The Experts below are selected from a list of 7065 Experts worldwide ranked by ideXlab platform
David L. Porter - One of the best experts on this subject based on the ideXlab platform.
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Cytokine Release Syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies.
The Journal of allergy and clinical immunology, 2020Co-Authors: Craig W. Freyer, David L. PorterAbstract:Chimeric antigen receptor T cells are a new and exciting immunotherapeutic approach to managing cancer, with impressive efficacy but potentially life-threatening inflammatory toxicities such as Cytokine Release Syndrome (CRS) and immune effector cell–associated neurotoxicity Syndrome (ICANS). Patients with severe CRS may develop capillary leak Syndrome and disseminated intravascular coagulation, with a Cytokine signature similar to that of macrophage activation Syndrome/hemophagocytic lymphohistiocytosis. Moderate-to-severe CRS is managed with the IL-6 receptor antagonist tocilizumab with or without corticosteroids, with questions remaining regarding the optimal management of nonresponders. ICANS is an inflammatory neurotoxicity typically occurring after CRS and characterized by impaired blood-brain barrier integrity. Symptoms of encephalopathy range from mild confusion and aphasia to somnolence, obtundation, and in some cases seizures and cerebral edema. ICANS is currently managed with corticosteroids; however, the optimal dose and duration remain to be determined. Little information is available to guide the management of patients with steroid-refractory ICANS. Numerous Cytokine-targeted therapies have been proposed to manage these inflammatory toxicities, but few clinical data are available. Management of inflammatory toxicities of chimeric antigen receptor T cells often requires multidisciplinary management and intensive care, during which allergists and immunologists may encounter patients with these unique toxicities.
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Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2018Co-Authors: Noelle V. Frey, David L. PorterAbstract:Abstract Chimeric antigen receptor (CAR)-modified T cells (CAR-Ts) targeting CD19 have resulted in unprecedented durable remissions for patients with relapsed and refractory B cell malignancies. Cytokine Release Syndrome (CRS), resulting from rapid immune activation induced by CAR-Ts, is the most significant treatment-related toxicity. CRS initially manifests with fever and can progress to life-threatening capillary leak with hypoxia and hypotension. The clinical signs of CRS correlate with T cell activation and high levels of Cytokines including IL-6. Tocilizumab, an anti-IL-6 receptor antagonist, is the standard for CRS management, but optimal timing of administration is unclear. The development of a supportive infrastructure by treatment centers is important to maintain safe administration as access expands. Collaborative efforts are underway to harmonize the definition and grading of CRS to allow for better interpretation of toxicities across CAR-T products and clinical trials and allow for informed management algorithms.
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Grading of Cytokine Release Syndrome associated with the CAR T cell therapy tisagenlecleucel.
Journal of hematology & oncology, 2018Co-Authors: David L. Porter, Noelle V. Frey, Patricia A. Wood, Yanqiu Weng, Stephan A. GruppAbstract:Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine Release Syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions. The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale. We show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.
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Cytokine Release Syndrome associated with chimeric-antigen receptor T-cell therapy: clinicopathological insights
Blood, 2017Co-Authors: Amrom E. Obstfeld, Joseph J Melenhorst, Simon F Lacey, Carl H June, David L. Porter, Noelle V. Frey, Keith Mansfield, Mariusz A WasikAbstract:To the editor: Chimeric-antigen receptor T-cell (CART-cell) immunotherapy has proven clinical efficacy,[1][1] particularly in B-cell leukemia and lymphoma.[2][2][⇓][3]-[4][4] However, it causes a unique set of toxicities, the foremost of which is Cytokine Release Syndrome (CRS).[5][5],[6][6] The
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Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia
Critical care medicine, 2017Co-Authors: Julie C. Fitzgerald, Joseph J Melenhorst, Simon F Lacey, Carl H June, Shannon L Maude, David M Barrett, Scott L. Weiss, Pamela A. Shaw, Robert A. Berg, David L. PorterAbstract:Objective Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine Release Syndrome, the most severe toxicity, presents a novel critical illness Syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of Cytokine Release Syndrome after chimeric antigen receptor-modified T cell therapy. Design Retrospective cohort study. Setting Academic children's hospital. Patients Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495). Interventions All subjects received chimeric antigen receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab. Measurements and main results Eighteen subjects (46%) developed grade 3-4 Cytokine Release Syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress Syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement. Conclusions Grade 3-4 Cytokine Release Syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.
Anthony J. Perissinotti - One of the best experts on this subject based on the ideXlab platform.
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successful reintroduction of blinatumomab in a patient with relapsed refractory acute lymphoblastic leukemia following grade 4 Cytokine Release Syndrome
Journal of Oncology Pharmacy Practice, 2018Co-Authors: Bernard L. Marini, Yihan Sun, Patrick W. Burke, Anthony J. PerissinottiAbstract:Relapsed/refractory acute lymphoblastic leukemia poses a clinical challenge due to its poor prognosis and lack of effective treatment. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, life-threatening toxicities such as Cytokine Release Syndrome have been reported in pivotal clinical trials. In this report, we describe the safe reintroduction of blinatumomab in an adult patient with relapsed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia after experiencing grade 4 blinatumomab-induced Cytokine Release Syndrome using a unique dosing strategy and a very diligent monitoring approach. As blinatumomab often represents a last-line therapeutic option for many patients, such a step-wise dosing approach and diligent monitoring plan may be useful in an attempt to retrial blinatumomab in patients who require reintroduction of therapy.
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Successful reintroduction of blinatumomab in a patient with relapsed/refractory acute lymphoblastic leukemia following grade 4 Cytokine Release Syndrome.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 2016Co-Authors: Bernard L. Marini, Yihan Sun, Patrick W. Burke, Anthony J. PerissinottiAbstract:Relapsed/refractory acute lymphoblastic leukemia poses a clinical challenge due to its poor prognosis and lack of effective treatment. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, life-threatening toxicities such as Cytokine Release Syndrome have been reported in pivotal clinical trials. In this report, we describe the safe reintroduction of blinatumomab in an adult patient with relapsed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia after experiencing grade 4 blinatumomab-induced Cytokine Release Syndrome using a unique dosing strategy and a very diligent monitoring approach. As blinatumomab often represents a last-line therapeutic option for many patients, such a step-wise dosing approach and diligent monitoring plan may be useful in an attempt to retrial blinatumomab in patients who require reintroduction of therapy.
Alina Tanase - One of the best experts on this subject based on the ideXlab platform.
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continuous renal replacement therapy in Cytokine Release Syndrome following immunotherapy or cellular therapies
Journal for ImmunoTherapy of Cancer, 2020Co-Authors: Catalin Constantinescu, Sergiu Pasca, Tiberiu Tat, Patric Teodorescu, Catalin Vlad, Sabina Iluta, Delia Dima, Dana Tomescu, Ecaterina Scarlatescu, Alina TanaseAbstract:Recently, an increasing number of novel drugs were approved in oncology and hematology. Nevertheless, pharmacology progress comes with a variety of side effects, of which Cytokine Release Syndrome (CRS) is a potential complication of some immunotherapies that can lead to multiorgan failure if not diagnosed and treated accordingly. CRS generally occurs with therapies that lead to highly activated T cells, like chimeric antigen receptor T cells or in the case of bispecific T-cell engaging antibodies. This, in turn, leads to a proinflammatory state with subsequent organ damage. To better manage CRS there is a need for specific therapies or to repurpose strategies that are already known to be useful in similar situations. Current management strategies for CRS are represented by antiCytokine directed therapies and corticosteroids. Based on its pathophysiology and the resemblance of CRS to sepsis and septic shock, as well as based on the principles of initiation of continuous renal replacement therapy (CRRT) in sepsis, we propose the rationale of using CRRT therapy as an adjunct treatment in CRS where all the other approaches have failed in controlling the clinically significant manifestations.
Bernard L. Marini - One of the best experts on this subject based on the ideXlab platform.
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successful reintroduction of blinatumomab in a patient with relapsed refractory acute lymphoblastic leukemia following grade 4 Cytokine Release Syndrome
Journal of Oncology Pharmacy Practice, 2018Co-Authors: Bernard L. Marini, Yihan Sun, Patrick W. Burke, Anthony J. PerissinottiAbstract:Relapsed/refractory acute lymphoblastic leukemia poses a clinical challenge due to its poor prognosis and lack of effective treatment. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, life-threatening toxicities such as Cytokine Release Syndrome have been reported in pivotal clinical trials. In this report, we describe the safe reintroduction of blinatumomab in an adult patient with relapsed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia after experiencing grade 4 blinatumomab-induced Cytokine Release Syndrome using a unique dosing strategy and a very diligent monitoring approach. As blinatumomab often represents a last-line therapeutic option for many patients, such a step-wise dosing approach and diligent monitoring plan may be useful in an attempt to retrial blinatumomab in patients who require reintroduction of therapy.
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Successful reintroduction of blinatumomab in a patient with relapsed/refractory acute lymphoblastic leukemia following grade 4 Cytokine Release Syndrome.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 2016Co-Authors: Bernard L. Marini, Yihan Sun, Patrick W. Burke, Anthony J. PerissinottiAbstract:Relapsed/refractory acute lymphoblastic leukemia poses a clinical challenge due to its poor prognosis and lack of effective treatment. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, life-threatening toxicities such as Cytokine Release Syndrome have been reported in pivotal clinical trials. In this report, we describe the safe reintroduction of blinatumomab in an adult patient with relapsed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia after experiencing grade 4 blinatumomab-induced Cytokine Release Syndrome using a unique dosing strategy and a very diligent monitoring approach. As blinatumomab often represents a last-line therapeutic option for many patients, such a step-wise dosing approach and diligent monitoring plan may be useful in an attempt to retrial blinatumomab in patients who require reintroduction of therapy.
David M Barrett - One of the best experts on this subject based on the ideXlab platform.
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Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2021Co-Authors: Stephan Kadauke, David M Barrett, Regina M Myers, Richard Aplenc, Diane Baniewicz, Allison Barz Leahy, Colleen Callahan, Joseph G Dolan, Julie C. FitzgeraldAbstract:PURPOSETo prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe Cytokine Release Syndrome (CRS) after CTL019, a CD19 chimeric anti...
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Diagnostic biomarkers to differentiate sepsis from Cytokine Release Syndrome in critically ill children.
Blood advances, 2020Co-Authors: Caroline Diorio, David M Barrett, Pamela A. Shaw, Richard Aplenc, Edward Pequignot, Alena Orlenko, Fang Chen, Hamid Bassiri, Edward M. Behrens, Amanda M. DinofiaAbstract:Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both Cytokine Release Syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different Cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified Cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1β were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1β was associated with sepsis. This combination of IFNγ and IL1β was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.
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Tocilizumab for the treatment of chimeric antigen receptor T cell-induced Cytokine Release Syndrome
Expert review of clinical immunology, 2019Co-Authors: Chelsea Kotch, David M Barrett, David T TeacheyAbstract:Introduction: Cancer-directed immunotherapies are transforming the landscape in oncology as new and exciting therapies move from the laboratory to the bedside. Chimeric antigen receptor T (CAR-T) cells are one of these novel therapies, demonstrating impressive efficacy against B-cell malignancies. With the development of new therapies, it is not uncommon to identify new and unanticipated toxicities. CAR-T cells cause unique toxicities not typically found with traditional cytotoxic chemotherapy or small molecule inhibitors. Areas covered: CAR-T cell associated toxicities include Cytokine Release Syndrome (CRS) and CAR-T cell-related encephalopathy Syndrome (CRES), alternatively known as immune effector cell-associated neurotoxicity Syndrome (ICANS). Prompt identification and management of CRS and CRES are imperative for the prevention of life-threatening complications of these innovative therapies. This literature review describes the seminal trials of CD19-directed immunotherapy and the pathophysiology and management of the toxicities found with CAR-T cells. In addition, the use of the interleukin-6 receptor antibody tocilizumab for CRS is reviewed. Expert opinion: This review describes the recommended management of CRS and CRES and examines the current limitations in management. Alternative therapies for the treatment of CAR-T cell related toxicities are also explored. Furthermore, the review proposes future directions for research.
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Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia
Critical care medicine, 2017Co-Authors: Julie C. Fitzgerald, Joseph J Melenhorst, Simon F Lacey, Carl H June, Shannon L Maude, David M Barrett, Scott L. Weiss, Pamela A. Shaw, Robert A. Berg, David L. PorterAbstract:Objective Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine Release Syndrome, the most severe toxicity, presents a novel critical illness Syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of Cytokine Release Syndrome after chimeric antigen receptor-modified T cell therapy. Design Retrospective cohort study. Setting Academic children's hospital. Patients Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495). Interventions All subjects received chimeric antigen receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab. Measurements and main results Eighteen subjects (46%) developed grade 3-4 Cytokine Release Syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress Syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement. Conclusions Grade 3-4 Cytokine Release Syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.
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Managing Cytokine Release Syndrome associated with novel T cell-engaging therapies.
Cancer journal (Sudbury Mass.), 2014Co-Authors: Shannon L Maude, David T Teachey, David M Barrett, Stephan A. GruppAbstract:Chimeric antigen receptor (CAR)-modified T cells and bispecific T cell-engaging antibodies have demonstrated dramatic clinical responses in recent clinical trials. The hallmark of these novel highly active immunotherapies is nonphysiologic T cell activation, which has correlated not only with greatly increased efficacy but also with notable toxicity in some cases. We and others have observed a Cytokine Release Syndrome (CRS), which correlates with both toxicity and efficacy in patients receiving T cell-engaging therapies. In addition to elevations in effector Cytokines, such as interferon-γ, Cytokines associated with hemophagocytic lymphohistiocytosis or macrophage activation Syndrome, such as interleukin (IL)-10 and IL-6, may also be markedly elevated. Whereas corticosteroids may control some of these toxicities, their potential to block T cell activation and abrogate clinical benefit is a concern. Detailed studies of T cell proliferation and the resultant immune activation produced by these novel therapies have led to more targeted approaches that have the potential to provide superior toxicity control without compromising efficacy. One approach we have developed targets IL-6, a prominent Cytokine in CRS, using the IL-6R antagonist tocilizumab. We will review the pathophysiology and management options for CRS associated with T cell-engaging therapies.
