Treatment Of Cytokine Release Syndrome Research Articles

Intrathecal Chemotherapy As a Potential Alternative Treatment for Steroid-Refractory Immune Effector Cell-Associated Neurotoxicity Syndrome

IntroductionChimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and other hematologic malignancies. However, its use is associated with serious adverse effects including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Severe ICANS can present with aphasia, mutism, somnolence, seizures, signs of increased intracranial pressure and rarely cerebral edema. Corticosteroids (CS) and IL-6 inhibitors are first line treatment for CRS and ICANS. Prolonged CS use has been associated with decreased over-all survival in CAR T-cell treated patients. Data on effective treatments for CART T-cell induced neurotoxicity is limited, especially in steroid-refractory ICANS. Blood-brain barrier (BBB) disruption and infiltration of myeloid and immune effector cells into the central nervous system are implicated in the pathogenesis of ICANS. This likely explains the role of intrathecal chemotherapy, which has been described in literature for treatment of steroid-refractory ICANS. Here, we report the outcomes of two patients with refractory DLBCL who developed severe ICANS after receiving axicabtagene ciloleucel (axi cel) and treated with intrathecal (IT) chemotherapy.Case PresentationOur first case is of a 66 year old male with diagnosis of R/R DLBCL, who was treated with R-CHOP, followed by R-GemOx, with no response then received axi cel. Patient developed grade 2 CRS and grade 1 ICANS (National Cancer Institute Common Terminology Criteria for Adverse Effects v4.03) on day +2 post infusion, treated with tocilizumab and dexamethasone with good response initially. While tapering dexamethasone on day +5, he developed grade 3 CRS and grade 3 ICANS. Brain MRI did not show any intracranial abnormality and EEG showed no seizure activity. Lumbar puncture (LP) was done on day +7 and showed opening pressure of 32 cm H2O, and 12 lymphocytes. He was started on IV solumedrol and tocilizumab was resumed. CRS improved while neurotoxicity progressed to grade 4 prompting intubation and mechanical ventilation on day +8. On day +9, patient received intrathecal methotrexate 12 mg and hydrocortisone 50 mg. On day +12, neurotoxicity improved to grade 1 and patient was extubated on day +13. Steroid taper stopped on +17. Despite disease response, patient remained hospitalized at day +45 for deconditioning and vocal cord paralysis related to a lengthy hospital stay and intubation. He was eventually discharged, however passed away on day +49 from complications of prolonged hospitalization.Our second case is of a 69 year old female with a diagnosis of R/R DLBCL with CNS involvement, treated with RCHOP x6 followed by salvage chemotherapy with refractory disease, She then received axi cel. Patient developed grade 1 CRS on day +4, treated with tocilizumab and dexamethasone, and patient responded well. On day +9, she developed grade 2 CRS and grade 3 ICANS. At that time, dexamethasone was switched to pulse dose solumedrol and tocilizumab was continued. CT head showed no acute intracranial abnormality and EEG did not show any epileptiform activity. LP showed opening pressure of 21, and 84 lymphocytes. On day +11, patient's CRS resolved, however ICANS developed to grade 4 and patient received 12 mg intrathecal methotrexate and hydrocortisone 50 mg for steroid-refractory ICANS. The very next day, patient showed significant neurological improvement. Steroid taper was initiated and patient's ICANS resolved on day +16. MRI brain showed decrease in size of nodular enhancement along periventricular white matter and left occipital area corresponding to treatment response. She was discharged on day +28 and continues to do well one year out of axi cel infusionConclusionOur abstract adds to the sparse literature about the use IT chemotherapy in cases with severe ICANS. It also highlights its importance as an alternative potential therapy to high doses and prolonged courses of corticosteroids which is associated with increased morbidity and mortality. Steroid-refractory ICANS has limited treatment options and further evaluation of the use of IT chemotherapy in large scale studies is warranted. DisclosuresKahn: Abbvie: Research Funding, Speakers Bureau; Astrazeneca: Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Epizyme: Research Funding, Speakers Bureau; Genetech: Research Funding, Speakers Bureau; GSK: Speakers Bureau; Karyopharm: Speakers Bureau; Kite: Speakers Bureau; Morphosys: Speakers Bureau; Sanofi: Speakers Bureau; SeaGen: Speakers Bureau. Fazal: Agios: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Lister: Oncology Analytics: Other: Academic Board.

Phase I First-in-Class Trial of MCARH109, a G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D) Targeted CAR T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma

Phase I First-in-Class Trial of MCARH109, a G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D) Targeted CAR T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma

Real-World Outcomes for Pediatric and Young Adult Patients with Relapsed or Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (ALL) Treated with Tisagenlecleucel: Update from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Real-World Outcomes for Pediatric and Young Adult Patients with Relapsed or Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (ALL) Treated with Tisagenlecleucel: Update from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

1014P Characterization of cytokine release syndrome (CRS) following treatment with tebentafusp in previously untreated patients with metastatic uveal melanoma

Tebentafusp (tebe), a bispecific fusion protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T-cells to target gp100+ cells, has shown an overall survival benefit for patients (pts) with untreated metastatic uveal melanoma (mUM) in a Ph3 trial (NCT03070392). In a post-hoc analysis of a Ph2 trial of 2L+ pts with mUM, mild to moderate episodes of CRS, a cytokine-mediated adverse event (AE), were common following each of the first 3 doses of tebe (Carvajal RD et al. ASCO 2021). Here, we reviewed the incidence, kinetics, and outcome of CRS in tebe-treated pts on the IMCgp100-202 trial of 1L pts with mUM. 245 HLA-A*02:01+ 1L mUM pts were treated weekly with tebentafusp following intra-patient dose escalation: 20mcg dose 1, 30mcg dose 2 and 68mcg dose 3+. Pts were monitored overnight during escalation to allow management of hypotension and other cytokine-related AEs; prophylactic corticosteroids, antihistamines or acetaminophen were not mandated. CRS was evaluated post-hoc according to ASTCT Consensus Grading criteria (Lee, DW et al. 2019). Analysis was conducted on primary analysis snapshot (Jan 2021). The most frequent treatment-related AEs, likely cytokine-mediated, included fever (76%), chills (47%), nausea (43%), hypotension (38%). Using ASTCT criteria, 89% of tebe treated pts (n=217) had any grade CRS. Most pts had either grade (G) 1 (12%; n=29) or G2 (76%; n=186), with 2 G3 (0.8%), no G4 and no deaths. Most CRS events occurred within the first 3 doses, reducing in frequency and severity thereafter; 3 episodes of G3 CRS in 2 patients occurred following dose 1, 3 and 4. Only 2 pts discontinued tebe due to CRS (1 G2; 1 G3). Treatment of CRS included antipyretics (n=192), IV fluids (n=93), IV steroids (n=57), oxygen (n=20), and vasopressor use (n=2). Two pts received tocilizumab. CRS, a common AE observed with T-cell engaging therapies, was frequently observed within 24 hours of initial tebe treatment. Most CRS events were mild or moderate in severity, reversible with standard management strategies, decreased in frequency and severity with subsequent doses, and rarely led to treatment discontinuation.

CAR-T cells : what intensivists need to know

Treatment with CAR-T cells represents an innovative therapeutic advance in patients with refractory hematological malignancies. Infectious complications must always be considered and empirically treated. Specific complications such as cytokine release syndrome (CRS) and neurotoxicity can be severe and patients often require intensive care unit admission. A close monitoring is necessary in these patients. While CRS treatment is based on the administration of anti-IL-6 receptor (tocilizumab) in mild forms, corticosteroids are recommended in severe CRS and/or neurotoxicity

Combination therapy of Tocilizumab and steroid for management of COVID-19 associated cytokine release syndrome: A single center experience from Pune, Western India.

Cytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednislone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroid in COVID-19 associated CRS.This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India between April 2 and November 2, 2020. All patients administered TCZ and steroids during this period were included. The primary endpoint was incidence of all cause mortality. Secondary outcomes studied were need for mechanical ventilation and incidence of systemic and infectious complications. Baseline and time dependent risk factors significantly associated with death were identified by Relative risk estimation.Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. Thirty seven percent patients were managed in wards and did not need intensive care unit (ICU) admission. Infectious complications like hospital acquired pneumonia, blood stream bacterial and fungal infections were observed in 2.13%, 2.13% and 0.06% patients respectively. Age ≥ 60 years (P = .014), presence of co-morbidities like hypertension (P = .011), IL-6 ≥ 100 pg/ml (P = .002), D-dimer ≥ 1000 ng/ml (P < .0001), CT severity index ≥ 18 (P < .0001) and systemic complications like lung fibrosis (P = .019), cardiac arrhythmia (P < .0001), hypotension (P < .0001) and encephalopathy (P < .0001) were associated with increased risk of death.Combination therapy of TCZ and steroids is likely to be safe and effective in management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled trials.

Chimeric antigen receptor T-cell toxicities - using steroids to spare steroids?

Chimeric antigen receptor T-cell toxicities - using steroids to spare steroids?

Cytokine Release Syndrome Associated with T-Cell-Based Therapies for Hematological Malignancies: Pathophysiology, Clinical Presentation, and Treatment.

Cytokines are a broad group of small regulatory proteins with many biological functions involved in regulating the hematopoietic and immune systems. However, in pathological conditions, hyperactivation of the cytokine network constitutes the fundamental event in cytokine release syndrome (CRS). During the last few decades, the development of therapeutic monoclonal antibodies and T-cell therapies has rapidly evolved, and CRS can be a serious adverse event related to these treatments. CRS is a set of toxic adverse events that can be observed during infection or following the administration of antibodies for therapeutic purposes and, more recently, during T-cell-engaging therapies. CRS is triggered by on-target effects induced by binding of chimeric antigen receptor (CAR) T cells or bispecific antibody to its antigen and by subsequent activation of bystander immune and non-immune cells. CRS is associated with high circulating concentrations of several pro-inflammatory cytokines, including interleukins, interferons, tumor necrosis factors, colony-stimulating factors, and transforming growth factors. Recently, considerable developments have been achieved with regard to preventing and controlling CRS, but it remains an unmet clinical need. This review comprehensively summarizes the pathophysiology, clinical presentation, and treatment of CRS caused by T-cell-engaging therapies utilized in the treatment of hematological malignancies.

Neurological Consequences of Cytokine Release Syndrome Following Subcutaneous Recombinant IL-15 and Haploidentical Donor Natural Killer Cell Therapy for Advanced Acute Myeloid Leukemia

Abstract Cytokine Release Syndrome (CRS) is associated with elevated cytokine levels, macrophage activation, and IL-6 production after antibody or cell-based immunotherapy. We have observed over 200 patients with no CRS following adoptively transferred haploidentical donor natural killer (haplo-NK) cell products after lymphodepleting chemotherapy plus IL-2; and achieved complete remission in 30-50% of patients with refractory AML. To promote NK cell expansion without stimulation of Treg that may compromise NK function, we tested the substitution of IL-2 with the NCI manufactured rIL-15. Using the same lymphodepleting preparative regimen (Fludarabine 25 mg/m2IV for 5 days and Cyclophosphamide 60 mg/kg IV for 2 days) we infused CD3- and CD19-depleted haplo-NK incubated overnight with rIL-15 (10 ng/mL) prior to infusion. Two cohorts received rIL-15; either intravenously x 12 daily doses (at the Phase I MTD of 0.75 mcg/kg) or subcutaneously x 10 doses (5 days on, 2 days off, 5 days on at 2 mcg/kg SQ, the MTD when used as monotherapy in solid tumor patients). CRS was defined by modified CRS grading criteria (Lee et al. Blood, 2014). Results: Forty patients with relapsed/refractory AML were treated with haplo-NK plus IV rIL-15 (n=24) or SQ rIL-15 (n=16). Patients received an average of 11.6 IV doses [9-12, 96% of planned doses] or 7.5 SQ doses [1-10, 75% of planned doses]. Dosing was stopped for toxicity. No CRS events were observed after IV dosing. However, after SQ dosing, 9 of 16 patients [56%] had grade 1-4 CRS; [4 (25%) with grade 3-4 CRS) (Table 1). The median time from NK infusion to onset of CRS was 8 days [2-44]. Six of the 9 CRS patients (66%) had neurological events. Neurological toxicities included grade 1-2 encephalopathy (n=2), intracranial hemorrhage (ICH) (n=2, grade 1 and grade 5), and grade 4 seizures (n=2). One additional event (a patient with a fall resulting in ICH due to pre-existing gait abnormality) without evidence of CRS was not considered as IL-15 associated neurotoxicity CRS. Symptoms resolved in 4 of 5 patients who received treatment for neurologic CRS (3 received both steroids and Tocilizumab, 1 received steroids only, 1 patient did not require treatment as symptoms resolved with stopping IL-15). Non-neurologic toxicity included hypoxia (n=2) and hypotension (n=3). No significant correlations were found between development of CRS and absolute lymphocyte or monocyte count, presence or absence of haplo-NK expansion at day 14, number of rIL-15 doses received, or disease burden at baseline as measured by blast percentage in bone marrow. In the IV rIL-15 cohort, only 2 of 14 patients at the MTD (14%) cleared leukemia and underwent transplantation. In contrast, 8 of 16 patients (50%, P=0.04) in the SQ rIL-15 cohort achieved CR (n=7) or CRp (n=1), with 6 patients proceeding to alloHCT consolidation. CRS did not limit the clinical benefit in the SQ cohort as 4 of 9 [44%] patients with CRS achieved CR/PR compared to 4 of 7 [57%] patients without CRS. Pharmacokinetic data showed slower clearance of rIL-15 in SQ compared to IV dosing, as shown by higher trough levels prior to dose 2 (501 vs. 233 pg/mL, p Download : Download high-res image (163KB) Download : Download full-size image Disclosures Bachanova: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Miller: Celegene: Consultancy; Oxis Biotech: Consultancy; Fate Therapeutics: Consultancy, Research Funding.

Tocilizumab Is Safe after T-Cell Replete Peripheral Blood Haploidentical Donor Transplantation

Introduction: Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient's only curative intent treatment. Overall outcomes for haploidentical transplantation appear to be excellent, however, this novel approach brings toxicities that are particular to its biological and clinical milieu. We previously described occurrence of severe cytokine release syndrome (CRS) after haplo-HCT. Severe CRS was associated with poor clinical outcomes, including transplant related mortality (TRM), overall survival (OS), and neutrophil engraftment (Abboud et al, BBMT, 10/2016). Furthermore, tocilizumab rapidly reversed the signs and symptoms of the dysregulated inflammatory reaction in most cases of CRS.Here we compare short and long term complications in peripheral blood haplo-HCT patients who did and did not receive tocilizumab.Patients and Methods: We performed a retrospective review of patients who underwent haplo-HCT transplantation at our institution from July 2009 through January 2017. A total of 169 patients were identified, 9% (15) received tocilizumab for treatment of CRS. We compared rates of acute and chronic GVHD, time to relapse, and incidence infection related deaths between patients who received tocilizumab and those who did not.Results: We found no difference in acute GVHD (hazard 1.08, p 0.83), time to relapse (hazard 1.06, p 0.90), or incidence of infection related deaths (hazard 0.764, p 0.65) between patients who received tocilizumab and those who did not.There was a trend towards a lower rate of chronic GVHD in patients who received tocilizumab compared with those who did not, with a hazard of 0.56 (95% CI 0.158 - 0.99, p= 0.37).Conclusions: Tocilizumab is safe following haplo-SCT. Tocilizumab did not increase the risk of acute GVHD, chronic GVHD, time to relapse, or incidence of infection related deaths. There was a trend towards a lower rate of chronic GVHD in patients who received tocilizumab. [Display omitted] DisclosuresUy:Boehringer Ingelheim: Consultancy; Novartis: Consultancy, Other: Travel Suppport; GlycoMimetics: Consultancy. Vij:Celgene: Honoraria; Konypharma: Honoraria; Bristol-Meyers-Squibb: Honoraria; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Jazz: Honoraria; Abbvie: Honoraria; Janssen: Honoraria.

Pharmacokinetics and Pharmacodynamics of Tocilizumab for the Management of Cytokine Release Syndrome (CRS) in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL) Treated with CAR T-Cell Therapy, CTL019

Background: ELIANA (NCT02435849) is a pivotal multicenter study to test the efficacy of CTL019 (tisagenlecleucel; anti-CD19 CAR-T) in children and young adult patients (pts) with relapsed/refractory B-ALL. Tocilizumab (toci) has been used for the management of moderate/severe (grade 3/4) CRS in ≈ 38% of pts treated with CTL019 (Buechner J et al, EHA 2017) at the same doses used in approved non-oncologic pediatric indications (<30 kg received 12 mg/kg and ≥30 kg received 8 mg/kg [800 mg max dose]). CRS onset generally occurred at a median of 3 days (range 1-22 days) after CTL019 infusion, requiring administration of 1-3 doses of toci in some patients per the Penn CRS treatment algorithm. Toci is a humanized mAb that binds to and blocks IL-6 receptor (IL-6R) signaling. The pharmacokinetics (PK) and pharmacodynamics (PD) of toci in pediatric B-ALL patients with CAR-associated CRS has not previously been described.Objectives: To characterize the PK/PD of toci for the management of CRS following CTL019 infusion in B-ALL in the ELIANA study. To describe the impact of toci on CTL019 cellular kinetics and expansion.Methods: Pharmacokinetics of toci and pharmacodynamics of soluble IL-6R (sIL-6R) concentrations (conc) were determined from serum and quantified using validated assays to provide mechanistic support for the use of toci in the management of CRS in B-ALL. Maximum toci conc (Cmax) was derived using non-compartmental methods and compared with levels in approved indications. sIL-6R, proinflammatory cytokines and time to CRS resolution were characterized to describe the pharmacodynamic effects of toci. Summary statistics and graphical analyses of CTL019 exposure by number of toci doses were performed for patients that responded to CTL019 infusion to describe the impact of toci on CTL019 expansion and persistence.Results: A total of 28 out of 58 pts with CRS received their first dose of toci at a median of 5 days (range 1-18) after CRS onset. 17 pts received 1 IV dose of toci; 8 pts 2 doses; 3 pts 3 doses. First dose of toci ranged from 6.9 to 12 mg/kg; second dose of toci ranged from 8 to 12 mg/kg. Following the first and second dose of toci, the mean Cmax (SD) were ≈ 111 (30.6) µg/mL and 265 (376) µg/mL, respectively (Table 1). Individual patient PK/PD concentration-time profiles in B-ALL, show increased sIL-6R after the first toci dose that remained elevated following the second dose (Figure 2). The median time to CRS resolution (including fever resolution) was 5 days (range, 2-29 days) after toci administration. CRS onset coincided with CTL019 expansion, and was followed by a peak in serum cytokines, including IL-6. Maximal expansion of the CTL019 transgene (determined by qPCR) was 159% higher in patients treated with toci (n=14) compared with patients that did not receive toci (n=28) demonstrating tocilizumab does not negatively impact expansion (Figure 3).Conclusions: Toci administration resulted in resolution of CRS symptoms within a median of 5 days after administration. Notably, levels of toci achieved in B-ALL were similar to levels published in pediatric non-oncologic indications [tocilizumab label], resulting in concentration- and time-dependent increases in sIL-6R. CTL019 transgene expanded and persisted following tocilizumab administration. Together these data support the use of toci for the management of CRS, showing the compound to be 1) pharmacologically active, 2) able to achieve levels consistent with those achieved in other disorders in spite of CRS and 3) able to be given without impairing CTL019 expansion. [Display omitted] DisclosuresLee:Novartis Pharmaceuticals Corporation: Other: Post-Doctoral Fellow; The State University of New Jersey: Other: Post doctoral fellow. Bittencourt:Novartis Pharmaceuticals Corporation: Consultancy; Amgen Inc.: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel Grant. Rives:Novartis Pharmaceuticals Corporation: Consultancy; Jazz Pharmaceutical: Other: Travel expenses; Shire: Consultancy. Boyer:Novartis Pharmaceuticals Corporation: Honoraria. Pulsipher:Adaptive: Other: Advisory board 6/17; CSL Behring: Other: advisory board Feb 2017; Jazz Pharmaceuticals: Other: advisory board, education; Chimerix: Other: Advisory board Dec 2015; Novartis Pharmaceuticals Corporation: Consultancy, Other: Phase II steering committee. Jaitner:Novartis Pharma AG: Employment. Yi:Novartis Pharmaceuticals Corporation: Employment. Lund:Novartis Pharmaceuticals Corporation: Employment. Leung:Novartis Pharmaceuticals Corporation: Employment. Awasthi:Novartis Pharmaceuticals Corporation: Employment. Wood:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Maude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy; University of Pennsylvania: Patents & Royalties. Mueller:Novartis Pharmaceuticals Corporation: Employment.

Estimating costs of adverse events (AEs) and healthcare resource use (HRU) in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) receiving tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel): A summary of real-world evidence.

e19551 Background: The AE rates and HRU reported in multiple real-world evidence (RWE) studies of chimeric antigen receptor T-cell (CAR-T) therapies tisa-cel and axi-cel in r/r DLBCL have differed from those in their clinical trials. However, the cost implications from these findings are not well understood in existing literature. This study summarizes information from these RWE studies of tisa-cel and axi-cel and quantifies the associated costs. Methods: A literature review was conducted to identify RWE studies reporting AE rates and HRU of tisa-cel and axi-cel in the United States (US). AE rates and HRU were summarized and the associated costs were estimated using a micro-costing approach. Costs of AE management included hospitalization and pharmacy costs, such as intensive care unit (ICU) stays, inpatient admissions, and medications for the treatment of cytokine release syndrome (CRS) and neurotoxicity events (NE). HRU costs included hospitalization, ICU stays, and outpatient visit costs. Unit costs were from public health databases that are representative of US healthcare system and from literature. Costs were inflated to 2020 US dollars. A range was reported to present evidence if inputs are available from multiple studies. Results were summarized for tisa-cel and axi-cel separately. Results: Four publications were identified: Jaglowski 2019, Pasquini 2019, Riedell 2019, and Jacobson 2020. Across studies, grade 3+ CRS and NE occurred in 1%-4% and 0%-5% of tisa-cel-treated patients and 7%-16% and 20%-35% of axi-cel-treated patients, respectively. Tocilizumab usage was reported in 14%-20% of tisa-cel- and 62%-71% of axi-cel-treated patients. CAR-T infusion was inpatient for 36% of tisa-cel- and 92%-100% of axi-cel-treated patients. The median hospitalization days was 2 for tisa-cel and 15-16 for axi-cel. ICU transfer was observed for 7% and 28%-38% of tisa-cel- and axi-cel-treated patients, respectively, with median stays of 4 and 5 days, respectively. The median number of outpatient visits within 28 days after infusion was 6 for tisa-cel and 4 for axi-cel. The total estimated costs for managing AEs per patient were $843-$1,962 for tisa-cel and $5,979-$10,878 for axi-cel. The total estimated HRU costs per patient were $3,321 for tisa-cel and $32,394-33,166 for axi-cel. Conclusions: RWE studies suggest that patients with r/r DLBCL receiving tisa-cel had numerically lower AE rates, HRU, and cost burden than those receiving axi-cel in the US. The additional cost burden for axi-cel was primarily driven by the incremental ICU and hospitalization care due to a higher proportion of inpatient infusion among patients receiving axi-cel. Further research is warranted to compare the costs associated with the two CAR-Ts in r/r DLBCL.

Therapeutic Potential of TNFα and IL1β Blockade for CRS/ICANS in CAR-T Therapy via Ameliorating Endothelial Activation.

Severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) strongly hampered the broad clinical applicability of chimeric antigen receptor T cell (CAR-T) therapy. Vascular endothelial activation has been suggested to contribute to the development of CRS and ICANS after CAR-T therapy. However, therapeutic strategies targeting endothelial dysfunction during CAR-T therapy have not been well studied yet. Here, we found that tumor necrosis factor α (TNFα) produced by CAR-T cells upon tumor recognition and interleukin 1β (IL1β) secreted by activated myeloid cells were the main cytokines in inducing endothelial activation. Therefore, we investigated the potential effectiveness of TNFα and IL1β signaling blockade on endothelial activation in CAR-T therapy. The blockade of TNFα and IL1β with adalimumab and anti-IL1β antibody respectively, as well as the application of focal adhesion kinase (FAK) inhibitor, effectively ameliorated endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Moreover, adalimumab and anti-IL1β antibody exerted synergistic effect on the prevention of endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Our results indicate that TNFα and IL1β blockade might have therapeutic potential for the treatment of CAR-T therapy-associated CRS and neurotoxicity.

Anti-inflammatory Effects of Naïve Stem Cells Dampen Systemic/Compartmental Overreactive Immune Responses

A cytokine release syndrome (CRS), associated with elevated circulating levels of several cytokines including interleukin (IL)-6 and interferon (IFN)-γ, might be seen in some infectious insults, for instance in severe acute respiratory syndrome (SARS) induced by Coronavirus (Cov)-2, as well as following administration of natural and bispecific antibodies and, more recently, following adoptive T-cell therapies for cancer. Normally, inflammatory conditions activate the innate and adaptive immune systems, which results in the release of cytokines, responsible for the phagocytosis of apoptotic vesicles and resolution of inflammation. Pro-inflammatory cytokines such as IL-1β, tumor necrosis factor alpha (TNFα) and, especially in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storms, IL-6 play crucial roles in inflammation. In some instances, however, this release gets out of hand, and features of overzealous immune responses (macrophage activation syndromes) might occur, leading to cytokine release syndromes (CRS) with inflammatory signs such as fever, fatigue, nausea, and sometimes secondary organ dysfunction or multi-organ failure. Apart from specific vaccines and maybe the anti-viral remdesivir and/or dexamethasone for treatment of CRS, there are no convincing disease-modifying interventions. So far, though, non-antiviral and immune-targeted interventions, also affecting non-target cells, were found associated with many side effects. A more targeted or focused approach is thus needed. Pending the site of the CRS-inducing insult, CRSs may occur systemic or compartmental. Recently, preclinical research yielded a beneficial anti-inflammatory effect of fresh naive bone marrow-derived stem cells (bm-SCs) in the treatment of various compartmental CRSs in the immune-privileged central nervous system (CNS). Therefore, it is argued that bm-SCs might also play a disease-modifying role in the systemic CRS. Bm-SCs have the advantage of targeting only the cells of interest as they are very selective in their actions. In addition, they actively move to the sight of inflammation.

Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management.

Chimeric antigen receptor T-cells (CAR-T) are improving outcomes in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemias and subtypes of non-Hodgkin Lymphoma. As this treatment is being increasingly utilized, a better understanding of the unique toxicities associated with this therapy is warranted. While there is growing knowledge on the diagnosis and treatment of cytokine release syndrome (CRS), relatively little is known about the associated cardiac events that occur with CRS that may result in prolonged length of hospital stay, admission to the intensive care unit for pressor support, or cardiac death. This review focuses on the various manifestations of cardiotoxicity, potential risk factors, real world and clinical trial data on prevalence of reported cardiotoxicity events, and treatment recommendations.

Interleukin 17 antagonist netakimab is effective and safe in the new coronavirus infection (COVID-19).

BackgroundCytokine release syndrome is a serious complication of the new coronavirus infection (COVID-19). The aim of the study was to assess effectiveness and safety of the IL-17 antagonist nekatimab for its treatment.MethodsThe retrospective study included COVID-19 patients with C-reactive protein levels >60 mg/L. Patients received either netakimab (group NET), IL-6 antagonist tocilizumab (group TOC) or no anti-cytokine treatment (group CON).ResultsForty-four patients were enrolled in the NET group, 27 patients in the TOC group, and 47 patients in the CON group. Mortality was lower in the NET group than in TOC and CON groups (2.3% vs. 14.8% and 31.9%; p = 0.018 and p < 0.001). NET group patients required intensive care unit admission (6.8% vs. 25.9% and 46.3%; p = 0.025 and p < 0.001) and mechanical ventilation (4.6% vs. 22.2% and 31.9%; p = 0.022 and p = 0.002) less frequently than patients of the TOC and CON groups. After 7–10 days of anti-cytokine drug administration, a reduction in lung lesion volume (p = 0.016) and an increase in the proportion of patients who did not need oxygen support (p = 0.005) or stayed in prone position (p = 0.044) was observed in the NET group only group; C-reactive protein levels were the same in the TOC and NET groups (p = 0.136) and lower in the CON group (p < 0.001 and p = 0.005). IL-6 levels decreased in the NET group (p = 0.005) and did not change in the TOC group (p = 0.953). There was no difference in the incidence of side effects between groups.ConclusionThe IL-17 antagonist netakimab is effective and safe in the treatment of cytokine release syndrome in COVID-19.Electronic Supplementary MaterialSupplementary material is available in the online version of this article at 10.1684/ecn.2021.0463.

Clinical trial enrollment at a rural satellite hospital during COVID-19 pandemic.

Controlled clinical trials (CCTs) have traditionally been limited to urban academic clinical centers. Implementation of CCTs in rural setting is challenged by lack of resources, the inexperience of patient care team members in CCT conductance and workflow interruption, and global inexperience with remote data monitoring. We report our experience during the coronavirus disease 2019 (COVID-19) pandemic in activating through remote monitoring a multicenter clinical trial (the Study of Efficacy and Safety of Canakinumab Treatment for cytokine release syndrome (CRS) in Participants with COVID-19-induced Pneumonia [CAN-COVID] trial, ClinicalTrials.gov Identifier: NCT04362813) at a rural satellite hospital, the VCU Health Community Memorial Hospital (VCU-CMH) in South Hill, VA, that is part of the larger VCU Health network, with the lead institution being VCU Health Medical College of Virginia Hospital (VCU-MCV), Richmond, VA. We used the local resources at the facility and remote guidance and oversight from the VCU-MCV resources using a closed-loop communication network. Investigational pharmacy, pathology, and nursing were essential to operate the work in coordination with the lead institution. Fifty-one patients with COVID-19 were enrolled from May to August 2020, 35 (69%) at VCU-MCV, and 16 (31%) at VCU-CMH. Among the patients enrolled at VCU-CMH, 37.5% were female, 62.5% Black, and had a median age of 60 (interquartile range 56-68) years. Local decentralization of this trial in our experience gave rural patients access to a novel treatment and also accelerated enrollment and more diverse participants' representative of the target population.

Plasma Exchange to Treat Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome after Anti-CD19 Chimeric Antigen Receptor-T Cell Infusion: A Case Report

Adoptive cell immunotherapy with chimeric antigen receptor-T (CAR-T) cells has shown remarkable clinical outcomes. However, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the two most significant toxicities during this therapy and can be life-threatening. We described a 12-year-old juvenile who had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia (r/r B-ALL). The patient was recruited into our phase I clinical trial concerning ssCAR-T-19 (anti-CD19 CAR-T cells with shRNA targeting IL-6), and 5*106 /kg of engineered ssCAR-T-19 cells were administered. After infusion, the patient underwent a typical CRS reaction, with fever and increased cytokine levels. He was treated with antipyretic drugs, methylprednisolone, and tocilizumab, but the effect was limited. He developed coagulation abnormalities, multiple organ dysfunction, lung infection and ICANS. Apart from the necessary supportive and symptomatic treatment, plasma exchange was performed three times in four days while methylprednisolone pulse was performed for two consecutive days. After that, the body temperature, heart rate, and especially the cytokine levels declined. But digestive tract hemorrhage occurred to him and he was transferred to intensive care unit. To make things worse, he developed acute respiratory failure and received intubation and mechanical ventilation. In addition, symptomatic treatment such as suppression of stomach acid and anti-infection was given. The bleeding was controlled, and his respiratory function improved, and the CRS and ICANS-related symptoms were relieved. He received extubation and was transferred back to the general ward. Additionally, abone marrow smear showed no lymphoblast cells, and minimal residual disease in bone marrow was negative on day +22 and day +30. The patient was eventually discharged in a normal condition. In conclusion, CRS and ICANS as two most common toxicities after CAR-T therapy, which often cause patient death. Several methods such as anti-IL-6 therapy and/or corticosteroids have been adopted in the management guidelines of CRS and ICANS except plasma exchange. This case shows the validity of plasma exchange in a patient with severe CRS and ICANS after receiving ssCAR-T.

Therapeutic Effect of Macrophage-Derived Biomimetic Nanoparticles for Cytokine Release Syndrome

Cytokine release syndrome (CRS) is a severe complication of infectious diseases such as coronavirus disease 2019 (COVID-19) that cause serious damage to public health. Currently, no effective therapeutic strategy exists for CRS treatment in clinic, and supportive therapy is still the main method. Here, we show the potential of macrophage membrane-biomimetic nanoparticles for CRS treatment. By fusing macrophage membrane on the surface of the PLGA skeleton, we constructed biomimetic nanoparticles that inherited the membrane receptors from the "parental" macrophages, enabling the neutralization of CRS-related cytokines. We compared three types of macrophage membranes to screen out more effective biomimetic nanoparticles for CRS treatment. Our results show that biomimetic nanoparticles containing M0 macrophage membrane can decrease the levels of pro-inflammatory cytokines involved in CRS to the greatest extent. In a mouse model of RNA virus analog-induced CRS, the macrophage membrane-biomimetic nanoparticles manifested significant therapeutic efficacy by reducing cytokine levels and alleviating organ damage.Funding Information: This work was supported by Scientific Research Project of Tongji University (22120200021), the National Natural Science Foundation of China (82073385 and 81803078), Shanghai Science and Technology Committee (20DZ2255200 and 21140901900).Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: All animal studies were approved under the guidelines of Tongji University Institutional Animal Care and Use Committee.

Increased Secondary Infection in COVID-19 Patients Treated with Steroids in New York City.

Steroids are expected to be effective in the treatment of cytokine release syndrome, which is considered to be associated with severe cases of coronavirus disease 2019 (COVID-19). We aimed to investigate the use of steroids and its effects. We conducted a retrospective chart review and an analysis of 226 consecutive hospitalized patients with confirmed COVID-19. Patients were divided into those who received steroids (steroid group) and those who did not (no steroid group). Inverse probability weighted analysis was performed to assess the effect of steroids on in-hospital mortality. The steroid group had higher rates of preexisting hypertension and peripheral vascular disease as well as higher lactate dehydrogenase levels, d-dimer levels, and inflammatory markers than the no steroid group (all P <0.05). The steroid group had significantly higher rates of multifocal pneumonia than the no steroid group at admission (75.4% vs. 50.3%, P = 0.001). Notably, the steroid group had higher rates of developing bacterial infection (25% vs. 13.1%, P = 0.041) and fungal infection (12.7% versus 0.7%, P <0.001) during the hospital course than the no steroid group. After adjustment, it was observed that steroids did not decrease or increase in-hospital mortality (odds ratio [95% confidence interval]: 1.02 [0.60-1.73, P = 0.94]). There was an increase in bacterial and fungal infections with steroid use.