1 Management of Toxicities Associated with Bispecific Immune Cell Engager Monoclonal Antibodies - Adult - Inpatient/Ambulatory/Emergency Department Consensus Care Guideline Note: Active Table of Contents – Click each header below to jump to the section of interest Table of Contents INTRODUCTION .................................................................................................................................3 SCOPE ................................................................................................................................................3 DEFINITIONS ......................................................................................................................................4 RECOMMENDATIONS .........................................................................................................................4 METHODOLOGY ............................................................................................................................... 10 REFERENCES .................................................................................................................................... 13 APPENDIX ........................................................................................................................................ 14 Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 2 Content Expert: Mike Fallon, PharmD, BCOP - Pharmacy Phone Number: (608) 263-7230 Email Address: Mike Fallon Contact for Changes: Jason Bergsbaken, PharmD, BCOP - Pharmacy Phone Number: (608) 265-0341 Email Address: Jason Bergsbaken Guideline Authors: Mike Fallon, PharmD, BCOP - Pharmacy Cameron Ninos, PharmD, BCOP - Pharmacy Harpreet Sandhu, PharmD - Pharmacy Workgroup Members Jason Bergsbaken, PharmD, BCOP - Pharmacy Julie Chang, MD - Medicine, Hematology/Oncology Elizabeth Dow-Hillgartner, PharmD, BCPS, BCOP - Pharmacy Vaishalee Kenkre, MD - Medicine, Hematology/Oncology Tim Schmidt, MD - Medicine, Hematology/Oncology Elaine Stenstrup, MSN, RN - Nursing Nataliya Uboha, MD, PhD - Medicine, Hematology/Oncology Reviewers: Natalie Callander, MD - Medicine, Hematology/Oncology Aric Hall, MD - Medicine, Hematology/Oncology Ryan Mattison, MD - Medicine, Hematology/Oncology Linda Eckstein, NP - Medicine, Hematology/Oncology Christopher Nemergut, PharmD - Center for Clinical Knowledge Management Jennifer Trott, NP - Medicine, Hematology/Oncology Committee Approvals: Chemotherapy Council: August 2023 Pharmacy & Therapeutics Committee: September 2023 Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 3 Introduction Bispecific immune cell engager monoclonal antibodies are novel immunotherapeutics designed to bind two different antigens simultaneously to activate immune cells leading to subsequent lysis and death of targeted cells. Currently all FDA-approved products are bispecific T-cell engaging (BiTE) agents, but development continues for products that engage other immune cells such as macrophages, natural killer cells, or dendritic cells. Administration of these products may be accompanied by cytokine release which can evolve to a potentially severe and life-threatening inflammatory syndrome. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are supraphysiologic responses following an immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.1-3 The supraphysiologic response is related to increased levels of several cytokines including IL-2, IL-5, IL-6, IL-8, IL-10, IFN-γ, and TNF-α as well as granulocyte macrophage-colony stimulating factor (GM-CSF). The predominate cytokine primarily implicated in CRS toxicity is IL-6 that initiates a proinflammatory response at elevated levels. CRS symptoms can be progressive, must include fever at onset, and may include hypotension, capillary leak (hypoxia), and end organ dysfunction requiring urgent medical attention and supportive care based on presenting signs and symptoms.3 ICANS symptoms may range from subtle inattention, dysgraphia, language disturbance, confusion, altered mental status, and may progress to seizures or cerebral edema. CRS and ICANS can occur concomitantly. UW Health Hematology/Oncology practitioners have agreed to endorse recommendations from the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading for CRS and ICANS associated with immunotherapeutics including BiTE agents. There is significant variation in the incidence, onset, and time to resolution of CRS among available products (See Appendix). Site of care coordination will be optimized based on product-specific CRS and ICANS features.4-7 While there is a unified grading system for CRS and ICANS, the optimal management strategies for BiTE products are less well defined. The efficacy of bispecific immune cell engager monoclonal antibodies in combination with “off-the- shelf” convenience has led to increased use and rapid development of multiple products. Recent advances in both solid tumor and hematologic malignancy immunotherapies have demonstrated the need for guidance on CRS and ICANS management in non-cellular therapies. Other BiTE adverse effects (e.g., infections, cytopenias, and hemophagocytic lymphohistiocytosis) are outside the scope of this guideline but also require vigilant monitoring.1 Scope Intended Users: Physicians, Advanced Practice Providers, Pharmacists, Nurses, Technical Support Objective: To provide guidance on the grading and prompt management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome arising from bispecific immune cell engager monoclonal antibody therapy in adult patients based on manufacturer recommendations and evidence-based interventions Target Population: Adult patients with toxicities associated with bispecific immune cell engager monoclonal antibody therapies in the inpatient, emergency department, or ambulatory setting Clinical Questions Considered: • What clinical assessment should be conducted when evaluating a patient with suspected CRS and/or ICANS? • How long should patients be monitored after receiving bispecific immune cell engager monoclonal antibody therapies for CRS and/or ICANS? When is it safe to administer therapy as in the outpatient setting? • How are toxicities classified for CRS and/or ICANS and what are the appropriate treatments for the various levels of severity? • When should tocilizumab be used for the treatment of CRS and/or ICANS? Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 4 Definitions • ASTCT: American Society for Transplantation and Cellular Therapy • BiTE: Bispecific T-cell Engager • CTCAE: Common Terminology Criteria for Adverse Events • CAR-T: Chimeric antigen receptor T cell • CRS: Cytokine release syndrome. A supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms can be progressive, must include fever at the onset, and may include hypotension, capillary leak (hypoxia), and end organ dysfunction. • HLH/MAS: Hemophagocytic lymphohistiocytosis/macrophage activation syndrome • ICANS: Immune effector cell-associated neurotoxicity syndrome. A disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. Symptoms or signs can be progressive and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema. • Organ specific toxicity is defined according to CTCAE Recommendations 1. Therapy Coordination 1.1. Bispecific T-cell engager medication prior authorization approval should be completed prior to therapy start. If needed, home health infusion coverage prior authorization also must be completed. (UW Health Strong Recommendation, Very Low Quality of Evidence) 1.2. Timely patient scheduling should include clear site of care (i.e. ambulatory, inpatient, or a mix of ambulatory/inpatient) and length of required monitoring communication to the patient and clinical care team.4-7 Refer to product-specific details (Refer to Appendix) for clinical site of administration and post- infusion monitoring time recommendations. (UW Health Strong Recommendation, Moderate Quality of Evidence) 1.3. Ambulatory post-dose monitoring plan should be established with patients and caregivers prior to the first dose. Plan should support reasonable access to continuous adverse event monitoring during the first cycle and reliable transportation to a medical facility that can support adverse effect management if needed.1-3 An appropriate emergency department should be identified. If needed, home health infusion staff travel limits should also be assessed (e.g., some providers will only travel up to two hours). (UW Health Strong Recommendation, High Quality of Evidence) 1.4. The Hematology or Oncology attending physician will maintain primary responsibility for patient and provide oversight to other providers and specialties to provide prompt evaluation and treatment of side effects. (UW Health Strong Recommendation, Very Low Quality of Evidence) 1.4.1. The Hematology or Oncology attending physician should be notified whenever care is escalated, and prior to administering tocilizumab, anakinra, siltuximab, and/or corticosteroids. Order sets should be utilized for management of adverse effects. (UW Health Strong Recommendation, Low Quality of Evidence) 1.5. Nurses are responsible for providing patient wallet cards and educating patients/families/caregivers regarding CRS and ICANS symptom monitoring and reporting upon administration of the first dose of therapy.1,4-6 (UW Health Strong Recommendation, High Quality of Evidence) 1.6. Ambulatory patient management1,3-6 1.6.1. Patients should be monitored for signs/symptoms of CRS and ICANS on days of therapy and at least twice weekly during weeks 1 and 2 and at least weekly during weeks 3 and 4 with increased monitoring as clinically appropriate. Monitoring after week 4 will be based on provider discretion. (UW Health Strong Recommendation, High Quality of Evidence) 1.6.2. Patients should be instructed to take their temperature twice daily and call their clinic/provider immediately for a fever greater than or equal to 100.4 °F (38 °C), or any other signs/symptoms of CRS or ICANS. (UW Health Strong Recommendation, High Quality of Evidence) Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 5 1.6.3. Patients should be provided a dexamethasone 8 mg once if needed prescription for severe CRS (e.g. shaking chills, difficulty breathing, feeling severely ill, etc.) to take at home if instructed prior to travel to the Emergency Department. (UW Health Conditional Recommendation, Moderate Quality of Evidence) 1.6.4. Consider inpatient admission for patients who develop CRS or ICANS. (UW Health Strong Recommendation, High Quality of Evidence) 1.7. Inpatients patient management1,3-6 1.7.1. Admission order sets should be utilized to ensure standardized monitoring. (UW Health Strong Recommendation, Moderate Quality of Evidence) 1.7.2. Patients should be monitored daily to every eight hours for signs/symptoms of CRS and daily at a minimum for signs/symptoms of ICANS with increased monitoring as clinically appropriate. (UW Health Strong Recommendation, Moderate Quality of Evidence) 1.7.3. Guidelines for transfer to a higher level of care.1-3 (UW Health Strong Recommendation, Moderate Quality of Evidence): 1.7.3.1. Monitoring required more frequently than every 4 hours 1.7.3.2. Persistent hypotension (SBP below 90 mmHg) after 500 to 1000 mL normal saline bolus 1.7.3.3. Low-dose vasopressor support required 1.7.3.4. Oxygen needs greater than 6 L nasal cannula or oxymask, rapidly increasing oxygen needs, or inability to keep oxygen saturation greater than 90% 1.7.3.5. Neurologic changes (ICE less than 7, Grade 3 or higher ICANS, moderate somnolence or encephalopathy limiting instrumental ADLs, moderate disorientation or confusion, seizures, moderate dysphagia impairing ability to communicate spontaneously, deep focal motor weakness such as hemiparesis or paraparesis or focal/local edema on neuroimaging) 2. Cytokine Release Syndrome (CRS) Monitoring and Treatment 2.1. CRS Grade Monitoring1,3 2.1.1. CRS grading should be determined using criteria from Table 1 (UW Health Strong Recommendation, High Quality of Evidence) 2.1.2. Timing of CRS grading should occur during ambulatory clinic visits or every eight hours to daily in the inpatient setting or based on manufacturer recommendations if specified and/or as clinically appropriate. Monitoring after week 4 will be based on provider discretion. (UW Health Conditional Recommendation, Moderate Quality of Evidence) 2.1.3. Ambulatory patients should be instructed to take their temperature twice daily and call their clinic/provider immediately for a fever greater than or equal to 100.4 °F (38 °C), or any other signs/symptoms of CRS. Patients should be directed to seek emergency room care if clinically appropriate. (UW Health Strong Recommendation, Moderate Quality of Evidence) 2.1.4. CRS grading will be determined by the most severe event: hypotension or hypoxia not attributable to other causes. (UW Health Strong Recommendation, High Quality of Evidence) 2.1.5. CRS can contribute to systemic multiorgan dysfunction which should be graded according to CTCAE v 5.0 guidelines; consider treating as severe CRS as clinically appropriate.1,3,8 (UW Health Strong Recommendation, High Quality of Evidence) 2.1.6. Early treatment escalation may be considered for elderly patients or those with considerable comorbidities.1,4-7 (UW Health Conditional Recommendation, Moderate Quality of Evidence) Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 6 Table 1. ASTCT CRS Consensus Grading Parameter Grade 1 Grade 2 Grade 3 Grade 4 Fever Temp ≥38°C Temp ≥38°C Temp ≥38°C Temp ≥38°C With With With Hypotension None Hypotension, not requiring vasopressors Requiring vasopressor with or without vasopressin Requiring multiple vasopressors (excluding vasopressin) And/or And/or And/or Hypoxia None Requiring low-flow nasal cannulaA or blow-by Requiring high-flow nasal cannulaB, facemask, nonrebreather mask, or Venturi mask Requiring positive pressure (i.e., CPAP, BiPAP, intubation and mechanical ventilation) A Low-flow nasal cannula defined as oxygen delivered at ≤6 L/minute B High-flow nasal cannula defined as oxygen delivered at >6 L/minute C Vasopressors: Norepinephrine, Dopamine, Phenylephrine, Epinephrine, Vasopressin Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 7 Table 2. CRS Management and Treatment1,3,8-19 All Grades Management • Hold BiTE infusion or hold further doses until CRS resolves • Evaluate for infection (e.g., pan-culture, respiratory viral panel, CXR and/or non-contrast CT) • Monitor CMP, CBC ferritin, C-reactive protein, and coagulation lab panels daily at a minimum or more frequently if clinically appropriate • Monitor pulmonary, renal, and hepatic function closely • If no improvement within 24 to 72 hours or ferritin rising despite management assess for HLH/MAS and treat separately if clinically indicated • Assess product specific package insert for guidance on subsequent dosing following CRS including: timing to next dose, infusion time and dose modifications, premedication recommendations, and hospitalization requirements CRS grade Assessment/Monitoring Supportive care Tocilizumab Corticosteroids 1 • Follow All Grades management • Consider telemetry and/or continuous pulse oximetry • Vitals every 2-4 hours or as clinically appropriate • Consider hospitalization until symptoms resolve • Antipyretics per provider discretion: acetaminophen preferred as primary treatment option for fever • Intravenous fluids per provider discretion; judicious use encouraged given vascular leak etiology of CRS related hypoxia • Consider empiric broad spectrum antibiotics • If no improvement after 24 to 48 hours, consider tocilizumab 8 mg/kg IV (maximum 800 mg). Consider earlier use if significant symptoms, comorbidities, and/or over 65 years old. If concurrent ICANS give corticosteroids prior to tocilizumab. • If no clinical improvement in CRS after the first dose, repeat tocilizumab 8 mg/kg IV (maximum) once • If no resolution of fever after 48 to 72 hours, consider one dose of dexamethasone 10 mg IV 2 • Follow All Grades management • Telemetry and continuous pulse oximetry • Vitals every 2-4 hours or as clinically appropriate • Supportive measures as above • Hospitalize until symptoms resolve • Administer 1L normal saline fluid bolus over 1 hour; repeat as needed for up to 3L to maintain systolic BP ≥90 mm Hg • Supplemental oxygen as needed • If recurrent Grade 2 consider treating as Grade 3 • Give tocilizumab 8 mg/kg IV (maximum 800 mg). If concurrent ICANS give corticosteroids prior to tocilizumab. • If no clinical improvement in CRS after the first dose, may repeat tocilizumab every 8 hours as needed. Limit to a maximum of 3 doses in a 24- hour period; maximum total of 4 doses. • If no improvement within 24 hours of starting tocilizumab, consider dexamethasone 10 mg IV daily • If improving, continue corticosteroids use until the event is Grade 1 or less, then quickly taper as clinically appropriate • If no improvement, manage as per Grade 3 3 • Follow All Grades management • If patient transferred to higher acuity unit, increase frequency of monitoring as clinically appropriate • If recurrent grade 3 consider permanently discontinue offending BiTE therapy • Supportive measures as above • May consider ICU transfer • May require vasopressor • Continue as needed IV fluid bolus to maintain perfusion • Give tocilizumab 8 mg/kg IV (maximum 800 mg) • If no clinical improvement in CRS after the first dose, repeat tocilizumab every 8 hours as needed. Limit to a maximum of 3 doses in a 24- hour period; maximum total of 4 doses. • If no improvement or rapid progression after 2 doses of tocilizumab/escalation of steroids, consider alternative immunosuppressants (e.g., anakinra 8-10 mg/kg/day IV in 3 to 4 divided doses, siltuximab 11 mg/kg IV once) • Administer dexamethasone 10 mg IV every 8 hours • If improving, continue corticosteroids use until the event is Grade 1 or less, then quickly taper as clinically appropriate • If no improvement within 24 hours or rapid progression of CRS, administer dexamethasone 20 mg IV every 6 hours. If no improvement within 24 hours or continued rapid progression switch to high-dose methylprednisolone 1000 mg IV daily for 3 days. 4 • Follow All Grades management • If patient transferred to higher acuity unit, increase frequency of monitoring as clinically appropriate • Permanently discontinue offending BiTE therapy • Supportive measures as above • Transfer to ICU • May utilize multiple vasopressors as appropriate • Continue as needed IV fluid bolus to maintain perfusion • Give tocilizumab per Grade 3 • If no improvement or rapid progression after 2 doses of tocilizumab/escalation of steroids, consider alternative immunosuppressants (e.g, anakinra 8-10 mg/kg/day IV in 3 to 4 divided doses, siltuximab 11mg/kg IV once) • As above or administer high dose methylprednisolone 1000 mg IV daily for 3 days • If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 8 3. Immune Effect Cell-Associated Neurotoxicity Syndrome (ICANS) Management 3.1. ICANS Grade Monitoring1,3 3.1.1. ICANS grading may be determined using criteria from Table 5. (UW Health Strong Recommendation, High Quality of Evidence) 3.1.2. Timing of ICANS grading should occur on the day of ambulatory visits or at least daily in the inpatient setting or based on manufacturer recommendations if specified and/or as clinically appropriate. (UW Health Strong Recommendation, Moderate Quality of Evidence) 3.1.3. Ambulatory patients should be instructed to call their clinic/provider immediately for any signs/symptoms of ICANS and should be directed to seek Emergency Departmenmt care if appropriate. (UW Health Strong Recommendation, Moderate Quality of Evidence) 3.1.4. To determine ICANS grading, encephalopathy must be evaluated using BOTH neurotoxicity clinical assessment AND the Immune Effector Cell-Associated Encephalopathy (ICE) score (UW Health Strong Recommendation, High Quality of Evidence) 3.1.4.1. ICE scores should be documented using the Cellular Therapy Toxicity [HL 511]: Encephalopathy Assessment Tool Flowsheet. 3.1.5. Management is determined by the most severe event, not attributable to any other cause. (UW Health Strong Recommendation, Moderate Quality of Evidence) Table 3. ASTCT ICANS Consensus Grading for Adults1,3 Neurotoxicity Domain Grade 1 Grade 2 Grade 3 Grade 4 ICE Score 7-9 3-6 0-2 0 Depressed level of consciousness not attributable to another cause Awakens spontaneously Awakens to voice Awakens only to tactile stimulus Unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma Seizure N/A N/A Clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention Life-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between Motor findings N/A N/A N/A Deep focal motor weakness such as hemiparesis or paraparesis Elevated ICP/cerebral edema N/A N/A Focal/local edema on neuroimaging Diffuse cerebral edema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema; or Cushing’s triad Table 4. ICE Scoring Tool (Total of 10 points) Category Tasks Associated Points Orientation Orientation to year, month, city, hospital 4 points Naming Ability to name 3 objects 3 points Following commands Ability to follow simple commands 1 point Writing Ability to write a standard sentence 1 point Attention Ability to count backwards from 100 by 10 1 point Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 9 Table 5. Management and Treatment and of ICANS2,3,9,12-19 Grade If concurrent CRS, manage CRS per above Section 2 1 • Monitor neurologic symptoms and consider Neurology consultation and evaluation • Consider anti-seizure prophylaxis (e.g., levetiracetam preferred) 2 • Consider anti-seizure prophylaxis (e.g., levetiracetam preferred) • Consider Neurology consultation and other specialists (e.g. Critical Care) for further evaluation, as needed • Administer dexamethasone 10 mg IV every 12 hours; if improvement not rapid consider dexamethasone 10 mg IV every 6 hours • Continue dexamethasone use until the event is Grade ≤1, then taper 3 • Consider anti-seizure prophylaxis (e.g., levetiracetam preferred) • Consult Neurology and other specialists (e.g. Critical Care) for further evaluation, as needed. • Administer dexamethasone 10 mg IV every 6 hours; if improvement not rapid consider dexamethasone 20 mg IV every 6 hours • Continue dexamethasone use until the event is Grade ≤1, then taper • If not improving consider methylprednisolone 1000 mg IV daily for up to 3 days and consider alternative immunosuppressants (e.g. anakinra 8-10 mg/kg/day IV in 3-4 divided doses) 4 • Consider anti-seizure prophylaxis (e.g., levetiracetam preferred) • Consult Neurology and other specialists (e.g. Critical Care) for further evaluation, as needed • Dexamethasone as above or consider administration of methylprednisolone 1000 mg IV per day for 3 days • Consider alternative immunosuppressants (e.g. anakinra 8-10 mg/kg/day IV in 3-4 divided doses); siltuximab 11 mg/kg IV once may be considered for Grade 4 ICANS refractory to high-dose methylprednisolone and anakinra • Continue dexamethasone use until the event is Grade ≤1, then taper Disclaimer Clinical practice guidelines assist clinicians by providing a framework for the evaluation and treatment of patients. This guideline outlines the preferred approach for most patients. It is not intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely establish the only appropriate approach to a problem. Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 10 Methodology Methods Used to Collect the Evidence: The following criteria were used by the guideline authors and workgroup members to conduct electronic database searches in the collection of evidence for review. Development of clinical question(s) and rationale: (From A3/PICOT) • In patients receiving bispecific immune cell engager monoclonal antibody therapy (non-CAR-T therapy), how does standardized grading for CRS compare with manufacturer grading affect toxicity treatment within inpatient stays? Literature Sources: • Electronic database search (e.g., PubMed) • Databases of systematic reviews (e.g., Cochrane Library) • Hand-searching journals, external guidelines, and conference publications Time Period: Published articles after 2019 due to the novel nature of these medications and reactions Search Terms: • [(“cytokine release syndrome management” OR “CRS”)] • [(“cytokine release syndrome”) AND [(“solid malignancy”) • [(“cytokine release syndrome”) AND [(“bispecific t-cell engager”) • [(“blinatumomab” OR “tebentafusp OR “mosunetuzumab” OR “teclistamab” OR “epcoritamab” OR “glofitamab” OR “talquetamab” AND “tocilizumab”)] • [(“blinatumomab” OR “tebentafusp OR “mosunetuzumab” OR “teclistamab” OR “epcoritamab” OR “glofitamab” OR “talquetamab”) AND (“CRS” OR “Cytokine release syndrome”) • [(“blinatumomab” OR “tebentafusp OR “mosunetuzumab” OR “teclistamab” OR “epcoritamab” OR “glofitamab” OR “talquetamab”) AND (“CRS management” OR “Cytokine release syndrome management”) • [(“blinatumomab” OR “tebentafusp OR “mosunetuzumab” OR “teclistamab” OR “epcoritamab” OR “glofitamab” OR “talquetamab”) AND [(“side effect” or “adverse effect”) Methods to Select the Evidence: Describe the inclusion/exclusion criteria used for selecting the literature; include chosen variables such as language, study design, outcomes, and comparisons. Describe outcome measures and intervention selection criteria. Methods Used to Formulate the Recommendations: The workgroup members agreed on recommendations via a consensus process using discussion of the literature and expert experience/opinion. If issues or controversies arose where consensus could not be reached, the topic was escalated appropriately per the guiding principles outlined in the UW Health Clinical Practice Guideline Resource Guide. Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations: Internally developed recommendations were evaluated by the guideline workgroup using an algorithm adapted from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (see Figure 1).20 Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 11 Figure 1. GRADE Methodology adapted by UW Health Rating Scheme for the Strength of the Evidence/Recommendations: GRADE Ranking of Evidence High We are confident that the effect in the study reflects the actual effect. Moderate We are quite confident that the effect in the study is close to the true effect, but it is also possible it is substantially different. Low The true effect may differ significantly from the estimate. Very Low The true effect is likely to be substantially different from the estimated effect. GRADE Ratings for Recommendations For or Against Practice Strong (S) Generally should be performed (i.e., the net benefit of the treatment is clear, patient values and circumstances are unlikely to affect the decision) Conditional (C) May be reasonable to perform (i.e., may be conditional upon patient values and preferences, the resources available, or the setting in which the intervention will be implemented) ASTCT Grading Evidence Experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. Recognition of Potential Health Care Disparities: Disparities in the treatment of patients with malignancies exist. The availability of novel diagnostic and therapeutic measures (novel chemotherapy) and the opportunity to participate in clinical trials may be affected by multiple factors (e.g., geographical location, socioeconomic status). Distrust of the health care system, stigmas related to cancer and death, literacy and language barriers, and poor expectations regarding the outcome from cancer care may also influence treatment outcomes. Barriers may include race/ethnicity, socioeconomic status, and distance. Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 12 Collateral Tools & Resources The following collateral tools and resources support staff execution and performance of the evidence-based guideline recommendations in everyday clinical practice. Metrics • Utilization of tocilizumab per year for bispecific immune cell engager monoclonal antibodies (i.e., non- CAR-T products) • Average tocilizumab use for tebentafusp • Incidence of cytokine release syndrome Grade 1 or higher • Number of cytokine release syndrome events per patient • Incidence of siltuximab use for CRS management Beacon Protocols • CSC HEM INPT/OUTPT BLINATUMOMAB(42D:1-28) MRD- POSITIVE B-ALL AND PATIENT WEIGHT LESS THAN 45 KG VER: 5-19-22 [HL 7355] • CSC HEM INPT/OUTPT BLINATUMOMAB(42D:1-28) MRD- POSITIVE B-ALL AND PATIENT WEIGHT GREATER THAN OR EQUAL TO 45 KG VER: 5-19-22 [HL 6970] • CSC HEM INPT/OUTPT BLINATUMOMAB(42D:1-28) RELAPSED/REFRACTORY B-ALL VER: 5-19-22 [HL 5728] • CSC HEM INPT/OUTPT EPCORITAMAB(28D) VER: 6-30-23 [HL 10023] • CSC HEM INPT/OUTPT GLOFITAMAB(21D)/OBINUTUZUMAB(C1D1 ONLY) VER: 8-4-23 [HL 10082] • CSC HEM MOSUNETUZUMAB(21D) VER: 4-6-23 [HL 9921] • CSC MELANOMA TEBENTAFUSP VER: 4-12-22 [HL 9586] • CSC HEM INPT/OUTPT TECLISTAMAB(28D) STEP-UP DOSING C1D1,3,5 VER: 1-6-23 [HL 9857] • CSC HEM INPT/OUTPT TECLISTAMAB(28D) STEP-UP DOSING C1D1,4,7 VER: 1-6-23 [HL 9803] HealthLink Flowsheets • UW BMT CELLULAR THERAPY TOXICITY [HL 511]: Encephalopathy Assessment Tool Order Sets & Smart Sets • Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Management for Bispecific T-Cell Engager Agents [9887] • IP - CAR-T Therapy - Adult - Admission [6804] Patient Resources • Blinatumomab Wallet Card • Epcoritamab Wallet Card • Glofitamab Wallet Card • Mosunetuzumab Wallet Card • Talquetamab Wallet Card: Navigate to Resources for Prescribers and then Patient Wallet Card • Tebentafusp Patient Guide • Teclistamab Wallet Card: Navigate to Resources for Prescribers and then Patient Wallet Card Procedures • Inventory Management of Tocilizumab for CAR-T Patients Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 13 References 1. National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities (Version 2.2023). https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Updated February 2023. Accessed June 1, 2023. 2. Cobb DA, Lee DW. Cytokine Release Syndrome Biology and Management. Cancer J. Mar-Apr 01 2021;27(2):119-125. doi:10.1097/ppo.0000000000000515 3. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. Apr 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758 4. A Study Evaluating Efficacy and Safety of Mosunetuzumab in Combination With Polatuzumab Vedotin Compared to Rituximab in Combination With Gemcitabine Plus Oxaliplatin in Participants With Relapsed or Refractory Aggressive B-Cell Non-Hodgkin's Lymphoma (SUNMO). ClinicalTrials.gov identifier: NCT05171647. Updated May 23, 2023. Accessed June 19, 2021. https://clinicaltrials.gov/ct2/show/NCT05171647. 5. A Study of Teclistamab in Combination With Daratumumab Subcutaneously (SC) (Tec-Dara) Versus Daratumumab SC, Pomalidomide, and Dexamethasone (DPd) or Daratumumab SC, Bortezomib, and Dexamethasone (DVd) in Participants With Relapsed or Refractory Multiple Myeloma (MajesTEC-3). ClinicalTrials.gov identifier: NCT05083169. Updated May 31, 2023. Accessed June 19, 2021. https://clinicaltrials.gov/ct2/show/NCT05083169. 6. Nathan P, Hassel JC, Rutkowski P, et al. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. Sep 23 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485 7. Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. J Clin Oncol. Apr 20 2023;41(12):2238-2247. doi:10.1200/jco.22.01725 8. National Cancer Institute. Common terminology criteria for adverse events (CTCAE). Version 5.0. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed April 24, 2023. 9. Gazeau N, Liang EC, Wu QV, et al. Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy. Transplant Cell Ther. Jul 2023;29(7):430-437. doi:10.1016/j.jtct.2023.04.001 10. Hines MR, Knight TE, McNerney KO, et al. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome. Transplant Cell Ther. Jul 2023;29(7):438.e1-438.e16. doi:10.1016/j.jtct.2023.03.006 11. Lipe BC, Renaud T. Siltuximab as a primary treatment for cytokine release syndrome in a patient receiving a bispecific antibody in a clinical trial setting. J Oncol Pharm Pract. Jun 2023;29(4):1006-1010. doi:10.1177/10781552221140320 12. Strati P, Ahmed S, Kebriaei P, et al. Clinical efficacy of anakinra to mitigate CAR T-cell therapy-associated toxicity in large B- cell lymphoma. Blood Adv. Jul 14 2020;4(13):3123-3127. doi:10.1182/bloodadvances.2020002328 13. Blincyto (blinatumomab) [prescribing information]. Thousand Oaks, CA: Amgen Inc; June 2023. 14. Lunsumio (mosunetuzumab) [prescribing information]. South San Francisco, CA: Genentech, Inc; December 2022. 15. Kimmtrak (tebentafusp) [prescribing information]. Conshohocken, PA: Immunocore Commercial LLC; November 2022. 16. Tecvayli (teclistamab) [prescribing information]. Horsham, PA: Janssen Biotech Inc; October 2022. 17. Epkinly (epcoritamab) [prescribing information]. Plainsboro, NJ: Genmab US Inc; May 2023. 18. Columvi (Glofitamab) [prescribing information]. South San Francisco, CA: Genentech Inc; June 2023. 19. Talvey (talquetamab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; August 2023. 20. Goss E, Lopez AM, Brown CL, Wollins DS, Brawley OW, Raghavan D. American society of clinical oncology policy statement: disparities in cancer care. J Clin Oncol. Jun 10 2009;27(17):2881-5. doi:10.1200/jco.2008.21.1680 Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 14 Appendix Table. FDA-approved bispecific immune cell engager monoclonal antibodies13-19 Drug Targets Indication CRS Incidence Grade 3 or 4 CRS Incidence Median Time to CRS Onset Median Time to CRS Resolution Blinatumomab CD19 CD3 Treatment of B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children 7% to 15% 2% to 5% 3 days (range 1-22 days) 2 days (range 1-14 days) Epcoritamab CD20 CD3 Treatment of relapsed/refractory DLBCL adult patients 51% 2.5% 1 day (range 1-10 days) 2 days (range 1-27 days) Glofitamab CD20 CD3 Treatment of relapsed/refractory DLBCL adult patients 63% 4% 13.5 hours (range 6-52 hours) 1.3 days (range 0.02-13 days) Mosunetuzumab CD20 CD3 Treatment of relapsed/refractory follicular lymphoma adult patients 39% 2.5% Cycle 1 Day 1: 5 hours Cycle 1 Day 8: 28 hours Cycle 1 Day 15: 25 hours Cycle 2 Day 1: 46 hours 3 days (range 1-29 days) Talquetamab GPRC5D CD3 Treatment of relapsed/refractory multiple myeloma adult patients 76% 1.5% 27 hours (range 0.1-167 hours) 0.7 days (range 0-26 days) Tebentafusp gp100 peptide CD3 Treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma 89% 1% Within a few hours after administration of first 3 doses 2 days Teclistamab BCMA CD3 Treatment of relapsed/refractory multiple myeloma adult patients 72% 0.6% 2 days (range 1-6 days) 2 days (range 1-9 days) Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023 15 Table. Monitoring for FDA-approved BsAb products13-19 Drug UW Administration LocationA Recommendations for Initial and Subsequent DosingB Blinatumomab IV • First 3 to 9 days of Cycle 1 and first 2 days of Cycle 2: Inpatient • Late Cycle 1/2 and additional Cycles: Ambulatory • MRD-positive B-cell ALL / MRD-negative B-cell ALL o Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle • Relapsed/refractory B-cell ALL o Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle • If patient develops Grade 3 CRS, admit to hospital to restart at 9 mcg/day, and escalate to 28 mcg/day after 7 days if tolerated Epcoritamab SubQ • Step-up dosing (Cycle 1 - Day 1, 8): Ambulatory • Step-up dosing (Cycle 1 - Day 15): Inpatient • Cycle 1 Day 22 and beyond: Ambulatory • Cycle 1 ambulatory doses to include three CRS checks (pre-administration, 30 minutes post-dose, and prior to clinic discharge) o Hospitalization is recommended for 24 hours after administration of Cycle 1 Day 15 • If patient develops Grade 2 CRS following any dose, monitor more frequently and consider hospitalization for the next dose • If patient develops Grade 3 CRS following any dose, patient should be hospitalized for 24 hours following the subsequent dose; permanently discontinue if recurrent Grade 3 CRS Glofitamab IV • Initial dosing (Cycle 1 - Day 1): Ambulatory • Step-up dose #1 (Cycle 1 - Day 8): Inpatient • Step-up dose #2 (Cycle 1 - Day 15): Ambulatory unless CRS with step-up dose #1 • Cycle 2 and beyond: Ambulatory • Hospitalization is recommended for 24 hours after administration of Cycle 1 Day 8 • If patient develops any grade CRS following Cycle 1 Day 8 they should be hospitalized for 24 hours following step-up dose #2 (Cycle 1 Day 15) • If patient develops Grade 2 or higher CRS with any previous infusion, they should be hospitalized for 24 hours for the subsequent infusion Mosunetuzumab IV Ambulatory • Cycle 1 ambulatory doses to include three CRS checks (pre-administration, 30 minutes post-dose, and prior to clinic discharge) • If patient develops Grade 2 CRS, monitor more frequently and consider hospitalization for the subsequent dose • If patient develops Grade 3 CRS, hospitalize for the subsequent dose Talquetamab SubQ • Step-up dosing (Cycle 1 - Day 1, 3, 5): Inpatient • Subsequent Cycle 1 weekly doses: Ambulatory • Cycle 2 and beyond biweekly doses: Ambulatory • Hospitalization is recommended for 48 hours after administration of the first three step-up doses • If patient experiences Grade 2 or 3 CRS during or after the third infusion, hospitalize for 48 hours following the subsequent dose Tebentafusp IV • Step-up dosing (Cycle 1 - Day 1, 8, and 15): Inpatient • Subsequent weekly doses: Ambulatory • Hospitalization is recommended for at least 16 hours after administration of the first three step-up doses • If the patient does not experience Grade 2 or worse hypotension during or after the third infusion, administer subsequent doses in an appropriate ambulatory care setting Teclistamab SubQ • Step-up dosing (Cycle 1 - Day 1, 3, 5): Inpatient • Subsequent weekly doses: Ambulatory • Hospitalization is recommended for 48 hours after administration of the first three step-up doses • If patient experiences Grade 2 or 3 CRS during or after the third infusion, hospitalize for 48 hours following the subsequent dose A Hospital at home work flows may be utilized as clinically appropriate if staffing levels support B See product specific package insert on need for step-up dosing restart if significant dose delays Effective 9/21/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 09/2023