CBB–A1000



BMT-CL-PR.XXX:IMMUNE EFFECTOR CELL TOXICITY MANAGEMENTPURPOSETo provide guidance regarding monitoring, grading and management of immune effector cell (IEC) toxicity management, particularly cytokine release syndrome (CRS), neurotoxicity/ chimeric antigen receptor T cell (CAR-T) related encephalopathy syndrome (CRES) and macrophage activation syndrome/ hemaphagocytic lymphohistiocytosis (MAS/HLH).BACKGROUNDImmunotherapy, particularly utilizing IECs, is a promising approach for the treatment of cancer. With the administration of the IECs, notable examples being CAR-T and natural killer (NK) cell therapy, toxicities related to immunotherapy are encountered. These can be severe, even fatal, if not addressed promptly. CRS can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with lifethreatening multiorgan dysfunction. Rarely severe CRS can evolve into fulminant hemaphagocytic lymphohistiocytosis (HLH). Neurotoxicity, commonly termed CART cell related encephalopathy syndrome (CRES) can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with these therapies.SCOPEThis procedure is applicable to the following bone marrow transplant (BMT) team members that have completed IEC training:Physician (for CAR-T, must be certified to prescribe CAR-T therapy)Advanced Practice Professional (APP)Registered Nurse (RN)Clinical PharmacistThis procedure is applicable to UF Health/Shands Hospital providers involved with the BMT team in the management of toxicities resulting from IEC therapy. Including but not limited to:NeurologyNeurosurgeryIntensive Care (MICU, NSICU, PICU, SICU)Emergency Room StaffMATERIALS / EQUIPMENTN/ASAFETYN/ARELATED DOCUMENTS / REQUIRED FORMSN/APROCEDUREA.ASSESSMENT OF IMMUNE EFFECTOR CELL TOXICITY Routine assessment for IEC toxicity begins prior to infusion of IEC to establish a baseline, and continues for at least 2 weeks post infusion or until resolution of IEC toxicity, whichever is later. 1.Routine assessment will consists of the following:a.Vital signs (to be completed every 4 hours, or more frequently if specified in individual treatment plan)i.Temperatureii.Heart rateiii.Respiratory rateiv.Blood pressurev.Oxygen saturationvi.Strict fluid monitoring to include fluid intake and urinary outputvii. Neurological assessments will be performed and documented by nursing every 4 hours. b.Remote Telemetry monitoring i.For 24 hours from start of infusion ii.As clinically indicatedc.Physical examination (appendix 1)i.Examination will occur once daily unless a change in clinical status occurs and then should be repeated. ii.Examination will be performed and documented by APP, or ponents will include the followingRoutine physical examinationNeurologic assessment CTCAE neurology toxicity grading (Refer to Appendix 2: CTCAE Neurological Toxicity)CARTOX-10 (Refer to Appendix 3: CRES Grading and Appendix 4: CARTOX-10 Scoring) Assessment for any changes in mental status (headache. confusion, tremor, somnolence, agitation, memory impairment, handwriting changes, hallucinations, motor weakness)Focal neurological deficits, generalized encephalopathy, seizures, papilledema, increased ICP, cerebral edemaSkin examination for rashGastrointestinal assessment of nausea, vomiting, and/or diarrhead.Laboratory assessmenti.Starts on day of cell infusion (day 0) until discharge or resolution of toxicity.plete blood count with differential and platelets daily prehensive metabolic panel, including renal and hepatic function panel dailyiv.Coagulation tests daily for leukemia patients twice a week or as indicated for all other patientsProthrombin Time (PT)Partial Thromboplastin Time (PTT) International Normalization Ratio (INR)Fibrinogenv.Biomarkers C-reactive protein dailyFerritin daily2.Routine assessment must be performed by APP, or MD with the following frequency:a.Inpatient: Twice daily following infusion or more frequent if necessary b.Outpatient: daily or more frequent if necessary c.If any change in patient status is observed, IEC assessment and grading of toxicity must be performed and documentedNOTE: Any change in patient status observed in outpatient setting will require urgent assessment and possible admission. B.Management of IEC toxicity (CRS, CRES, MAS/HLH)IEC certified attending must be notified immediately with any suspected IEC toxicity.NOTE: Do not administer STEROIDS OR IL-6 ANTAGONIST (TOCILIZUMAB) FOR SUSPECTED IEC TOXICITY WITHOUT IEC ATTENDING APPROVAL. A MINIMUM OF THREE DOSES OF TOCILIZUMAB PER PATIENT MUST BE AVAILABLE AND RESERVED FOR CAR-T USE AT ALL TIMES.1.Cytokine Release Syndrome (CRS):Onset of CRS toxicity usually occurs within the first week after CAR-T cell therapy, and typically peaks within 1–2 weeks of cell administration. The clinical manifestations of CRS include: diarrhea, N/V, coagulopathy, capillary leak, rash, hypoxia, fever, hypotension, cardiotoxicity, encephalopathy, transaminitis, renal dysfunction, and myalgias.a.Risk factors for severe CRS include: high tumor burden, bulky disease, comorbidities, early onset CRS (< 3 days of cell infusion), lymphodepleting regimen, higher cell dose, elevated C-reactive protein, and bulk CD8+ T-cell selection.b.Grading of CRS The CRS grade should be determined and documented by APP or MD at least twice a day and whenever a change in the patient’s status is observed. Grading of organ toxicities is performed according to Common Terminology Criteria for Adverse Events, (CTCAE) version 4.03 (reference 5)Grade 1 CRS can manifest as fever and/or grade 1 organ toxicity.Grade 2, 3, or 4 CRS – any one of the criteria other than fever is sufficient. Refer to Appendix 1 for the CRS Grading (Organ toxicity via CTCAE v4.03).c.Management of CRS should be in accordance with the grade of toxicity as outlined in Table 1.Table 1. Management of CRSGradeManagementGrade 1FeverAssess for infection with blood and urine cultures, and chest x-rayAcetaminophen and hypothermia blanket as needed for fever (38° C)IV fluids if necessary Initiate empiric broad spectrum antibioticsConsider filgrastim (if neutropenic)Consider tocilizumab for persistent (> 3 days) or refractory feverOrgan Toxicity: Symptomatic management of Grade 1 organ toxicities and symptomsGrade 2Hypotension: IV Hydration (administer 500 mL – 1000 mL normal saline bolus for hypotension of SBP <90 mmHg; administer 2nd 1L bolus if SBP still <90 mmHg following 1st bolus)Tocilizumab 8 mg/kg (max 800 mg) if refractory to 2 IVF bolusesVasopressors and ICU transferDexamethasone 10 mg IV Q6H (persistent hypoperfusion [decreased UOP < 0.5 mL/kg/hr; lactate ≥4 mmol/L, rising lactate, and/or poor lactate clearance (<10%) despite fluid resuscitation], or with rapid deterioration)Notify Medical ICU and transfer if hypotension persists following 2 liter bolus as patient will require vasopressor support (management per ICU)Hypoxia (O2 saturation <90%; FiO2 <40%): sSupplemental oxygen and supportive care; tTocilizumab corticosteroidsGrade 2 organ toxicity: Tocilizumab corticosteroidsManage toxicity as per standard guidelinesNOTE: Tocilizumab can be repeated every 8 hours (not to exceed 24 mg/kg in 24 hour period).Grade 3Hypotension: IV fluid boluses, tocilizumab, vasopressors ad ICU transfer as in Grade 2Dexamethasone 10 mg IV Q6H, which can be increased to 20 mg IV Q6H if refractoryHypoxia (O2 saturation <90%; FiO2 ≥40% or BiPAP): sSupplemental oxygen and supportive care; tTocilizumab corticosteroidsMay require ventilation for respiratory compromiseGrade 3 organ toxicity of grade 4 transaminitis: Anti- IL-6 therapy + corticosteroidsManage organ toxicity as per standard guidelinesMUST BE MONITORED IN ICU UNTIL CRS reduced to GRADE 1Grade 4Hypotension: As per Grade 3SteroidsHypoxia (ventilator support): Mechanical ventilationSteroids, tocilizumab , and supportive careGrade 4 organ toxicity (excluding transaminitis):Steroids, tocilizumab , and supportive careManage organ toxicity as per standard guidelines**Once initiated, tocilizumab and steroids should continue until CRS grade is 1 or less, or clinically inicatedindicated2.Neurotoxicity/ CAR-T related Encephalopathy Syndrome (CRES)a.CAR-T associated neurotoxicity may occur independent of, or concurrent with, CRS. The earliest signs are diminished attention, language disturbance, and impaired handwriting. Other symptoms and signs include confusion, disorientation, agitation, aphasia, somnolence, and tremors. Severe cases of CRES (grade >2 per CARTOX-10) - seizures, motor weakness, incontinence, mental obtundation, increased intracranial pressure, papilledema, and cerebral edema. b.Biphasic presentation: i.Early – often occurs with fever during CR. May respond to tocilizumab if concurrent CRS. Often mild/self-limiting. ii.Late: after or unrelated to CRS, and does NOT respond to tocilizumab. Often more severe/protracted. c.GradingGrading of neurotoxicity is performed according to CTCAE version 4.03 and CAR-T cell therapy associated toxicity 10-point (CARTOX-10) neurological assessment. Refer to Appendix 2: CTCAE Neurological Toxicity, Appendix 3: CARTOX-10 Grading and Appendix 4: CARTOX-10 Scoring.d.Management should be in accordance with the grade of toxicity as outlined in Table 2.Urgent Neurology consult is required for any suspected neurotoxicity.Management is based upon the higher grade e.g. if Grade 3 CARTOX-10 and Grade 2 CTCAE, treat as a Grade 3 neurotoxicity.Table 2. Management of CRES/NeurotoxicityGradeManagementGrade 1 (MILD)Neurology consultation (EEG and fundoscopic examination for papilledema)CNS imaging (MRI>CT)Neurologic checks (by neurological team) and then every 4-6 hours by nursing and medical staffAnti-epileptics if EEG findings of non-convulsive status epilepticusNOTE: patients receiving CAR-T therapy should be prescribed levetiracetam 750 mg PO Q12H x 30 days, starting the day of CAR-T infusionConsider lumbar puncture to rule out infection, check CSF for cytokines and CAR-T where feasibleAspiration precautions (bed 30 degrees, swallow evaluation)Convert all oral medications and/or nutrition to IV if swallowing is impairedAvoid medications that cause CNS depressionLow doses of lorazepam (0.25-0.5 mg IV every 8 hours) or haloperidol (0.5 mg IV every 6 hours) may be used for agitated patients with careful monitoringDaily CARTOX 10-point neurological assessmentDaily 30-minute EEG; if no seizures detected on EEG, continue levetiracetamConsider IL-6 antagonist, if associated with concurrent CRSGrade 2 (MODERATE)Supportive care and neurological workup as per Grade 1IL-6 antagonist, if associated with concurrent CRSDexamethasone or methylprednisolone1 for CRES not associated with concurrent CRS, or if refractory to IL-6 antagonist therapy when it is administeredConsider ICU transfer if associated with Grade 2 or greater CRSGrade 3 (SEVERE)Supportive care and neurological workup as per Grade 1ICU transfer is recommendedIL-6 antagonist, if associated with concurrent CRS and if not administered previouslyDexamethasone or methylprednisolone around the clock, if symptoms worsen despite IL-6 antagonist therapy or for CRES without concurrent CRS. Continue corticosteroids until improvement to Grade 1 and then taper or stop.Low grade (Stage 1 or 2) papilledema with CSF OP less than 20 mmHgConsider repeat neuro-imaging (CT or MRI) every 2-3 days if persistent CRES greater than or equal to Grade 3Grade 4 (LIFE-THREAT-ENINGSupportive care and neurological workup as per Grade 1ICU monitoring; consider mechanical ventilation for airway protectionIL-6 antagonist and repeat neuro-imaging as per Grade 3High dose methylprednisoloneFor convulsive status epilepticus, treat per current standardsFor high grade (Stage 3, 4, or 5) papilledema, CSF OP greater than or equal to 20 mmHg, or cerebral edema manage per current standards3.HLH / MAS Assessment and ManagementRare condition characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms. Thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction, typically occurring within 5 days of cellular infusion.a.Diagnosed during CRS phase with peak ferritin levels of > 10K AND any two of the following: Grade 3 or greater liver toxicity Grade 3 or greater kidney toxicityGrade 3 or greater lung toxicity.iii.Hemophagocytosis of the BM or organs based on either morphology or CD68+ immunohistochemistry.b.ManagementTreat per algorithm as CRS grade 3 -4i.If no resolution in 48 hours can consider (with approval of IEC attending)IV etoposide for treatment of HLH per HLH guidelinesIT cytarabine if evidence of neurotoxicity4.Infection ManagementPatients receiving CAR-T therapy are at increased risk of infection. Patients should receive prophylactic anti-infective agents (antibacterials, antifungals, antivirals). These will be administered in accordance with BMT unit standards. In the event of a suspected infection, patients will be worked-up in a consistent manner as per BMT standard, with implementation of treatment as clinically indicated.RESULTS / INTERPRETATIONATTACHMENTSAppendix 1:CRS GRADING (Organ Toxicity via CTCAE v4.03)Appendix 2:CTCAE NEUROLOGICAL TOXICITYAppendix 3:CARTOX-10 GRADINGAppendix 4:CARTOX- SCORINGREFERENCES1.Lee DW, Gardner R, Porter D, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124:188-95. 2.Maude SL, Barrett D, Teachey DT and Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 2014;2:119-122. 3.Teachey DT, Rheingold SR, Maude SL et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 2013;121:5154-7. 4. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, Komanduri KV, Lin Y, Jain N, Daver N, Westin J, Gulbis AM, Loghin ME, de Groot JF, Adkins S, Davis SE, Rezvani K, Hwu P, Shpall EJ. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018 Jan;15(1):47-625.U.S. Department of Health & Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_5x7.pdf (2010).Written By:Hemant Murthy MDDate:TBD 2018Revised By:N/ADate:N/AApprovalsTitleSignatureDateBMT Program Medical Director, as applicableClinical Service Manager, as applicableClinical Service Medical Director, as applicableBMT Program Quality Management CoordinatorRevision HistoryDate Change InitiatedChange Initiated ByDescription of ChangeDate Change ApprovedDate Change ImplementedAppendix 1:CRS Grading (Organ toxicity via CTCAE v4.03)Symptom or sign of CRSCRS Grade 11CRS Grade 22CRS Grade 32CRS Grade 42Vital signsTemperature ≥ 38°C (fever)YesAnyAnyAnySystolic BP < 90 mmHg (hypotension)NoResponds to IVF or low-dose vasopressorsRequires high-dose δ or multiple vasopressorsLife threateningNeeding oxygen to keeo O2 saturation > 90% NoFiO2 <40%FiO2 ≥40% Requires ventilator supportOrgan ToxicitiesOrgan toxicities (see below clinical signs for each organ system and refer to Appendix XX)Grade 1Grade 2Grade 3 or Grade 4 transaminitisGrade 4 (except Grade 4 transaminitis)1Grade 1 CRS may manifest as fever and/or grade 1 organ toxicity 2For grades 2, 3, or 4 CRS: any one of the criteria other than temperature is sufficient. 3 High-dose vasopressors are defined as any of the following: norepinepherine ≥20 mcg/min; dopamine ≥100 mcg/kg/min; phenylephrine ≥ 200 mcg/minute, epinephrine monotherapy ≥ 10 mcg/minute; vasopressin + norepinephrine equivalent of ≥10 mcg/minute; Combination vasopressors (not including vasopressin): norepinephrine equivalent ≥20 mcg/minute. The noradrenaline equivalent dose is calculated using the VASST trial vasopressor equivalent equation: [norepinephrine (?g/minute)] + [dopamine (?g/kg/minute)/2] + [epinepherine (?g/minute)] + [phenylephrine (?g/minute)/10].Cardiac: tachycardia, arrhythmias, heart block, low ejection fractionRespiratory: tachypnea, pleural effusion, pulmonary edemaGI: nausea, vomiting, diarrheaHepatic: increased serum ALT, AST, or bilirubin levelsRenal: acute kidney injury (increased serum creatinine levels), decreased urine outputDermatological: rash (less common)Coagulopathy: disseminated intravascular coagulation (less common)Appendix 2: CTCAE Neurological Toxicity Symptom / SignGrade 1Grade 2Grade 3Grade 4Level of ConsciousnessMild drowsiness / sleepinessModerate somnolence, limiting instrumental ADLObtundation or stuporLife- threatening needing urgent intervention or mechanical ventilationOrientation / ConfusionMild disorientation / confusionModerate disorientation, limiting instrumental ADLSevere disorientation, limiting self-care ADLADL / EncephalopathyMild limiting of ADLLimiting instrumental ADLLimiting self-care ADLSpeechDysphasia not impairing ability to communicateDysphasia with moderate impairment in ability to communicate spontaneouslySevere receptive or expressive dysphasia, impairing ability to read, write or communicate intelligiblySeizureBrief partial seizure; no loss of consciousnessBrief generalized seizureMultiple seizures despite medical interventionLife-threatening; prolonged repetitive seizuresIncontinent or motor weaknessBowel / bladder incontinence; Weakness limiting self-care ADL, disablingAppendix 3: Grading of CRESSymptom or signGrade1Grade2Grade3Grade4Neurological assessment score (by CARTOX-10)7 – 9(mild impairment)3 – 6 (moderate impairment)0 – 2(severe impairment)Patient in critical condition, and/or obtunded and cannot perform assessment of tasksRaised intracranial pressureNoNoStage 1 – 2 papilledema, or CSF opening pressure <20 mmHgStage 3 – 5 papilledema, or CSF opening pressure ≥ 20 mmHg or cerebral edemaSeizures or motor weaknessNoNoPartial seizure, or non-convulsive seizures on EEG with response to benzodiazepinesGeneralized seizures, or convulsive or non-convulsive status epilepticus, or new motor weaknessAppendix 4: CARTOX-10 Scoring One point for each task answered/performed correctly.Orientation to:PointAssignmentScoreCurrent Year1Current Year1City1Hospital1Current President1Name three objects3Write a sentence1Count backwards from 100 in 10s1TOTAL points ................
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