was longer among pts who had CRS (18−23 days; n = 62) or NEs (20−24 days; n = 89) (strict CRS/NE criteria). Conclusions: HCRU and TCOC among pts with DLBCL treated with CAR T cell therapies were generally higher among pts who experienced CRS or NEs. Payors and health care systems may benefit from considering the total cost of CAR T cell therapy, including HCRU associated with treatment-emergent AEs. [Table: see text]

scholarly journals Potential strategies against resistance to CAR T-cell therapy in haematological malignancies

2020 ◽  
Vol 12 ◽  
pp. 175883592096296
Author(s):  
Qing Cai ◽  
Mingzhi Zhang ◽  
Zhaoming Li
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Haematological Malignancies ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy is a rapidly developing method for adoptive immunotherapy of tumours in recent years. CAR T-cell therapies have demonstrated unprecedented efficacy in the treatment of patients with haematological malignancies. A 90% complete response (CR) rate has been reported in patients with advanced relapse or refractory acute lymphoblastic leukaemia, while >50% CR rates have been reported in cases of chronic lymphocytic leukaemia and partial B-cell lymphoma. Despite the high CR rates, a subset of the patients with complete remission still relapse. The mechanism of development of resistance is not clearly understood. Some patients have been reported to demonstrate antigen-positive relapse, whereas others show antigen-negative relapses. Patients who relapse following CAR T-cell therapy, have very poor prognosis and novel approaches to overcome resistance are required urgently. Herein, we have reviewed current literature and research that have investigated the strategies to overcome resistance to CAR T-cell therapy.

scholarly journals Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy

Blood ◽  
2019 ◽  
Vol 134 (24) ◽  
pp. 2149-2158 ◽  
Author(s):  
Rebecca A. Gardner ◽  
Francesco Ceppi ◽  
Julie Rivers ◽  
Colleen Annesley ◽  
Corinne Summers ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Lymphocytic Leukemia ◽  
Negative Impact ◽  
Lymphocytic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cell ◽  
Car T ◽  
Antileukemic Effect ◽  
Life Threatening

Gardner et al report that early intervention with tocilizumab and steroids at the first signs of mild cytokine release syndrome (CRS) following CD19 chimeric antigen receptor (CAR) T-cell infusion for B-cell acute lymphocytic leukemia reduces the development of life-threatening severe CRS without having a negative impact on antileukemic effect.

scholarly journals DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality

2020 ◽  
Vol 4 (13) ◽  
pp. 3024-3033 ◽  
Author(s):  
Kitsada Wudhikarn ◽  
Martina Pennisi ◽  
Marta Garcia-Recio ◽  
Jessica R. Flynn ◽  
Aishat Afuye ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

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