ASBMT Consensus Grading for CRS - PowerPoint Presentation

1. ASBMT Consensus Grading for CRSStephan Grupp MD PhDChief, Cell Therapy and Transplant SectionChildren’s Hospital of PhiladelphiaUniversity of Pennsylvania Perelman School of MedicineASTCT Webinar

2. DisclosuresResearch and/or clinical trial support from Novartis, Servier, Vertex and KiteStudy steering committees, consulting, or scientific advisory boards: Novartis, Adaptimmune, Eureka, TCR2, Juno, CRC Oncology, Cure Genetics, GlaxoSmithKline, Cellectis, Janssen, Vertex, RocheToxicity management patent managed by U Penn policies

3. ASBMT consensus conference: Grading for CRS and NeurotoxicityJune 20-21 201849 participantsBroad group of leaders from major academic CAR T centersPharmaASBMTCIBMTRASHNCI

4. Writing Committee Daniel LeeBianca SantomassoFrederick LockeArmin GhobadiCam TurtleJennifer BrudnoMarcela MausJae ParkElena MeadSteven PavleticWilliam GoLamis EldjerouRebecca A. Gardner Noelle FreyKevin Curran Karl PeggsJohn DiPersioMarcel van den BrinkKrishna Komanduri Stephan GruppSattva NeelapuEx officio doer of all things Mollie Corbett

5. Consensus meeting goalsDevelop consensus grading of CRS and neurotoxicityGoal is to apply across trials and commercial productsClinically based – based on what clinician observes and what she then does about itApplied at the bedsideEasily verifiable in chart reviewNot use CTCAe grade 4 lab values to upgrade

6. ELIANA Safety: AE of special interest (AESI) (Safety set; N=62)AESI group term*All grades%Grade 3%Grade 4%Cytokine release syndrome (CRS)792127Cytopenias not resolved by day 28371119Infections40233Transient neuropsychiatric events45150Tumor lysis syndrome5506*Defined only for the period of 8 weeks post CTL019 infusion2 deaths within 30 days of CTL019 (1 ALL, 1 cerebral hemorrhage) No deaths due to CRSNo cases of cerebral edema reportedMaude et al. N Engl J Med. 2018

7. Cytokine Release SyndromeCRS was graded using the Penn scale and managed by a protocol-specific algorithm1 CRS, cytokine release syndrome; ICU, intensive care unit.Porter DL, et al. Sci Transl Med. 2015;7(303):303ra139.Patients Infused(N = 79)Patients developed CRS, n (%)61 (77)Time to onset, median (range), days3.0 (1-22)Duration of CRS, median (range), days8.0 (1-36)ICU admission, n (%)38 (48)Anticytokine therapy, %31 (39)Tocilizumab, %31 (39) 1 dose18 (23) 2 doses10 (13) 3 doses3 (4)Corticosteroids, %16 (20)Hypotension that required intervention, %42 (53)High-dose vasopressors, %19 (24)Intubation, %12 (15)Dialysis, %8 (10)ASH 2018

8. CHOP/Penn CRS managementResponse based toxicity management (not grading based)Step 1 – toci for unstable hypotension (most common) or other significant changes in clinical statusSecond bolus in a short time – start of unstable hypotensionTrigger for toci – rapid decline, escalating single pressor, definitely 2nd pressor Step 2 – no change in 12-18 hrs – methylpred 2 mg/kg or equivrapid wean of steroids after hypotension resolvedMaude SL et al. N Engl J Med. 2014;371:1507-1517

9. CHOP/Penn CRS managementResponse based toxicity management (not grading based)Step 3 – no improvement in 12-18 hrs – 2nd dose of tociStep 4 – no improvementconsider siltuximab. Alternatives could include:30 mg/kg solumedrol (1 gram)Gamifant?Cyclophosphamide?Anakinra?Cytabsorb column??

10. CRS: Grading SchemesDifficult to compare CRS across studies24 yo w/ ALL develops hypotension requiring low dose pressors after CD19 CARGrade 2 on 2014 Consensus scaleGrade 3 on PENN/CHOP scaleGrade 4 on CTCAE scale

11. CRS: Grading SchemesCTCAE Versions 4.03 & Version 5.0Lee CriteriaPenn CriteriaMSKCC Criteria CARTOX (Neelapu, et al)

12. CRS definition (ASTCT consensus paper)CRS: “a supraphysiologic response following the activation or engagement of ...T cells for therapeutic intent. Symptoms can be “Progressive“must include fever at the onset“may include hypotension, capillary leak (hypoxia) and end organ dysfunction” CRS should be applied to any T-cell activating/engaging therapy, not just CAR T cellsAs new, effective immunotherapies (non-T cell) are developed, the definition may need to be altered.

13. CRS definition (ASTCT consensus paper)We don’t use cytokine measurements to define CRSThis is a clinical definitionCRS should be applied to any T-cell activating/engaging therapy, not just CAR T cellsAs new, effective immunotherapies (non-T cell) are developed, the definition may need to be altered.

14. CRS grading – specific commentsFever = 38°C After Rx, fever is no longer required. In this case, CRS grading is driven by hypotension and/or hypoxiaCRS grade is determined by the more severe event: hypotension or hypoxiaOrgan toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading

15. CRS gradingCRS ParameterGrade 1Grade 2Grade 3Grade 4Fever† not attributable to any other causeTemperature 38°C with or without constitutional symptomsTemperature 38°CTemperature 38°CTemperature 38°CWith either:Hypotension not attributable to any other causeNoneNot requiring vasopressorsRequiring one vasopressor with or without vasopressinRequiring multiple vasopressors (excluding vasopressin)And/or‡Hypoxia not attributable to any other causeNoneRequiring low-flow nasal cannula^ or blow-byRequiring high-flow nasal cannula^, facemask, non-rebreather mask, or Venturi maskRequiring positive pressure (eg: CPAP, BiPAP, intubation and mechanical ventilation)

16. Toxicity reporting in the commercial settingLarge effect sizes have meant that CAR T indications are FDA approved on <100 patientsFurther data collection is paramount15 year followup, but no RCL/RCR testingData will not be collected in a research setting with research budgets and direct regulatory mandates on the centersExcessive, inconsistent, or conflicting data requests from companies or health authorities in the commercial setting may interfere with getting necessary data#Askforeverythinggetnothing

17. Toxicity reporting in the commercial settingMultiple potential mechanisms:Medwatch to FDAWhat will EMA want?Direct reporting to the companyside effect – large numbers of queries, many irrelevantRegistry reporting (CIBMTR)Large reporting mandates (all grade 4 and especially grade 3 tox, grade 1 or 2 CRS) will bury the signal in noise and are not feasible

18. Toxicity reporting in the commercial settingWhat we want to avoid:a gap between what the FDA or EMA wants companies to collect and what centers are actually able to provideWhat we need: simplified and unified approach to reportinga single portal for data entryManageable data entryHealth authorities will need to harmonize

19. Toxicity reporting in the commercial settingA registry approach is likely to be the best method of providing consistency and as complete data as possible.CIBMTR reporting should achieve this

20. ASTCT Consensus Grading for ICANSSattva S. Neelapu, M.D.Professor and Deputy ChairDepartment of Lymphoma and MyelomaThe University of Texas MD Anderson Cancer CenterHouston, TXASTCT WebinarOctober 02, 2019

21. DisclosuresResearch support from Kite/Gilead, Merck, BMS, Cellectis, Poseida, Karus, Acerta, and Unum TherapeuticsAdvisory Board Member / Consultant for Kite/Gilead, Merck, Celgene, Novartis, Unum Therapeutics, Pfizer, Precision Biosciences, Cell Medica, Allogene, Incyte, and Legend Biotech

22. Neurotoxicity in multicenter CD19 CAR T trials in adult NHLStudyProductNT All GradesNT Grade ≥3 ReferenceNT All GradesNT Grade ≥3 ReferenceZUMA-1CD19/CD3z/CD2867%32%Neelapu et al, NEJM 2017Locke et al, Lancet Oncol 201987%31%Axicabtagene ciloleucel US Prescribing InformationJULIET CD19/CD3z/4-1BB21%12%Schuster et al, NEJM 201958%18%Tisagenlecleucel US Prescribing InformationCTCAE vs 4.03 criteria for neurotoxicity (NT) gradingMonitoring strategies for neurotoxicity differed between the two studiesAdverse event terms used also differed between the two studiesAdverse events included under neurotoxicity differed between investigator reporting and USPI

23. Neurologic and psychiatric adverse reactions reported with approved CAR T productsTisagenlecleucelAxicabtagene ciloleucelencephalopathy--includes: encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, somnolence, and automatismdelirium--includes: delirium, agitation, hallucination, hallucination visual, irritability, restlessnessheadache--includes headache and migraineanxiety sleep disorder--includes: sleep disorder, insomnia, and nightmareencephalopathy--includes: encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, hypersomnia, leukoencephalopathy, memory impairment, mental status changes, paranoia, somnolence, stupordelirium--includes: agitation, delirium, delusion, disorientation, hallucination, hyperactivity, irritability, restlessnessheadachedizziness--includes: dizziness, presyncope, syncopeaphasia: includes aphasia, dysphasiamotor dysfunctionmotor dysfunction--includes: muscle spasms, muscular weakness tremorataxiaseizure dyscalculiamyoclonusLee et al. Biol Blood Marrow Transplant, 2019 Apr;25 (4):625-638

24. CTCAE v4.03 grading of neurotoxicitySymptom/SignGrade 1Grade 2Grade 3Grade 4Level of consciousnessMild drowsiness / sleepinessModerate somnolence, limiting instrumental ADLObtundation or stuporLife-threatening needing urgent intervention/ mechanical ventilationOrientation / ConfusionMild disorientation / confusionModerate disorientation, limiting instrumental ADLSevere disorientation, limiting self-care ADLLife-threatening needing urgent intervention/ mechanical ventilationEncephalopathyMild limiting of ADL Limiting instrumental ADLLimiting self-care ADLLife-threatening needing urgent intervention/ mechanical ventilationSpeechDysphasia not impairing ability to communicateDysphasia with moderate impairment in ability to communicate spontaneouslySevere receptive or expressive dysphasia, impairing ability to read, write or communicate-SeizureBrief partial seizure; no loss of consciousnessBrief generalized seizureMultiple seizures despite medical interventionLife-threatening; prolonged repetitive seizuresTremorsMild symptomsModerate symptoms; limiting instrumental ADLSevere symptoms; limiting self-care ADL-Motor weaknessSymptomatic; perceived by patient but not evident on physical examSymptomatic; evident on physical exam; limiting instrumental ADLLimiting self-care ADL, disabling-Bowel or bladder incontinence--Intervention indicated; limiting self care ADL-Cerebral edema---Life-threatening; urgent intervention indicated

25. CTCAE v5.0 grading of neurotoxicityLee et al. Biol Blood Marrow Transplant, Dec 2018Adverse Event TermGrade 1Grade 2Grade 3Grade 4EncephalopathyMild symptomsModerate symptoms; limiting instrumental ADLSevere symptoms; limiting self care ADLLife threatening consequences, urgent intervention indicatedSeizureBrief partial seizure and no loss of consciousnessBrief generalized seizureNew onset seizures (partial or generalized); multiple seizures despite medical interventionLife threatening consequencesDysphasiaAwareness of receptive or expressive characteristics; not impairing ability to communicateModerate receptive or expressive characteristics; impairing ability to communicate spontaneously Severe receptive or expressive characteristics; impairing ability to read, write, communicate intelligibly TremorMild symptomsModerate symptoms; limiting instrumental ADLSevere symptoms; limiting self care ADL HeadacheMild painModerate pain; limiting instrumental ADLSevere pain; limiting self care ADL ConfusionMild disorientationModerate disorientation; limiting instrumental ADLSevere disorientation; limiting self care ADLLife threatening consequences; urgent intervention indicatedDepressed level of consciousnessDecreased level of alertnessSedation; slow response to stimuli; limiting instrumental ADLDifficult to arouseLife threatening consequences; coma; urgent intervention indicatedCerebral edema  New onset; worsening from baselineLife-threatening consequences; urgent intervention indicated

26. CTCAE v 4.03/5.0 definition of ADLsInstrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.

27. Need for better grading system for neurotoxicityObjectiveReproducibleEasy to useUsable by all healthcare providers involved in patient careAllow rapid and dynamic assessmentPractical tool for grade-based management of toxicities

28. CARTOX (CAR TOXicity) GuidelinesNeelapu et al. Nat Rev Clin Oncol, Jan 2018Mahadeo et al, Nat Rev Clin Oncol, Aug 2018AdultsChildren

29. ASBMT WorkshopJune 20-21, 2018Washington, DC

30. ASTCT definition of ICANS(IEC-Associated Neurotoxicity Syndrome)ICANS is “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.” Similar to CRS, ICANS should be applied to any immune effector cell engaging therapy, not just CAR T cells. Lee et al. Biol Blood Marrow Transplant, 2019 Apr;25 (4):625-638

31. ASTCT Consensus Encephalopathy Assessment ScoreCARTOX ScoreImmune-Effector Cell-Associated Encephalopathy (ICE) ScoreOrientation: Orientation to year, month, city, hospital, President: 5 points Naming: Name 3 objects (e.g., point to clock, pen, button): 3 pointsFollowing commands: (e.g., Show me 2 fingers or Close your eyes and stick out your tongue): 1 point Writing: Ability to write a standard sentence (e.g., Our national bird is the bald eagle): 1 point Attention: Count backwards from 100 by ten: 1 pointOrientation: Orientation to year, month, city, hospital: 4 points Naming: Name 3 objects (e.g., point to clock, pen, button): 3 points Following commands: (e.g., Show me 2 fingers or Close your eyes and stick out your tongue): 1 pointWriting: Ability to write a standard sentence (e.g., Our national bird is the bald eagle): 1 point Attention: Count backwards from 100 by ten: 1 pointLee et al. Biol Blood Marrow Transplant, 2019 Apr;25 (4):625-638Neelapu et al. Nat Rev Clin Oncol, 2018 Jan; 15(1):47-62

32. Impaired handwriting is a sensitive sign of neurotoxicityDay 49 amDay 501:30 PMDay 503:30 PMDay 69 amMMSE score29/3027/3027/3029/30

33. ASTCT Consensus Grading of ICANS for Adults (IEC-Associated Neurotoxicity Syndrome)Neurotoxicity Domain‡ Grade 1Grade 2Grade 3Grade 4ICE Score7-93-60-20 (patient is unarousable and unable to perform ICE)Depressed level of consciousnessAwakens spontaneouslyAwakens to voiceAwakens only to tactile stimulusPatient is unarousable or requires vigorous or repetitive tactile stimuli to arouse or stupor or coma SeizureN/AN/AAny clinical seizurefocal or generalized that resolves rapidly ; or Non-convulsive seizures on EEG that resolve with intervention Life-threatening prolonged seizure (>5 min); orRepetitive clinical or electrical seizures without return to baseline in between Motor findingsN/AN/AN/ADeep focal motor weakness such as hemiparesis or paraparesis Raised intracranial pressure / Cerebral edemaN/AN/AFocal/local edema on neuroimaging#Diffuse cerebral edema on neuroimaging; Decerebrate or decorticate posturing; or Cranial nerve VI palsy; or Papilledema; or Cushing's triadLee et al. Biol Blood Marrow Transplant, 2019 Apr;25 (4):625-638‡ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) not attributable to any other cause

34. ICANS Grading: Specific commentsNot be attributable to any other causeDepressed level of consciousness should be attributable to no other cause (e.g. no sedating medication)ICANS grade is determined by the more severe eventTremors and myoclonus may be graded according to CTCAE v5.0 but they do not influence ICANS gradingIntracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may be graded according to CTCAE v5.0.Lee et al. Biol Blood Marrow Transplant, 2019 Apr;25 (4):625-638

35. Encephalopathy Assessment: CAPD Score for Children <12 years (Cornell Assessment of Pediatric Delirium)Answer the following based on interactions with the child over the course of the shiftNever4Rarely3Sometimes2Often1Always01. Does the child make eye contact with the caregiver?     2. Are the child’s actions purposeful?     3. Is the child aware of his/her surroundings?     4. Does the child communicate needs and wants?      Never0Rarely1Sometimes2Often3Always45. Is the child restless?     6. Is the child inconsolable?     7. Is the child underactive – very little movement while awake?     8. Does it take the child a long time to respond to interactions?     Lee et al. Biol Blood Marrow Transplant, 2019 Apr;25 (4):625-638

36. Encephalopathy Assessment: CAPD Score for Children Age 1-2 years (Cornell Assessment of Pediatric Delirium)For patients age 1-2 years, the following serve as guidelines to the corresponding questions:Holds gaze. Prefers primary parent. Looks at speaker.Reaches and manipulates objects, tries to change position, if mobile may try to get upPrefers primary parent, upset when separated from preferred caregivers. Comforted by familiar objects (i.e., blanket or stuffed animal)Uses single words or signsNo sustained calm stateNot soothed by usual comforting actions, for example, singing, holding, talking, and readingLittle if any paly, efforts to sit up, pull up, and if mobile crawl or walk aroundNot following simple directions. If verbal, not engaging in simple dialogue with words or jargonLee et al. Biol Blood Marrow Transplant, 2019 Apr;25 (4):625-638

37. ASTCT Consensus Grading of ICANS for Children (IEC-Associated Neurotoxicity Syndrome)Neurotoxicity DomainGrade 1Grade 2Grade 3Grade 4ICE Score for children 12 years^7-9 3-6 0-2 0 (patient is unarousable and unable to perform ICE)CAPD score for children 12 years1-81-89Unable to perform CAPD Depressed level of consciousness❖Awakens spontaneouslyAwakens to voiceAwakens only to tactile stimulusPatient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or comaSeizure (any age)N/AN/AAny clinical seizurefocal or generalized that resolves rapidly; or Non-convulsive seizures on EEG that resolve with interventionLife-threatening prolonged seizure (>5 min); orRepetitive clinical or electrical seizures without return to baseline in between. Motor weakness (any age)§N/A N/AN/ADeep focal motor weakness such as hemiparesis or paraparesisRaised ICP / Cerebral Edema (any age)  Focal/local edema on neuroimaging#Decerebrate or decorticate posturing; or Cranial nerve VI palsy; or Papilledema; or Cushing's triad; or Signs of diffuse cerebral edema on neuroimagingNeurotoxicity DomainGrade 1Grade 2Grade 3Grade 47-9 3-6 0-2 0 (patient is unarousable and unable to perform ICE)1-81-89Unable to perform CAPD Depressed level of consciousness❖Awakens spontaneouslyAwakens to voiceAwakens only to tactile stimulusPatient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or comaSeizure (any age)N/AN/AAny clinical seizurefocal or generalized that resolves rapidly; or Non-convulsive seizures on EEG that resolve with interventionLife-threatening prolonged seizure (>5 min); orRepetitive clinical or electrical seizures without return to baseline in between. Motor weakness (any age)§N/A N/AN/ADeep focal motor weakness such as hemiparesis or paraparesisRaised ICP / Cerebral Edema (any age)  Focal/local edema on neuroimaging#Decerebrate or decorticate posturing; or Cranial nerve VI palsy; or Papilledema; or Cushing's triad; or Signs of diffuse cerebral edema on neuroimagingLee et al. Biol Blood Marrow Transplant, 2019 Apr;25 (4):625-638

38. CTCAE vs. ASTCT grading of ICANSCTCAE GradingASTCT GradingMultiple AE terms usedComposite gradeFive neurotoxicity domains – ICE score, level of consciousness, seizures, motor weakness, signs of raised ICP/cerebral edemaGrade based on subjective terms or assessment of ADLs (instrumental or self-care)ADLs not taken into accountGrading subjective (mild, moderate, severe)Grading objective based on ICE score and other objective criteriaSeizures can be grade 1-4Seizures are either grades 3 or 4Electrical seizures are not consideredElectrical seizures are consideredMotor weakness can be grades 1-3Motor weakness is grade 4

39. Summary: ASTCT Consensus GradingConsensus grading for CRS and ICANSObjective and easy to use at the bedside (ASTCT App / CARTOX App)Grading could be incorporated and automated in EMRsEasily verifiable in chart reviewData can be imported from EMRs to institutional DatabasesGoal is to apply across all trials and standard of care setting including reporting to CIBMTR for commercial products

40. AcknowledgementsWorkshop ParticipatantsVeronika BachanovaSonghai BarcliftMichael BishopKaren ChaginAndrea Chassot AgostinhoDavid ChonziSteven DevineOlivia GardnerDennis GastineauParameswaran HariHelen HeslopMary HorwitzRon KlineAna KosticAlice KuabanNavneet MajhailShannon MaudeRichard MaziarzJosh McFeestersWilliam MerrittDavid MiklosTonia NesheiwatSarah NikiforowMiguel-Angel PeralesDavid PorterTravis QuigleyStephen SchusterElizabeth ShpallPatricia SteinertSudhakar TummalaASTCT LeadershipJohn F DiPersioMarcel R M van den BrinkKrishna V KomanduriWriting CommitteeDaniel W Lee Bianca D SantomassoFrederick L LockeArmin GhobadiCameron J TurtleJennifer N. BrudnoMarcela V MausJae H. ParkElena MeadSteven PavleticWilliam Y GoLamis EldjerouRebecca A. GardnerNoelle FreyKevin J CurranKarl PeggsMarcelo PasquiniJohn F DiPersioMarcel R M van den BrinkKrishna V KomanduriStephan A GruppSattva S NeelapuAdministrative SupportMollie Corbett