1 Management of Toxicities Associated with CAR- T-Cell Therapies - Adult/Pediatric - Inpatient/Emergency Department Clinical Practice 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 ......................................................................................................................................3 RECOMMENDATIONS .........................................................................................................................4 METHODOLOGY ............................................................................................................................... 15 CONFLICTS OF INTEREST ................................................................................................................... 17 COLLATERAL TOOLS & RESOURCES ................................................................................................... 17 APPENDIX A ..................................................................................................................................... 18 REFERENCES .................................................................................................................................... 19 Effective 4/28/2023. 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: 04/2023 2 Content Experts: Name: Cameron Ninos, PharmD, BCOP Phone Number: (608) 219-2372 Email Address: Cameron Ninos Name: Jason Jared, PharmD, BCOP Phone Number: (608) 263-1290 Email Address: Jason Jared Contact for Changes: Name: Jason Bergsbaken, PharmD, BCOP Phone Number: (608) 265-0341 Email Address: Jason Bergsbaken Guideline Authors: Jason Jared, PharmD, BCOP - Pharmacy Cameron Ninos, PharmD, BCOP - Pharmacy Workgroup Members: Vaishalee Kenkre, MD - Adult Hematology/Oncology Priyanka Pophali, MD - Adult Hematology/Oncology Reviewers: Christian Capitini, MD - Pediatric Hematology/Oncology Christopher Nemergut, PharmD - Center for Clinical Knowledge Management Committee Approvals: Chemotherapy Council Subcommittee: March 2023 Pharmacy & Therapeutics Committee: April 2023 Effective 4/28/2023. 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: 04/2023 3 Introduction Immunotherapy agents are designed to augment a patient’s immune response to specific targets. One specific product, Chimeric antigen receptor T cell (CAR-T), are engineered specifically to target tumor cells. This therapy achieves specificity through linking T cells to a tumor-specific antigen resulting in supraphysiologic cytotoxicity against tumor cells. Anti-CD19 CAR-T therapies including axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi), and Idecabtagene vicleucel (Abecma) are indicated for treatment of relapsed or refractory mantle cell lymphoma, large B-cell lymphoma, multiple myeloma, or acute lymphoblastic leukemia (ALL). Due to profound and generalized immune system activation with CAR-T therapy, the major adverse effects of treatment include autoimmune and cytokine-associated toxicities. Cytokine release syndrome (CRS) is a supraphysiologic response following an 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 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. The supraphysiologic response is related to increased levels of several cytokines, including IL-2, IL-5, IL-6, IL-8, IL-10, IFNγ, and TNFα, 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. Independent of CRS, patients may also experience (ICANS). ICANS may manifest as delirium, encephalopathy, aphasia, lethargy, difficulty concentrating, agitation, tremor, seizures, and rarely, cerebral edema requiring separate monitoring and management strategies. UW Health hematology/oncology practitioners have agreed to endorse recommendations from the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading for cytokine release and neurologic toxicity associated with immune effector cells guidance. Scope Intended Users: Physicians, Advanced Practice Providers, Pharmacists, Nurses, Technical Support Objectives: To provide guidance on the grading and prompt management of cytokine release syndrome and neurotoxicity associated with chimeric antigen receptor T-cell therapy in adult and pediatric patients based on REMs requirements and evidence-based interventions Target Population: Adult and pediatric patients with toxicities associated with novel T-cell therapies including chimeric antigen receptor (CAR) T-cell therapies in the inpatient and emergency department setting. Clinical Questions Considered: • What clinical assessment should be conducted when evaluating a patient with suspected CRS and/or ICANS? • How are toxicities classified for CRS and 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? • When should siltuximab be used for the treatment of CRS and/or ICANS? Definitions 1. CTCAE: Common Terminology Criteria for Adverse Events 2. CAR-T: Chimeric antigen receptor T cell 3. 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. 4. ICANS: Immune effector cell-associated neurotoxicity syndrome. A disorder characterized by a pathologic process involving the central nervous system following any immune therapy that Effective 4/28/2023. 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: 04/2023 4 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. 5. Organ specific toxicity is defined according to CTCAE Recommendations 1. CRS Monitoring and Grading 1.1. Patients may be monitored closely for CRS symptoms, following standard monitoring procedures described in H1.01, for a specified period following treatment to ensure prompt symptom management1 1.2. CRS grading may be determined using criteria from Table 1 1.3. CRS grade may be evaluated at least once daily and as needed any time 1.4. CRS grading will be determined by the most severe event between hypotension and hypoxia 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 vasopressorsA Requiring vasopressorA with or without vasopressin Requiring multiple vasopressorsA (excluding vasopressin) And/or And/or And/or Hypoxia None Requiring low-flow nasal cannulaB or blow-by Requiring high-flow nasal cannulaC, facemask, nonrebreather mask, or Venturi mask Requiring positive pressure (e.g. CPAP, BiPAP, intubation and mechanical ventilation) AVasopressors: Norepinephrine, dopamine, phenylephrine, epinephrine, vasopressin BLow-flow nasal cannula defined as oxygen delivered at ≤6 L/minute CHigh-flow nasal cannula defined as oxygen delivered at >6 L/minute Effective 4/28/2023. 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: 04/2023 5 2. CRS Treatment Table 2.1 Adult CRS Treatment CRS Grade Tocilizumab Corticosteroids 1 Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg) for fever within 72 hours of CAR-T infusion, or if no improvement in fever after 24 hours If no clinical improvement in CRS after the first dose, repeat tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg) x 1 Consider dexamethasone 10 mg IV once daily for 2-3 days for fever occurring within 72 hours of CAR- T infusion If no resolution of fever after 2-3 days, give one dose of dexamethasone 10 mg IV 2 Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg) If no clinical improvement in CRS after the first dose, repeat every 8 hours as needed. Limit to a maximum of 3 doses in a 24-hour period. If no improvement after two doses of tocilizumab, escalate dexamethasone dosing as per Grade 3. If improving, discontinue tocilizumab. Administer dexamethasone 10 mg IV once daily. If improving, continue corticosteroids until the severity is Grade 1 or less, then quickly taper as clinically appropriate. If not improving, manage as Grad 3. 3 Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 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. If improving, discontinue tocilizumab. After 2 doses of tocilizumab and escalation of dexamethasone 20 mg every 6 hours, consider alternative immunosuppressants Administer dexamethasone 10 mg IV every 8 hours If improving, continue corticosteroids until the severity 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 once per day for 3 days. If no improvement after three days of high dose methylprednisolone, consider treating with anakinra. 4 Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 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. If improving, discontinue tocilizumab. After 2 doses of tocilizumab, if patient not improving consider starting anakinra in addition to corticosteroids.1-4 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 once per day for 3 days. Once improving taper corticosteroids. Effective 4/28/2023. 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: 04/2023 6 Adult Treatment of CRS Effective 4/28/2023. 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: 04/2023 7 Table 2.2. Pediatric CRS ManagementA CRS GradeB Symptomatic Management Tocilizumab Corticosteroids Grade 1 Mild symptoms requiring symptomatic treatment only (e.g. low fever, fatigue, anorexia) • Exclude other causes (e.g. infection) and treat specific symptoms (e.g. antipyretics, antiemetics, analgesics) • If neutropenic administer antibiotics per local guidelines • In patients with persistent (> 3 days) or refractory fever, consider managing as Grade 2 CRS • Not applicable Grade 2 Symptoms requiring moderate intervention (e.g. high fever, hypoxia, mild hypotension) • Administer oxygen, intravenous fluids and/or low dose vasopressors as needed • Administer high dose or multiple vasopressors, oxygen, mechanical ventilation and/or other supportive care as needed • Administer tocilizumab o <30 kg: 12 mg/kg IV o ≥30 kg: 8 mg/kg IV (max dose: 800 mg) o Repeat every 8 hours if no clinical improvement for max of 4 doses o If no response to second dose, administer third and consider alternatives • If no clinical improvement within 24 hours of first tocilizumab dose, or worsening at any time, administer methylprednisolone 2 mg/kg daily until vasopressors and high flow oxygen are no longer needed, then taper Grade 3 Symptoms requiring aggressive intervention (e.g. hypoxia requiring high-flow oxygen supplementation or hypotension requiring high- dose or multiple vasopressors) • High-flow oxygen intravenous fluids and high-dose vasopressors • Treat other organ toxicities per local guidelines Grade 4 Life-threatening symptoms (e.g. hemodynamic instability despite IV fluids and vasopressors, worsening respiratory distress, rapid clinical deterioration) • Mechanical ventilation • Intravenous fluids and high dose vasopressors • Treat other organ toxicities per local guidelines • Administer methylprednisolone 1,000 mg IV one to two times per day for 3 days. If not improving, consider methylprednisolone 1,000 mg intravenously two to three times a day or alternate therapyB ACRS management per Tisagenlecleucel (Kymriah) prescribing information5 BIf no improvement after tocilizumab and steroids, consider other anti-cytokine and anti-T cell therapies. These therapies may include siltuximab (11 mg/kg IV over 1 hour), high doses of steroids (e.g. high dose methylprednisolone or equivalent steroid dose according to local ICU practice), cyclophosphamide, anti-thymocyte globulin (ATG), or alemtuzumab Effective 4/28/2023. 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: 04/2023 8 Cytokine Release Syndrome (CRS) following haploidentical hematopoietic stem cell transplant: 1. It is recommended to administer tocilizumab 4-8 mg/kg IV (max dose: 800 mg) in the following circumstances6-8: (UW Health GRADE moderate quality evidence, conditional recommendation) 1.1. Grade 2 CRS (per ASTCT grading) with concern for imminent clinical decompensation due to patient frailty and/or higher risk of severe consequences of altered hemodynamics or organ stress.6,8 1.2. Grade 3 CRS (per ASTCT grading)6-9 1.3. Grade 4 CRS (per ASTCT grading)6-9 2. Tocilizumab may be repeated every 8 hours as needed for no more than 3 doses per 24 hours or 4 doses total if no clinical improvement in CRS.5,10 (UW Health GRADE moderate quality evidence, conditional recommendation) 3. Glucocorticoids such as dexamethasone, prednisone, and methylprednisolone should be avoided in patients who received post-transplant cyclophosphamide unless used for adrenal support or a medical emergency.9 (UW Health GRADE moderate quality evidence, conditional recommendation) 4. Glucocorticoids may be considered for CRS in the following circumstances6: (UW Health GRADE Moderate quality evidence, conditional recommendation) 4.1. Addition to tocilizumab in Grade 3 or 4 CRS (per ASTCT grading) with lack of immediate clinical improvement with tocilizumab and end organ dysfunction 4.2. First-line monotherapy treatment in Grade 3 or 4 ICANS (per ASTCT grading) without significant hemodynamic instability or other life-threatening symptomatology 5. It may be reasonable to consider the following supportive care agents: (UW Health GRADE Low quality evidence, conditional recommendation) 5.1. Celecoxib 200 mg by mouth twice daily 5.2. Montelukast 10 mg by mouth nightly 5.3. Loratadine 10 mg by mouth daily 3. Immune Effect Cell-Associated Neurotoxicity Syndrome (ICANS): 1. ICANS monitoring and grading 1.1. Patients may be monitored closely for neurotoxicity symptoms, following standard monitoring procedures described in H1.01, for a specified period following treatment to ensure prompt symptom management11 1.2. ICANS grading may be determined using criteria from Tables 3.1 and 3.2 for adults and Tables 3.3 and 3.3 for pediatrics 1.3. To determine ICANS grading, encephalopathy must be evaluated using the Immune Effector Cell-Associated Encephalopathy (ICE) score from Table 3.2 Effective 4/28/2023. 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: 04/2023 9 Table 3.1. ASTCT ICANS Consensus Grading for Adults Neurotoxicity Domain Grade 1 Grade 2 Grade 3 Grade 4 ICE Score 7-9 3-6 0-2 0 Depressed level of consciousness 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 3.2. ICE scoringA 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 form 100 by 10 1 point ATotal of 10 points Effective 4/28/2023. 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: 04/2023 10 Table 3.3. ASTCT ICANS Consensus Grading for Children Neurotoxicity Domain Grade 1 Grade 2 Grade 3 Grade 4 ICE Score Children ≥12 years 7-9 3-6 0-2 0 ICE Score Children <12 years 1-8 1-8 ≥9 Unable to perform CAPD Depressed level of consciousness Awakens spontaneously Awakens to voice Awakens only to tactile stimulus Unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma Seizure (any age) N/A N/A Any 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 (any age) N/A N/A N/A Deep focal motor weakness such as hemiparesis or paraparesis Elevated ICP/cerebral edema (any age) N/A N/A Focal/local edema on neuroimaging Decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging Table 3.4. Encephalopathy Assessment for Children Age <12 Using CAPDA Never, 4 Rarely, 3 Sometimes, 2 Often, 1 Always, 0 Dose the child make eye contact with the caregiver? Are the child’s actions purposeful? Is the child aware of his/her surroundings? Does the child communicate needs and wants? Never, 0 Rarely, 1 Sometimes, 2 Often, 3 Always 4 Is the child restless? Is the child inconsolable? Is the child underactive; very little movement while awake? Does it take the child a long time to respond to interactions? ACAPD: Cornell Assessment of Pediatric Delirium Effective 4/28/2023. 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: 04/2023 11 4. Management of ICANs Table 4.1. Adult ICANs Management Grading Management 1 Occurring <72 hours after CAR-T infusion: consider dexamethasone 10 mg IV every 12 hours for 2-3 day Occurring ≥72 hours after CAR-T infusion: administer dexamethasone 10 mg IV once. If no improvement after one day, repeat dexamethasone 10 mg IV. If not improving after two doses, consider treating as Grade 2. 2 Administer dexamethasone 10 mg IV every 12 hours for 2-3 days, consider taper for total steroid exposure of >3 days. Consider intrathecal therapy with 100 mg hydrocortisone to reduce systemic steroid use if feasible, particularly if patient is high risk of progression to severe ICANS (high tumor burden, MCL, ALL, Yescarta, Tecartus). If no improvement within 24 hours, increase dexamethasone dose to 20 mg IV every 6 hours and give intrathecal therapy with 100 mg hydrocortisone if feasible, particularly if patient is at high risk of progression. If no improvement 24 hours after intrathecal hydrocortisone can consider giving 100 mg cytarabine IT (50 mg if given with methotrexate) + 100 mg hydrocortisone IT +/- 12 mg methotrexate IT. If improving, taper corticosteroids. If not improving then treat with methylprednisolone 1 g daily for up to 3 days and consider alternative immunosuppressants (anakinra 8-10 mg/kg/day daily in 3-4 divided doses) 3 Administer dexamethasone 10 mg IV every 6 hours. Give intrathecal therapy with 100 mg hydrocortisone if feasible. Test CSF for biofire, fungal culture, bacterial culture and flow cytometry for malignant cells. If no improvement 24 hours after IT hydrocortisone, give 12 mg methotrexate IT + 100 mg hydrocortisone IT +/- 50 mg cytarabine IT. If improving, taper corticosteroids. If not improving then treat with methylprednisolone 1 g daily for up to 3 days and consider alternative immunosuppressants (anakinra 8-10 mg/kg/day daily in 3-4 divided doses). 4 Administer dexamethasone 20 mg IV every 6 hours and if no improvement after two doses, escalate to methylprednisolone 1 g daily for up to three days (then decrease dose dexamethasone to 10 mg every 6 hours). Give intrathecal therapy with 12 mg methotrexate IT+ 100 mg hydrocortisone IT +/- 50 mg cytarabine IT. Test CSF for HSV, CMV, VZV, HHV6, and flow cytometry for malignant cells. Consider anakinra 8-10 mg/kg/day in 3-4 divided doses.1-4 Siltuximab 11 mg/kg may be considered for grade 4 ICANs refractory to high dose methylprednisolone, anakinra, and intrathecal therapy (if feasible). If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1 g every 24 hours for 3 days) and cyclophosphamide 1.5 g/m2 1. At onset of ICANS, initiate levetiracetam for seizure prophylaxis (UW Health GRADE low quality evidence, conditional recommendation) 2. Obtain MRI brain for persistent Grade 2 ICANS and Grade ≥3 ICANS (UW Health GRADE low quality evidence, conditional recommendation) 3. Consider Neurology consultation for all patients with persistent ICANS (UW Health GRADE low quality evidence, conditional recommendation) 4. If concurrent CRS, after first dose of tocilizumab, consider siltuximab in place of tocilizumab12 (UW Health GRADE very low quality evidence, conditional recommendation) Effective 4/28/2023. 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: 04/2023 12 Effective 4/28/2023. 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: 04/2023 13 Table 4.2. Pediatric Neurotoxicity ManagementA,B Neurotoxicity Grade Management Grade 1 • Offer supportive care with intravenous hydration and aspiration precautions • Consider non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis Grade 2 • Consider methylprednisolone 1 mg/kg IV every 12 hours until Grade 1 or less. If improving taper corticosteroids. • Consider non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis Grade 3 • Methylprednisolone 1 mg/kg every 12 hours • Consider non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis Grade 4 • High-dose methylprednisolone IV 1,000 mg one to two times per day for 3 days • If not improving, consider 1,000 mg of methylprednisolone two to three times per day or alternative therapy • Alternate therapy may include anakinra, siltuximab, ruxolitinib, cyclophosphamide, antithymocyte globulin, or intrathecal hydrocortisone (50 mg) plus methotrexate (12 mg) • Continue corticosteroids until improvement to Grade 1, and then taper as clinically appropriate • Treat seizures, status epilepticus, and cerebral edema as per institutional guidelines. • Consider non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis AManagement of neurotoxicity is adapted from Tisagenlecleucel (Kymriah) prescribing information5 BIf concurrent CRS is suspected during neurologic toxicity, administer: (1) Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity and (2) Tocilizumab dosing according to CRS Grade. Use caution with repeated tocilizumab doses in patients with ICANS. Consider adding corticosteroids to tocilizumab past the first dose. 5. Monitoring of Hemophagocytic Lymphohistiocytosis (HLH) / Macrophage activation syndrome (MAS)13-18 1. CRS may be associated with findings of HLH/MAS and physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition; in patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate patients for evidence of HLH/MAS (UW Health GRADE low quality evidence, conditional recommendation) 1.1. Signs and symptoms: The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia 1.2. Diagnostic Criteria 1.2.1. Diagnosis of HLH/MAS may be confounded by on-going CRS 1.2.2. In general, consider HLH/MAS if a patient has a peak ferritin >10,000 ng/mL during the CRS phase and develops any two of the following organ toxicities after immune effector cell therapy (CTCAE V5.0): (UW Health GRADE low quality evidence, conditional recommendation) • ≥Grade 3 increase in bilirubin, aspartate transaminase, or alanine transaminase • ≥Grade 3 oliguria or increase in creatinine • ≥Grade 3 pulmonary edema • Presence of hemophagocytosis by morphology and and/or CD68 immunohistochemistry in bone marrow or organs 1.2.3. If HLH/MAS is suspected, consider obtaining baseline fasting triglyceride level and serum soluble IL IL-2 receptor (UW Health GRADE low quality evidence, conditional recommendation) 1.3. Treatment 1.3.1. Treatment of HLH/MAS should be individualized per clinical judgement and may overlap with concurrent treatment of CRS and/or neurotoxicity (UW Health GRADE low quality evidence, conditional recommendation) 1.3.2. General treatment recommendations include: 1.3.2.1. Manage co-occurring CRS as outlined in “CRS Treatment” section (UW Health GRADE low quality evidence, conditional recommendation) 1.3.2.1.1. Manage ≥Grade 3 organ toxicity with tocilizumab and corticosteroids 1.3.2.1.2. Monitor laboratory parameters including: Effective 4/28/2023. 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: 04/2023 14 • Ferritin • LDH • Fibrinogen • Transaminases • Bilirubin • Creatinine 1.3.2.2. If there is no clinical improvement after 48 hours, consider HLH/MAS-specific therapies: (UW Health GRADE low quality evidence, conditional recommendation) • Consider adding etoposide (75-100 mg /m2 IV every 4-7 days) • Consider cytarabine (100 mg) intrathecally with or without hydrocortisone (50-100 mg) intrathecally for ICANS 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 4/28/2023. 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: 04/2023 15 Methodology Development Process All guidelines are developed using the guiding principles, standard processes, and styling outlined in the UW Health Clinical Practice Guideline Resource Guide. This includes expectations for workgroup composition and recruitment strategies, disclosure and management of conflict of interest for participating workgroup members, literature review techniques, evidence grading resources, required approval bodies, and suggestions for communication and implementation. Methods Used to Collect the Evidence: The following criteria were used by the guideline author(s) 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 CAR-T, how does tocilizumab and corticosteroids compare with no treatment overall affect cytokine release syndrome within inpatient stays? • In patients receiving CAR-T, how does standardized grading for CRS and ICANS compared with manufacturer grading affect toxicity treatment within inpatient stays? Literature Sources (from methods of systematic review template): • 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 2017 from which the last revision of these guideline was published Search Terms: • [(“CAR-T” OR “chimeric antigen receptor T-cell therapy”) AND (“CRS” OR “cytokine release syndrome”)] • [(“CAR-T” OR “chimeric antigen receptor T-cell therapy”) AND (“neurotoxicity” OR “immune effector cell-associated neurotoxicity syndrome” OR “ICANS”)] • [(“Kymriah” OR “tisagenlecleucel”)] AND [(“Tecartus” OR “brexucabtagene autoleucel”)] AND [(“Yescarta” OR “axicabtagene ciloleucel”)] AND [(“Breyanzi” OR “lisocabtagene maraleucel”)] AND [(“Abecma” OR “idecabtagene vicleucel”)] • [(“ASTCT” OR “American society for transplantation and cellular therapy”) AND (“CAR-T” OR “chimeric antigen receptor T-cell therapy”)] 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). Effective 4/28/2023. 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: 04/2023 16 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 (e.g., CAR-T therapies) 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.19 Although not entirely elucidated, limiting factors to access for CAR-T treatment share similarities to hematopoietic cellular transplant (HCT).20 These barriers include race/ethnicity, socioeconomic status, and distance among others. To optimize patient outcomes, CAR-T should preferentially be administered at centers with experience and established quality processes and practices. Effective 4/28/2023. 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: 04/2023 17 Conflicts of Interest A conflict of interest declaration must be signed/submitted by guideline workgroup and/or committee members to ensure balance, independence, objectivity, and scientific rigor in activities pertaining to the guideline development process. Guideline members must complete a conflict of interest statement annually or as new interest(s) arises. Potential, current and planned future, conflicts of interest will be identified and managed in accordance with institutional policies and procedures. This may include, but is not limited to, conflict disclosure, abstaining from voting, dismissal during comment and voting period, or recusal from requesting and/or participation in the decision-making process. 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 Describe metrics which could be used to assess compliance with the stated recommendations or to gauge improvement resulting from implementation of the guideline. Clearly define criteria or operational definitions to assess based on the key recommendations and at a specified interval (e.g., process measures, behavioral measures, clinical or health outcome measures). The data source may also be described (e.g., patient survey, manual chart review, analysis through Clarity). Staff in QSI can also help to identify externally reported measures required of the organization related to a particular guideline topic. • Total utilization of tocilizumab per year • Average tocilizumab use per patient • Average tocilizumab use per CAR-T product • Incidence of cytokine release syndrome ≥ Grade 1 • Incidence of siltuximab use for CRS management Beacon Protocols • CSC BMT CAR-T FOR TECARTUS - LYMPHOMA VER: 2-23-21 [HL 9297] • CSC BMT CAR-T FOR YESCARTA-LYMPHOMA VER: 1-16-20 [HL 6907] • CSC BMT CAR-T THERAPY FOR KYMRAH - ADULT ALL -CYCLOPHOSPHAMIDE / FLUDARABINE VER: 1-11-19 [HL 7723] • CSC BMT CAR-T THERAPY FOR KYMRIAH - LYMPHOMA – CYCLOPHOSPHAMIDE / FLUDARABINE VER ::1-11-19 [HL 7781] • CSC HEM Cytokine Release Syndrome Management Post CAR-T (Yescarta) Therapy VER: 5-2- 18 [HL 6928] • AFCH ONC SOC CYTOKINE RELEASE SYNDROME MANAGEMENT POST CAR-T THERAPY VER: 10-7-20 • AFCH ONC SOC LYMPHODEPLETING CHEMOTHERAPY FOR CAR-T THERAPY VER: 10-7- 20 • AFCH ONC SOC TISAGENLECLEUCEL (KYMRIAH) INFUSION VER: 10-7-20 Order Sets & Smart Sets • IP – Post CAR-T Therapy – Adult – Admission [6804] • IP – Post CAR-T (Kymriah) Therapy – Pediatric – Admission [6858] Policies • Immune Effector Cell Therapy [H1.01] • Chimeric Antigen Receptor T Cell (CAR-T Cell) Infusion [H1.02] Procedures • Inventory Management of Tocilizumab for CAR-T Patients Effective 4/28/2023. 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: 04/2023 18 Appendix A CTCAE Grading of Common Neurotoxicities21 Adverse Event term or Neurotoxicity Grade 1 Grade 2 Grade 3 Grade 4 C TC A E v5 .0 Encephalopathy Mild Symptoms Moderate symptoms limiting instrumental ADL Severe symptoms; limiting self-care ADL Life-threatening consequences; urgent intervention indicated Seizure Brief partial seizure and no loss of consciousness Brief generalized seizure New-onset seizures (partial or generalized); multiple seizures despite medical intervention Life-threatening consequences Dysphasia Awareness of receptive or expressive characteristics; not impairing ability to communicate Moderate receptive or expressive characteristic; impairing Severe receptive or expressive characteristics; impairing ability to read, write, communicate intelligibly Tremor Mild symptoms Moderate symptoms; limiting instrumental ADL Severe symptoms; limiting self-care ADL Headache Mild pain Moderate pain; limiting instrumental ADL Severe pain; limiting self-care ADL Confusion Mild disorientation Moderate disorientation; limiting instrumental ADL Severe disorientation; limiting self-care ADL Life-threatening consequences; coma; urgent intervention indicated Depressed level of consciousness Decreased level of alertness Sedation; slow response to stimuli; limiting instrumental ADL Difficult to arouse Life-threatening consequences; urgent intervention indicated Central Edema New onset; worsening from baseline Life-threatening consequences; urgent intervention indicated ADL = activities of daily living Effective 4/28/2023. 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: 04/2023 19 References 1. Diorio C, Vatsayan A, Talleur AC, et al. Anakinra utilization in refractory pediatric CAR T-cell associated toxicities. Blood Adv. Jun 14 2022;6(11):3398-3403. doi:10.1182/bloodadvances.2022006983 2. Gazeau N, Barba P, Iacoboni G, et al. Safety and Efficacy of Two Anakinra Dose Regimens for Refractory CRS or Icans after CAR T-Cell Therapy. Blood. 2021;138(Supplement 1):2816-2816. doi:10.1182/blood-2021- 147454 3. 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 4. Wehrli M, Gallagher K, Chen YB, et al. Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS). J Immunother Cancer. Jan 2022;10(1)doi:10.1136/jitc- 2021-003847 5. Kymriah (tisagenlecleucel) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2022. 6. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. Jul 10 2014;124(2):188-95. doi:10.1182/blood-2014-05-552729 7. Abboud R, Keller J, Slade M, et al. Severe Cytokine-Release Syndrome after T Cell-Replete Peripheral Blood Haploidentical Donor Transplantation Is Associated with Poor Survival and Anti-IL-6 Therapy Is Safe and Well Tolerated. Biol Blood Marrow Transplant. Oct 2016;22(10):1851-1860. doi:10.1016/j.bbmt.2016.06.010 8. Abboud R, Wan F, Mariotti J, et al. Cytokine release syndrome after haploidentical hematopoietic cell transplantation: an international multicenter analysis. Bone Marrow Transplant. Nov 2021;56(11):2763-2770. doi:10.1038/s41409-021-01403-w 9. Al-Homsi AS, Roy TS, Cole K, Feng Y, Duffner U. Post-transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease. Biol Blood Marrow Transplant. Apr 2015;21(4):604-11. doi:10.1016/j.bbmt.2014.08.014 10. Tecartus (brexucabtagene autoleucel) [prescribing information]. Santa Monica, CA: Kite Pharma Inc; October 2021. 11. 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 12. Santomasso BD, Nastoupil LJ, Adkins S, et al. Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. J Clin Oncol. Dec 10 2021;39(35):3978-3992. doi:10.1200/jco.21.01992 13. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. Feb 2007;48(2):124-31. doi:10.1002/pbc.21039 14. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. Oct 13 2011;118(15):4041-52. doi:10.1182/blood-2011-03-278127 15. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. Jun 6 2019;133(23):2465-2477. doi:10.1182/blood.2018894618 16. Munshi NC, Anderson LD, Jr., Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. Feb 25 2021;384(8):705-716. doi:10.1056/NEJMoa2024850 17. Sandler RD, Tattersall RS, Schoemans H, et al. Diagnosis and Management of Secondary HLH/MAS Following HSCT and CAR-T Cell Therapy in Adults; A Review of the Literature and a Survey of Practice Within EBMT Centres on Behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP). Front Immunol. 2020;11:524. doi:10.3389/fimmu.2020.00524 18. IEC Therapy Toxicity Assessment and Management (also known as CARTOX) - Adult. MD Anderson Cancer Center. Updated September 15, 2020. Accessed April 21, 2023. https://www.mdanderson.org/content/dam/mdanderson/documents/for-physicians/algorithms/clinical- management/clin-management-cytokine-release-web-algorithm.pdf. 19. 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 20. Kansagra A, Farnia S, Majhail N. Expanding Access to Chimeric Antigen Receptor T-Cell Therapies: Challenges and Opportunities. Am Soc Clin Oncol Educ Book. Mar 2020;40:1-8. doi:10.1200/edbk_279151 21. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. US Department of Health and Human Services. Updated November 27, 2017. Accessed April 21, 2023. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x1 1.pdf. Effective 4/28/2023. 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: 04/2023