Patterns of Hematologic Function and Cytokine Release Syndrome Severity in ALL Patients Receiving CAR-T and TCR-T Therapies Using Pooled Clinical Trial Data

Abstract Background: Despite the potential for durable disease remission seen with Chimeric Antigen Receptor (CAR-T) and T-Cell Receptor (TCR-T) therapies, their use is limited by the potential for acute toxicity from Cytokine-Release Syndrome (CRS).Across all grades, CRS has seen rates as high as 100% in some trials of patients receiving CAR-T, and up to 15% receiving TCR-T. Prior research indicates an association of hematologic abnormalities with CRS. Due to smaller average trial size and limited adoption, to date, of CAR and TCR therapies, there have been no large-scale studies to date exploring these associations with CRS severity in a wide range of patients across treatment types. This study sought to address these evidence gaps using retrospective analysis of pooled clinical trial data in Acute Lymphocytic Leukemia (ALL), using, to our knowledge, the single largest data repository of of CAR-T and TCR-T clinical patient data, with high resolution measurements across a spectrum of clinical domains. Methods: Eligible Phase I, II and III completed clinical trials in Acute Lymphocytic Leukemia (ALL), with patients receiving either CAR-T or TCR-T, were identified from the Medidata Enterprise Data Store, which comprises over 22,000 historical clinical trials, for de-identified retrospective aggregate analyses. Baseline characteristics, including demographics, medical history, prior treatment regimens were assessed and stratified by treatment type. Pre-trial history of hematologic conditions, such as neutropenia and anemia, were also assessed. Using Common Terminology Criteria for Adverse Events (CTCAE) 4.03, patients were assigned to categories of any CRS, mild CRS (grade 1) and moderate-to-severe CRS (2+). Hematologic function was assessed at baseline through first exposure to treatment, including counts of erythrocytes, neutrophils, eosinophils and basophils. Baseline marrow blast cell percentage was assessed as a marker of tumor burden. Univariate analyses of associations between pre-treatment baseline variables and CRS were conducted using Wilcoxon signed rank tests. Results: The pooled CT data contained 1,410 ALL patients, of whom over 60% were 18 year of age or greater. Baseline blood chemistries indicated 21% with anemia, 12% with thrombocytopenia, 6% neutropenic and 5.3% with elevated LDH. Although CAR-T patients accounted for 14.9% of the cohort, 47% of CRS events observed were associated with CAR-T treatment. In line with expectations from prior literature, factors associated with moderate-to-severe CRS included prior history of anemia, reduced platelet levels, low neutrophil counts, and delayed neutrophil recovery. Nearly all cases of moderate-to-severe CRS occurred in subjects exhibiting both low neutrophil and low platelet counts (Figure 1). Similar associations were seen in patients with pretreatment history of anemia (Figure 2). Consistent with literature on tumor burden and CRS, patients without CRS tended to have lower marrow blast percentages. Lymphocyte levels at baseline were far lower in patients receiving CAR-T therapy, with slower recovery than in patients receiving TCR-T. While consistent with CAR-T pre-treatment lymphodepletion, this finding was noteworthy given the association of neutropenia with CRS. Conclusions: Overall findings suggest patterns of routine hematologic function at baseline can potentially be used to assess risk of moderate-to-severe CRS in patients receiving CAR-T and TCR-T agents. The association with these markers could also suggest a mechanism of CRS as a function of tumor cell concentration, modified by the strength and presence of innate immunity mechanisms such as granulocytes, and potentially mediated by intermediates such as macrophages, in line with emerging literature., Further analysis may facilitate development of predictive algorithms to identify patients at greater risk for severe CRS prior to as well as shortly after treatment. This has implications for enhancing supportive care for patients receiving CAR- and TCR therapies. Additionally, a data-driven stratification of patients by risk of CRS will allow improved utilization and management of care resources. Figure 1 Figure 1. Disclosures Agarwal: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Socolov: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Buderi: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Rusli: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Bouzit: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Talwai: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Itzkovich: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Galaznik: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment, Current equity holder in publicly-traded company. Aptekar: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment.

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

Blood ◽

10.1182/blood.2019001463 ◽

2019 ◽

Vol 134 (24) ◽

pp. 2149-2158 ◽

Cited By ~ 42

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.

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Clinical Characterization and Risk Factors Associated with Cytokine Release Syndrome Induced By COVID-19 and Chimeric Antigen Receptor T-Cell Therapy

Blood ◽

10.1182/blood-2020-139007 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Ruimin Hong ◽

Houli Zhao ◽

Yiyun Wang ◽

Yu Chen ◽

Hongliu Cai ◽

...

Keyword(s):

Risk Factors ◽

T Cell ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Tumor Burden ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

T Cell Therapy ◽

Car T

Background: An excessive immune response during coronavirus disease (COVID-19) can induce cytokine release syndrome (CRS), which is associated with life-threatening complications and disease progression. Methods: This study was aimed to investigate the differences and similarities between CRS induced by COVID-19 and CAR-T therapy, then provide valuable experiences for early identification and controlling CRS progression in COVID-19. We retrospectively evaluated the clinical characteristics of severe CRS (sCRS, grade 3-4) induced by COVID-19 (40 patients) or chimeric antigen receptor T-cell (CAR-T) therapy as a comparator (41 patients). Results: Grade 4 CRS was significantly more common in the COVID-19 group (15/40 [35.7%] vs. 5/41 [12.2%], P=0.008). CAR-T group had more more dramatic increase in cytokine than COVID-19 group (Figure1), including IL-2 (7.3pg/mL [IQR: 2.0-12.7] vs.1.7 [0.7-2.7], P<0.001), IL-6 (7120.6 pg/mL [1066.8-15 136.4] vs. 110.3 [41.7-728.1], P<0.001), IL-10 (174.5pg/mL [61.7, 434.6] vs. 10.1 [6.3-20.6], P<0.001) and IFN-γ (1308.5pg/mL [296.6, 3108.2] vs .35.0 [16.9-60.8], P<0.001). Interestingly, COVID-19 group had significantly higher levels for TNF-α (31.1 pg/ml [16.1-70.0] vs. 3.3 [1.8-9.6], P<0.001).The correlations between viral load/ tumor burden and various cytokine levels were shown in Figure 2. Lg viral loads were correlated with lg IL-6 (R2=0.101; P<0.001) and lg IL-10 (R2=0.105; P<0.001) .In CAR-T group, LDH was a common indicator related to tumor burden among patients with ALL, NHL, and MM. The lg LDH concentration was correlated with the lg serum concentration of IL-6 (R2=0.161; P=0.01). The independent risk factors for COVID-19-related sCRS were hypertension history (OR: 7.167, 95% CI: 2.345-21.903; P=0.001) and minimum platelets <100×109 /L during disease course (OR: 9.237, 95% CI: 2.544-33.546; P=0.001). Conclusion: Our study demonstrated that there were similar processes but different intensity of inflammatory responses of sCRS in COVID-19 and CAR-T group. The diagnose and management of COVID-19 related sCRS can learn lessons from treatment of sCRS induced by CAR-T therapy. Keywords: Cytokine release syndrome, COVID-19, Chimeric antigen receptor T-cell therapy Figure 1 Disclosures No relevant conflicts of interest to declare.

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CD19 targeted chimeric antigen receptor T (CAR-T) cell immunotherapy has demonstrated significant anti-leukemia activity in pediatric patients with relapsed/refractory acute lymphocytic leukemia: A multicentre study in China.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e18512 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e18512-e18512

Author(s):

Lei Xiao ◽

Yongmin Tang ◽

Xiaofan Zhu ◽

Jing Chen ◽

Zhao Wu

Keyword(s):

T Cell ◽

Remission Rate ◽

Multicenter Trial ◽

Lymphocytic Leukemia ◽

Large Set ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Clinical Safety ◽

Car T Cell ◽

Car T

e18512 Background: Patients with relapsed/refractory B-ALL are difficult to be treated. Autologous CD19 CAR-T may overcome many limitations of conventional therapies and induce remission in patients with relapsed/refractory disease. We explored treatment of 11 pediatric cases (come from Multicenter) with r/r B-ALL and assessed the clinical safety and efficacy. Methods: We infused autologous CD19 CAR-T in patients at doses of 0.45 × 106 to 10.51 × 106cells per kilogram of body weight. Between Oct. 23 2015 and Jan. 12 2017, a total of 11 children from 3 clinical centers (in China) cases were treated with CAR-T cells (Table1). Patients were monitored for a response, toxic effects, and remission rate. Statistical analysis involving categorical or continuous covariates, univariates, or multivariates analyses. Results: 73% (8/11) of the patients achieved complete remission (CR) and MRD negative between Day7-14 after CD19 CART cell infusion. 4 patients received a repeat infusions following initial ones since they have endured the Cytokine release syndrome (CRS) and have no safety concerns. Cytokine release syndrome (CRS) was seen in 73% (8/11) of patients and severe CRS occurred in 18% (2/11) of patients. Severe CRS was relieved gradually when the anti-IL6R agent tocilizumab and Methylprednisolone were administrated. 1 patients performed bone marrow transplant after they achieved MRD negative. The median CR maintenance is 121 day. Conclusions: This effort provides the first large set of pediatrics data that describes the potential for CART19 therapy to benefit Chinese population. Autologous CD19 CAR-T was effective in treating relapsed/refractory B-ALL not only low leukemia burden, but also high-burden leukemia patients. The method also can associated with a high remission rate. Importantly, While the multicenter trial involves 3 clinical centers in China, the variable clinical settings do not seem to impact patient outcomes due to the highly standardized CAR T cell preparation protocol and manageable CRS in most. (NCT 02813837) Clinical trial information: NCT 02813837.

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Autologous-Collected Donor-Derived CD19-Directed Chimeric Antigen Receptor (CD19-CAR) T Cells Induce a Complete Remission in Chemotherapy-Refractory Childhood Acute Lymphocytic Leukemia (ALL) Relapsing After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Blood ◽

10.1182/blood.v120.21.2609.2609 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2609-2609

Author(s):

Daniel W. Lee ◽

Maryalice Stetler-Stevenson ◽

Marianna Sabatino ◽

Barbara Tumaini ◽

Kelly Richards ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

B Cells ◽

Complete Remission ◽

Lymphocytic Leukemia ◽

Maximum Temperature ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Car T Cells ◽

Car T

Abstract Abstract 2609 Children with relapsed or chemotherapy-refractory ALL have a poor prognosis despite the use of aggressive therapies such as HSCT. Chimeric antigen receptor modified T cells targeting the B-cell antigen CD19 have been reported to be effective in adults with B-cell lymphomas and chronic lymphocytic leukemia. We conducted pre-clinical studies with a CD19-CAR consisting of a CD19-specific scFv and the CD28 and CD3z signaling domains. These cells generated significant levels of IFNg, TNFa, and IL-2 in response to ALL blasts and rapidly eradicated human ALL in murine xenografts. We developed a Phase I clinical trial of CD19-CAR modified autologous T cells for children with CD19+ hematologic malignancies. HSCT-na•ve and post-transplant patients are eligible, and cells are collected directly from patients in both cases. CD19-CAR T cells are manufactured in a semi-closed system over an 11-day period. We report results with the first patient, a 13-year old with chemotherapy-refractory ALL that had relapsed after 2 prior matched related donor HSCTs. Peripheral blood (PB) mononuclear cells were collected from the patient on Day -11 by apheresis. T cells were positively selected and activated by incubation with anti-CD3/anti-CD28 paramagnetic beads in IL-2 for 48 hours then transduced with the CD19-CAR gene via retroviral supernatant for an additional 48 hours. Beads were removed and the expanding CD19-CAR T cells were maintained in culture with IL-2 until harvested for infusion on Day 0. A 59-fold expansion of CAR T cells with 65% transduction efficiency was achieved. The patient was pre-treated with fludarabine (25 mg/m2/day on Days -4, -3, -2) and cyclophosphamide (900 mg/m2 on Day -2) prior to the infusion of 1×106 CAR-transduced T cells/kg. The patient developed signs and symptoms of cytokine release syndrome (CRS) on Day +5 with full resolution by Day +11. Manifestations included fever (maximum 41°C), rigors (Grade 1), and hypotension (Grade 2), the latter of which was responsive to two IV fluid boluses. The patient also developed an erythematous rash (Grade 1) of the extremities from Days +7 to +12 and bilateral scrotal swelling and pain (Grade 1) from Days +8 to +10, which was associated with increased testicular blood flow by ultrasound. Cytokine analysis revealed high levels of IL-6 (53.1 pg/ml; normal <5), GM-CSF (59.4 pg/ml; normal <7.8) and IFNg (44.7 pg/ml; normal <15.6). As IL-6 induces release of C-reactive protein (CRP) from the liver, we monitored CRP levels, which mirrored the time course of CRS (Figure). Broad-spectrum antibiotics were administered for neutropenic fever, although all cultures were negative. No other therapeutic interventions were provided aside from routine supportive care. Figure. Maximum temperature in each 24-hour period (Tmax, red solid line) and CRP (blue solid line) correlate with cytokine release syndrome. Dotted lines indicate upper limits of normal. PB flow cytometry performed prior to cell infusion demonstrated 0.04% blasts and 1% normal B-cells. Repeat analysis after infusion revealed clearance of blasts, gradually decreasing B cells, and a maximum of 0.07% CD19CAR T cells (Days +3, +6, and +27). Re-staging evaluation on Day +27 revealed achievement of a complete remission with bone marrow (BM) blasts decreasing from 30% pre to 3% (flow cytometry 5% to 0.6%) and cerebrospinal fluid (CSF) blasts decreasing from 1.5% to 0%. 0.4% of BM T cells expressed the CD19CAR. (Table) Figure. Maximum temperature in each 24-hour period (Tmax, red solid line) and CRP (blue solid line) correlate with cytokine release syndrome. Dotted lines indicate upper limits of normal. PB flow cytometry performed prior to cell infusion demonstrated 0.04% blasts and 1% normal B-cells. Repeat analysis after infusion revealed clearance of blasts, gradually decreasing B cells, and a maximum of 0.07% CD19CAR T cells (Days +3, +6, and +27). Re-staging evaluation on Day +27 revealed achievement of a complete remission with bone marrow (BM) blasts decreasing from 30% pre to 3% (flow cytometry 5% to 0.6%) and cerebrospinal fluid (CSF) blasts decreasing from 1.5% to 0%. 0.4% of BM T cells expressed the CD19CAR. (Table) Day % BM Blasts (Flow) BM CAR % of T cells % PB Blasts PB CAR % of T cells PB B Cells % % CSF Blasts % CSF CAR Pre 30 (5) 0 0.04 0 1 1.5 0 +3 0 0.07 0.9 +6 0 0.07 0.2 +13 0 0 0.1 +27 3 (0.6) 0.4 0.01 0.07 0.06 0 0 Conclusions: A complete remission was successfully induced in a child with chemotherapy-refractory ALL and post-transplant relapse using a single infusion of autologous-collected, donor-derived T cells modified with a CD19-CAR. Treatment was well tolerated and was only associated with mild CRS that was characterized by high levels of IL-6, INFg, and GM-CSF but not IL-1b or TNFa. CRP levels can be used as a readily available biomarker of IL-6-associated CRS. To our knowledge, this is the first CAR-based therapy to be utilized in the post-allogeneic setting using donor-derived T cells collected directly from a pediatric patient. Disclosures: No relevant conflicts of interest to declare.

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Cord Blood T Regulatory Cells Can Dampen Cytokine Release Syndrome and Improve on Target Efficacy of CD19 CAR T Cells

Blood ◽

10.1182/blood-2020-138812 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Ke Zeng ◽

Li Li ◽

Meixian Huang ◽

Mi-Ae Lyu ◽

Mitsutaka Nishimoto ◽

...

Keyword(s):

T Cells ◽

Inflammatory Cytokines ◽

Research Funding ◽

Treg Cells ◽

Tumor Burden ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Raji Cells ◽

Car T Cells ◽

Car T

Background.As a T cell driven process where release of inflammatory cytokines as a result of the proliferation and on target cell kill by chimeric antigen receptor (CAR)-T cells, cytokine release syndrome (CRS) can be potentially targeted by adoptive therapy with T regulatory (Treg) cells. Specifically, allogeneic cord blood (CB) derived Treg cells have now shown safety and efficacy in graft vs host disease (GVHD), we hypothesized that CB Treg cell therapy can be exploited for treatment of CRS. Method.Xenogenic lymphoma model was created using NSG mice where 0.3x106 GFP-labeled Raji cells were injected on day 0 in all mice followed by 0.3x106 cells of i) mock-CAR T, ii) no CART, ii) CD19-CAR T cells on day +5. Additional injections of 1x107 CB Treg cells on day +11, +18, +25 were added to the no CAR T arm and the CD19-CAR T arm such that there were 3 mice per arm. Mice were followed for weight, GVHD score and survival. Non-invasive bioluminescence was used to perform serial imaging to evaluate the tumor burden. Serial blood was drawn for cell analysis and cytokine assay. Result. As shown in figure A, in vivo proliferation of GFP-labeled Raji cells was evident in all mice day by day +4. CD19-CAR T but not the mock-CAR T cells decreased the tumor burden at day+11. However, at day +14 all mice including CD19-CAR T cell recipients showed progression whereas CD19-CAR T+CB Treg cell recipient showed no evidence of bioluminescence. A superior survival in the CD19-CAR T+CB Treg cells recipients was evident when compared to other treatment arms (Table A). At the time of euthanasia, different organs were evaluated for the detection of the CD19-CART cells and were recovered only in the CD19-CART+CB Treg cells recipients (Table B) . The CD19-CAR T recipients showed an increase in the inflammatory cytokines on day +16 PB samples including IFN-gamma (Figure B) and TNF-alpha (Figure C) which were decreased in the CD19-CAR T + CB Treg arm. Furthermore, a reciprocal increase of the anti-inflammatory cytokine IL-1RA was observed in the CD19-CAR T + CB Treg arm compared to the CD19-CAR T alone (Figure D). Conclusion. The addition of CB Treg cells to CD19-CAR T cells in a xenogenic lymphoma model led to dampening of the cytokine storm and improved on target efficacy of CAR T cells. This combination should be examined in clinical setting. Disclosures Sadeghi: Cellenkos Inc.:Current Employment.Nastoupil:Genentech, Inc.:Honoraria, Research Funding;Karus Therapeutics:Research Funding;Bayer:Honoraria;Gamida Cell:Honoraria;Gilead/KITE:Honoraria;Novartis:Honoraria, Research Funding;Merck:Research Funding;TG Therapeutics:Honoraria, Research Funding;LAM Therapeutics:Research Funding;Janssen:Honoraria, Research Funding;Pfizer:Honoraria, Research Funding;Celgene:Honoraria, Research Funding.Patel:Oncopeptides:Consultancy;Janssen:Consultancy, Research Funding;Precision Biosciences:Research Funding;Takeda:Consultancy, Research Funding;Nektar:Consultancy, Research Funding;Celgene:Consultancy, Research Funding;Bristol Myers Squibb:Consultancy, Research Funding;Poseida:Research Funding;Cellectis:Research Funding.Parmar:Cellenkos Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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Gut microbiome modulates cytokine release syndrome and therapeutic response to CAR-T therapy in hematologic malignancies

10.21203/rs.3.rs-725566/v1 ◽

2021 ◽

Author(s):

He Huang ◽

Yongxian Hu ◽

Jingjing Li ◽

Fang Ni ◽

Zhongli Yang ◽

...

Keyword(s):

Gut Microbiome ◽

Hematologic Malignancies ◽

Lymphocytic Leukemia ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

T Cell Therapy ◽

Non Hodgkin Lymphoma ◽

Car T Cell Therapy ◽

Car T

Abstract Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic treatment for hematologic malignancies. By comparing the diversity and composition of the gut microbiome during different stages of CAR-T therapy, significant changes were detected, not only in patients with relapsed/refractory multiple myeloma (MM; n = 43), but also in those with acute lymphocytic leukemia (ALL; n = 23) and non-Hodgkin lymphoma (NHL; n = 12). Analysis of treatment responses revealed significant temporal differences in diversity and abundance of Bifidobacterium, Prevotella, Sutterella, and Collinsella between MM patients in complete remission (n = 24) and those in partial remission (n = 11). Furthermore, we found that patients with severe cytokine release syndrome (CRS) exhibited higher abundance of Bifidobacterium, Leuconostoc, Stenotrophomonas, and Staphylococcus. This study has important implications for understanding the biological role of the microbiome in the CAR-T treatment of patients with hematologic malignancies (ChiCTR1800017404).

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Extracorporeal Cytokine Adsorption as Additive Treatment of CAR-T Associated Cytokine Release Syndrome (CRS)

Case Medical Research ◽

10.31525/ct1-nct04048434 ◽

2019 ◽

Author(s):

Keyword(s):

Cytokine Release ◽

Cytokine Release Syndrome ◽

Car T ◽

Additive Treatment

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Nichts für Schönwetterkapitäne: CAR-T-Zellen – Immunonkologie trifft Intensivmedizin

TumorDiagnostik & Therapie ◽

10.1055/a-1294-7270 ◽

2020 ◽

Vol 41 (10) ◽

pp. 673-679

Author(s):

Jorge Garcia Borrega ◽

Michael von Bergwelt-Baildon ◽

Boris Böll

Keyword(s):

Real World ◽

Effector Cell ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Immune Effector Cell ◽

Immune Effector ◽

Car T

Zusammenfassung CRS und ICANS als Nebenwirkung von CAR-T-Zellen Das Cytokine-Release-Syndrome (CRS) ist die häufigste Nebenwirkung einer CAR-T-Zell-Therapie und kann von leichtem Fieber bis zu einem Multiorganversagen führen. Pathophysiologisch kommt es beim CRS zu einem Zytokinsturm und trotz einer Therapie mit Tocilizumab sind refraktäre und tödliche Verläufe beschrieben. Die Symptome des Immune-Effector-Cell-associated-Neurotoxicity-Syndrome (ICANS) variieren von leichter Desorientiertheit bis zum lebensbedrohlichen Hirnödem. Die Pathophysiologie und Therapie des ICANS sind noch nicht ausreichend erforscht. Die Differenzialdiagnosen von CRS und ICANS sind komplex und umfassen neben Infektionen und Sepsis unter anderem auch eine Toxizität der vorhergehenden Therapie, ein Tumorlysesyndrom und nicht zuletzt einen Progress der Grunderkrankung. Ein klinischer oder laborchemischer Parameter zum sicheren Beweis oder Ausschluss eines CRS oder ICANS gibt es zum heutigen Zeitpunkt nicht. Intensivmedizinische Relevanz und potenzielle Entwicklungen der CAR-T-Zell-Therapie Erste Auswertungen von Real-world-Daten deuten auf eine höhere Rate an schweren Nebenwirkungen im Rahmen der CAR-T-Zell-Therapie als in den Zulassungsstudien hin. Für die Indikation r/r-DLBCL könnten schätzungsweise bis zu maximal 300 Patienten pro Jahr in Deutschland eine intensivmedizinische Betreuung im Rahmen der CAR-T-Zell-Therapie benötigen. Studien mit wesentlich häufigeren soliden Tumoren könnten die Patientenzahl drastisch erhöhen. Therapieziel bei CAR-T-Zell-Patienten und Entscheidungen bei Therapiezieländerung Aufgrund des neuen Therapiekonzepts kann ein Konflikt zwischen bislang palliativem Patientenkollektiv und nun möglicherweise langfristigen Remissionen entstehen. Eine frühzeitige Aufklärung über potenziell lebensbedrohliche Nebenwirkungen im Rahmen der Therapie und eine interdisziplinäre Besprechung der Therapieziele mit den Patienten ist entscheidend.

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Left Ventricular Aneurysm Presenting as a Late Complication of Childhood Chemotherapy

Case Reports in Cardiology ◽

10.1155/2015/625451 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Braghadheeswar Thyagarajan ◽

Lubna Bashir Munshi ◽

Martin Miguel Amor

Keyword(s):

Myocardial Infarction ◽

Acute Lymphocytic Leukemia ◽

Late Complication ◽

Left Ventricular ◽

Lymphocytic Leukemia ◽

Left Ventricular Aneurysm ◽

Ventricular Aneurysm ◽

Past Medical History ◽

History Of ◽

High Index Of Suspicion

Cardiotoxicity is a well known adverse effect of chemotherapy. Multiple cardiac injuries have been reported including cardiomyopathy, pericarditis, myocarditis, angina, arrhythmias, and myocardial infarction. A left ventricular aneurysm due to chemotherapy is a rare and a dangerous complication which is particularly challenging in diagnosis requiring a high index of suspicion and periodic imaging. We present a case of a young Caucasian male with a past medical history of Acute Lymphocytic Leukemia status after chemotherapy during his childhood diagnosed with left ventricular aneurysm several years later.

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Myelopathy Due to CAR-T Related Neurotoxicity Treated with Siltuximab

Neurology Clinical Practice ◽

10.1212/cpj.0000000000001078 ◽

2021 ◽

pp. 10.1212/CPJ.0000000000001078

Author(s):

Yasmin Aghajan ◽

Alison Yu ◽

Caron A. Jacobson ◽

Austin I. Kim ◽

Leslie Kean ◽

...

Keyword(s):

Spinal Cord ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Hematologic Malignancy ◽

Case Series ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Car T ◽

Large Case Series ◽

Large Case

Chimeric antigen receptor T (CART) cell therapy is highly effective for relapsed/refractory hematologic malignancy [1,2]; however, cytokine release syndrome (CRS) and neurotoxicity are observed in up to 77% of patients [3]. In large case series, the most common presentations of neurotoxicity were encephalopathy (57%), headache (42%), tremor (38%) and aphasia (35%). CART mediated spinal cord toxicity is not well characterized. Structural neurologic damage (stroke and intracranial hemorrhage) was only observed in 1-2% and seizures were seen in 1%-8% of cases [3, 4]. Neuroimaging findings in patients with neurotoxicity are rare and not specific.

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