Cytokine Release Syndrome and Neurotoxicity: Ongoing...

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Transcript of Cytokine Release Syndrome and Neurotoxicity: Ongoing...

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Cytokine Release Syndrome and Neurotoxicity: Ongoing Efforts to Enhance Safety Sattva S. Neelapu, MD

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• Research support from Kite, Merck, BMS, Cellectis, Poseida, Karus, Acerta

• Advisory Board Member/Consultant for Kite, Merck, Celgene, Novartis, Unum Therapeutics, Pfizer

• I will discuss investigational use of anakinra and siltuximab in my presentation

Disclosures

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Cytokine Release Syndrome (CRS)

• Systemic inflammatory

response caused by

cytokines released by

CAR T cells and other

immune cells and

results in reversible

organ dysfunction

Brudno JN, Kochenderfer JN. Blood. 2016 June 30;127(26):3321-3330.

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• Typically manifests as a toxic encephalopathy oWord-finding difficulty, confusion, disorientation, agitation, dysphasia, aphasia,

somnolence, tremors, and impaired handwriting

o In more severe cases, seizures, motor weakness, incontinence, increased intracranial pressure, papilledema, and cerebral edema may also occur

• Onset may be during CRS or after CRS symptoms have subsided

• May last few hours to several days

• Generally reversible with no permanent neurological deficits

Neurotoxicity

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CRS Deaths After CD19 CAR T-Cell TherapyCAR T-cell product Malignancy

Day of death post-CAR T

Cause of death Reference

CD19-137-z B-ALL 5 CRS (+Influenza B) Frey NV, et al. Blood. 2014;124:2296.

CD19-137-z B-ALL 15 CRS (+Pseudomonas sepsis, pneumonia) Frey NV, et al. Blood. 2014;124:2296.

CD19-137-z B-ALL 15CRS (+Steno-trophomonas sepsis, pneumonia)

Frey NV, et al. Blood. 2014;124:2296.

CD19-137-z B-ALL 3 CRSTurtle CJ, et al. J Clin Invest. 2016 June 1;126(6):2123-2138.

CD19-137-z NHL 30 CRS (+GI bleed)Turtle CJ, et al. Sci Transl Med. 2016 Sep 7;8(355):355ra116.

CD19-28-z CLL 2 CRSBrentjens R, et al. Mol Ther. 2010 Apr;18(4):666-668.

CD19-28-z PMBCL 16Unknown (possibly cardiac arrhythmia)

Kochenderfer JN, et al. J Clin Oncol. 2015 Feb 20;33(6):540-549.

CD19-28-z NHL N/A Cardiac arrestNeelapu SS, et al. N Engl J Med. 2017 Dec 28;377(26):2531-2544.

CD19-28-z DLBCL N/A HLHNeelapu SS, et al. N Engl J Med. 2017 Dec 28;377(26):2531-2544.

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Neurotoxicity Deaths After CD19 CAR T-Cell TherapyCAR T-cell product

MalignancyDay of death post-CAR T

Cause of death Reference

CD19-137-z B-ALL 122 NeurotoxicityTurtle CJ, et al. J Clin Invest. 2016 June 1;126(6):2123-2138.

CD19-137-z NHL 13Neurotoxicity (+CNS bleed)

Turtle CJ, et al. Sci Transl Med. 2016 Sep 7;8(355):355ra116.

CD19-137-z FL N/A EncephalitisSchuster SJ, et al. N Engl J Med. 2017 Dec 28;377(26):2545-2554.

CD19-28-z ALL N/ACerebral edema(5 cases)

Juno press release

CD19-28-z NHL N/ACerebral edema(1 case)

Kite press release

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Study/Sponsor

Product N CRS all grades

CRS Grade ≥ 3

NT all grades

NT Grade ≥ 3

Toci usage Steroidusage

Reference

ZUMA-1Kite

CD19/CD3z/CD28

108 93% 13% 65% 31% 45% 29% Neelapu SS, et al. N Engl J Med. 2017 Dec 28;377(26):2531-2544.

JULIETNovartis

CD19/CD3z/4-1BB

111 58% 22% 21% 12% 15% 11% Borchmann P, et al. EHA Learning Center. June 16, 2018;214521.

TRANSCEND Juno

CD19/CD3z/4-1BB

102 37% 1% 23% 13% 17% 21% Abramson JS, et al. J Clin Oncol. 2018 May;36(15 suppl):7505-7505.

• Lee criteria used for CRS grading on ZUMA1 and TRANSCEND• U Penn criteria used for CRS grading on JULIET• All trials used CTCAE criteria for neurotoxicity (NT) grading• 3 deaths on ZUMA1 due to AEs – 1 cardiac arrest, 1 HLH, 1 pulmonary embolism

Safety in Multicenter CD19 CAR T Trials in Adult NHL

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Host/Tumor Factors

• Type of malignancy (ALL > DLBCL)

• Tumor burden

• Baseline inflammatory state

Therapy-Related Factors

• Lymphodepleting therapy

• CAR T dose

• CAR T design (CD28 > 4-1BB)

• CAR T expansion

• Cytokine profile

References

• Maude SL, et al. N Engl J Med. 2014

• Davila ML, et al. Sci Transl Med. 2014

• Lee DW, et al. Lancet. 2015

• Teachey DT, et al. Cancer Discov. 2016

• Turtle CJ, et al. J Clin Invest. 2016

• Turtle CJ, et al. Sci Transl Med. 2016

• Gust J, et al. Cancer Discov. 2017

• Hay KA, et al. Blood. 2017

• Neelapu SS, et al. N Engl J Med. 2017

• Maude SL, et al. N Eng J Med. 2018

• Park JH, et al. N Engl J Med. 2018

• Santomasso BD, et al. Cancer Discov. 2018

Factors Associated With Toxicity After CAR T Therapy

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• Proliferate

• Make cytokines

• Kill the target cells

CAR T cell

CAR T-Cell Response to Antigen

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Locke FL, et al. Mol Ther. 2017 Jan 4;25(1):285-295.

• Peak expansion observed within 2 weeks• CAR T cells detectable beyond 2 years after infusion• Each infused CAR T cell can proliferate to > 10,000 cells in the body

CAR T-Cell Expansion and Persistence After Axi-Cel Infusion

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ORR NE CRS

Neelapu SS, et al. N Engl J Med. 2017 Dec 28;377(26):2531-2544.

• Unique pharmacokinetics compared with traditional therapeutic agents• Up to 4-log difference in peak levels and AUC across patients• Need for tunable CARs!

ZUMA-1: CAR T-Cell Expansion Was Associated With ORR and Grade ≥ 3 NE, but not Grade ≥ 3 CRS

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Perez A, et al. ASH 2015. Session 801. Poster I.

IL-2IL-7IL-15

IL-6IL-8IL-10

IFNgTNFa Granzymes

Perforin

Cytokine Pattern After Axi-cel CAR T Infusion

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ProliferativeIL-15

IL-2

Inflammatory

IL-6

CRP

SAA

IL-5

Ferritin

IL-1Ra

IL-2Rα

Immune-modulating

GM-CSF

IFN-γ

IL-10

ChemokineIL-8

IP-10

MCP-1

Effector Granzyme B

Baseline Day 0 Day 1 Day 3 Day 5 Day 7 Day 14 Day 28

Fold

increase ab

ove b

aseline

0

10

20

• Analytes shown were elevated in ≥ 50% of patients with ≥ 2-fold induction above baseline out of a panel of 44 measured

Locke FL, et al. AACR 2017. Abstract CT019.

ZUMA-1: Distinct Biomarkers Peak Within7 Days After Axi-cel Treatment

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Maude SL, et al. N Engl J Med. 2014 Oct 16;371(16):1507-1517.

• Tocilizumab (anti-IL-6R Ab) or siltuximab (anti-IL-6 Ab) are used for management of severe CRS

• Tocilizumab was approved for management of CRS in the US and EU

IL-6 Levels Correlate With Severity of CRS

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Function AnalyteCRS Grade ≥ 3 vs Grades 0-2

NE Grade ≥ 3 vs Grades 0-2

Homeostatic IL-15

Inflammatory

IL-6

IL-1Ra

IL-2Rα

Immune-modulatingIFN-γ

IL-10

ChemokineIL-8

MCP-1

Effector Granzyme B

Adjusted P values are calculated from Holm's procedure after multiple testing using the Wilcoxon rank sum test

P < .05.05 < P < .10

*Peak levels after axi-cel infusion were used in the comparison. Locke FL, et al. AACR 2017. Abstract CT019.

ZUMA-1: Peak Levels of Biomarkers Associated With Grade ≥ 3 CRS and NE

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Maude SL. Blood. 2017 Nov 23;130(21):2238-2240.

Pathophysiology of CRS

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Neelapu SS, et al. Hematol Oncol. 2017 June 07;35(suppl S2):28.

ZUMA-1: Tocilizumab/Steroid Use Did Not Impact Responses But Was Associated With Higher CAR T-Cell Levels

Tocilizumab Steroids

Withoutn = 58

Withn = 43

PValue

Withoutn = 74

Withn = 27

PValue

ORR, n (%) 47 (81.0) 36 (83.7) .8 62 (83.8) 21 (77.8) .56

CR, n (%) 33 (56.9) 22 (51.2) .69 40 (54.1) 15 (55.6) 1

Ongoing, n (%) 28 (48.3) 16 (37.2) .31 33 (44.6) 11 (40.7) .82

Median peak CAR,

cells/μL (range)

27

(1-1226)

61

(1-1514).0011

32

(1-1226)

50

(1-1514).0618

Median CAR AUC,

cells/μL days (range)

290

(17-14329)

744

(5-11507).0022

408

(17-14329)

725

(5-11507).0967

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• Prophylactic tocilizumab given on Day +2.

Prophylactic Tocilizumab After Axi-cel: Baseline Characteristics

CharacteristicZUMA-1 Primary Analysis1

(N = 101)SMS Cohort 3

(N = 34)

Median (range) age, y 58 (23–76) 51 (21–74)

≥ 65 y, n (%) 24 (24) 7 (21)

Men, n (%) 68 (67) 19 (56)

ECOG PS 1, n (%) 59 (58) 19 (56)

Disease type, n (%)

DLBCL

PMBCL/TFL

77 (76)

24 (24)

21 (62)

13 (38)

Disease stage III/IV, n (%) 86 (85) 20 (59)

IPI score 3-4, n (%) 47 (47) 11 (32)

≥ 3 prior therapies, n (%) 70 (69) 25 (74)

Refractory subgroup before enrollment

Primary refractory 2 (2) 1 (3)

Refractory to second- or later-line therapy, n (%) 78 (77) 25 (74)

Relapse post-ASCT, n (%) 21 (21) 8 (24)

Locke FL, et al. Blood. 2017;130(suppl 1). ASH abstract 1547.

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Event, n (%)ZUMA-1 Primary Analysis

(N = 101)SMS Cohort 3

(N = 34)Any CRS 94 (93) 32 (94)

Worst grade 1 37 (37) 12 (35)

Worst grade 2 44 (44) 19 (56)

Worst grade 3 9 (9) 0

Worst grade 4 3 (3) 1 (3)

Worst grade 5 1 (1) 0

Worst grade ≥ 3 13 (13) 1 (3)

Any NE 63 (62) 29 (85)

Worst grade 1 21 (21) 9 (26)

Worst grade 2 14 (14) 6 (18)

Worst grade 3 26 (26) 12 (35)

Worst grade 4 2 (2) 1 (3)

Worst grade 5 0 1 (3)

Worst grade ≥ 3 28 (28) 14 (41)

Prophylactic Tocilizumab: Safety

Locke FL, et al. Blood. 2017;130(suppl 1). ASH abstract 1547.

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• Overall goal is to maximize the benefit from the CAR T-cell therapy while minimizing the risk for life-threatening complications of toxicities

Nat Rev Clin Oncol, Jan 2018Ideal grading system

• Objective

• Reproducible

• Easy to use

• Usable by all healthcare providers involved in patient care

• Allow rapid and dynamic assessment

• Practical tool for grade-based management of toxicities

Grading and Management of CRS and neurotoxicity

• ASBMT Workshop on Consensus Grading of CRS and Neurotoxicity

• June 20-21, 2018

• Manuscript submitted

CARTOX Guidelines

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a Grade 1 CRS may manifest as fever and/or Grade 1 organ toxicity.b For Grades 2, 3, or 4 CRS, any one of the criteria other than temperature is sufficient.c Use CTCAE, version 4 for grading of organ toxicity.d See Lee DW, et al. Blood. 2014 Jul 10;124(2):188-195 for definition of high-dose vasopressors.

• CRS grade should be determined at least twice daily and any time there is a change in patient’s status

Adapted from Lee DW, et al. Blood. 2014 Jul 10;12492):188-195.Neelapu SS, et al. Nat Rev Clin Oncol. 2018 Jan;15(1):47-62.

Determine the Grade of CRS (CARTOX Grading)

Category Symptom/Sign CRS Grade 1a

CRS Grade 2b

CRS Grade 3b

CRS Grade 4b

Vital signs Temp ≥ 380C Yes Any Any Any

SBP < 90 No Responds to IV fluids or low-dose vasopressor

Needs high-dose or multiple vasopressorsd

Life- threatening

Needing oxygen for O2 sat > 90%

No FiO2 <40% FiO2 ≥ 40% Needing ventilator support

Organ toxicityc See Step 1 Grade 1 Grade 2 Grade 3 or grade 4 transaminitis

Grade 4 except grade 4 transaminitis

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ASBMT Consensus Grading of CRSCRS Parameter* Grade 1 Grade 2 Grade 3 Grade 4

Fever#† Temperature 38°C Temperature 38°C Temperature 38°C Temperature 38°C

With either:

Hypotension# None Not requiring vasopressors Requiring one vasopressor with or without vasopressin

Requiring multiple vasopressors (excluding vasopressin)

And/ or‡

Hypoxia# None Requiring low-flow nasal cannula^ or blow-by

Requiring high-flow nasal cannula^, facemask, non-rebreather mask, or Venturi mask

Requiring positive pressure (eg: CPAP, BiPAP, intubation and mechanical ventilation)

#Not attributable to any other cause

†In patients who have CRS then receive tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity

‡CRS grade is determined by the more severe event

^Low-flow nasal cannula is 6 L/min and high-flow nasal cannula is > 6 L/min

*Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading

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* High risk for severe CRS: Bulky disease, comorbidities, early onset CRS (< 3 days)

Maximum of one siltuximab dose per patient

Management of CRS (CARTOX Gudelines)

CRS Grade Symptom or Sign ManagementGrade 1 Fever or Grade 1 organ toxicity • Acetaminophen and hypothermia blanket as needed for fever

• Ibuprofen may be used as second option for fever if not contraindicated• Assess for infection with blood and urine cultures, and chest x-ray• Empiric broad-spectrum antibiotics and filgrastim if neutropenic• Maintenance IV fluids for hydration• Symptomatic management of constitutional symptoms and organ toxicities• Consider IL-6 antagonist for persistent (> 3 days) or refractory fever

Grade 2 Hypotension • IV fluid bolus of 500–1000 mL normal saline• May give a second IV fluid bolus if SBP remains < 90 mm Hg• Consider IL-6 antagonist for hypotension refractory to fluid bolus• If hypotension persists after two fluid boluses and anti-IL-6 therapy, start vasopressors, consider

transfer to ICU, and obtain ECHO and initiate other methods of hemodynamic monitoring• In patients at high-risk* or if hypotension persists after IL-6 antagonist, may use dexamethasone 10

mg IV q 6h• Manage fever and constitutional symptoms as in grade 1 CRS

Hypoxia • Supplemental oxygen• IL-6 antagonist +/- corticosteroids and supportive care as in hypotension

Grade 2 organ toxicity • Symptomatic management of organ toxicity as per standard guidelines • Use IL-6 antagonist +/- corticosteroids and supportive care as in hypotension

Neelapu SS, et al. Nat Rev Clin Oncol. 2018 Jan;15(1):47-62.

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Neelapu SS, et al. Nat Rev Clin Oncol. 2018 Jan;15(1):47-62.

Management of CRS (cont.)

CRS Grade Symptom or Sign ManagementGrade 3 Hypotension • IV fluid boluses as needed as in grade 2

• IL-6 antagonist as in grade 2 if not administered previously• Vasopressors as needed • Transfer to ICU, ECHO and hemodynamic monitoring as in grade 2• Start dexamethasone 10 mg IV q 6h; increase to 20 mg IV every 6h if refractory• Manage fever and constitutional symptoms as in grade 1

Hypoxia • Supplemental oxygen including high flow oxygen delivery and non-invasive positive pressure ventilation• IL-6 antagonist + corticosteroids and supportive care as above

Grade 3 organ toxicity or grade 4 transaminitis

• Symptomatic management of organ toxicity as per standard guidelines • IL-6 antagonist + corticosteroids and supportive care as above

Grade 4 Hypotension • IV fluids, IL-6 antagonist, vasopressors, and hemodynamic monitoring as in grade 3• High-dose corticosteroids (e.g. Methylprednisolone IV 1 g/day x 3 days followed by rapid taper at 250 mg

q12 h x 2 days, 125 mg q12 h x 2 days, and 60 mg q12 h x 2 days); taper of corticosteroids may be individualized

• Manage fever and constitutional symptoms as in grade 1

Hypoxia • Mechanical ventilation• IL-6 antagonist + corticosteroids and supportive care as above

Grade 4 organ toxicity excluding transaminitis

• Symptomatic management of organ toxicities as per standard guidelines • IL-6 antagonist + corticosteroids and supportive care as above

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aPapilledema grading is performed according to Modified Frisén scale (Appendix 3).

Neelapu SS, et al. Nat Rev Clin Oncol. 2018 Jan;15(1):47-62.

Determine the Grade of Neurotoxicity (CARTOX Grading)

Symptom/Sign Grade 1 Grade 2 Grade 3 Grade 4Neurological assessment

score (see below)

Mild (7-9) Moderate (3-6) Severe (0-2) Critical/obtunded

Raised intracranial pressure - - Stage 1 or 2 papilledemaa with CSF opening pressure < 20 mmHg

Stage 3, 4, or 5 papilledemaa; or CSF

opening pressure ≥ 20 mmHg; or

cerebral edema

Seizures or motor weakness - - Partial seizure; non-convulsive seizures on EEG responding to benzodiazepine

Generalized seizures;

convulsive or non-convulsive status

epilepticus; new motor weakness

CARTOX 10-point neurological assessment (Assign one point for each task performed correctly; score of 10 = normal)• Orientation to year, month, city, hospital, president: 5 points• Name three objects (point to clock, pen, button): 3 points • Ability to write a standard sentence (e.g. Our national bird is the bald eagle): 1 point• Count backwards from 100 by 10: 1 point

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ASBMT Consensus Encephalopathy Assessment Tool

CARTOX ToolImmune-Effector Cell-Associated

Encephalopathy (ICE) Tool• Orientation: Orientation to year, month, city,

hospital, President: 5 points

• Naming: Name 3 objects (e.g., point to clock,

pen, button): 3 points

• 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 point

• Orientation: 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 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 point

Neelapu SS, et al. Nat Rev Clin Oncol. 2018 Jan;15(1):47-62. Manuscript Submitted

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ASBMT Consensus Grading of ICANS (IEC-Associated Neurotoxicity Syndrome)

Neurotoxicity Domain‡ Grade 1 Grade 2 Grade 3 Grade 4

ICE Score 7-9 3-6 0-2 0 (patient is unarousable and unable to

perform ICE)Depressed level of

consciousness

Awakens spontaneously

Awakens to voice

Awakens only to tactile stimulus

Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse or stupor or coma

Seizure N/A N/A Any 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 findings N/A N/A N/A Deep focal motor weakness such as hemiparesis or paraparesis

Raised intracranial pressure

/ 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

‡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.

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Maximum of one siltuximab dose per patient

Management of Neurotoxicity (CARTOX Guidelines)

Grade Management

Grade 1 • Vigilant supportive care; aspiration precautions; IV hydration• Withhold oral intake of food, medicines, and fluids and assess swallowing• Convert all oral medications and/or nutrition to IV if swallowing is impaired• Avoid medications that cause central nervous system depression• Low doses of lorazepam (0.25-0.5 mg IV every 8h) or haloperidol (0.5 mg IV every 6h) may be used for agitated patients

with careful monitoring• Neurology consultation• Fundoscopic exam to assess for papilledema• MRI brain with and without contrast; diagnostic lumbar puncture with opening pressure; MRI spine if focal peripheral

neurological deficits; CT scan of brain may be performed if MRI brain is not feasible• Daily 30-min EEG until toxicity symptoms resolve; if no seizures on EEG, continue levetiracetam 750 mg every 12h• If EEG shows non-convulsive status epilepticus, treat as per algorithm in Appendix 4• Consider IL-6 antagonist if associated with concurrent CRS

Grade 2 • Supportive care and neurological work-up as per grade 1 • If associated with concurrent CRS symptoms, IL-6 antagonist• If NOT associated with CRS, dexamethasone 10mg IV every 6h or methylprednisolone 1 mg/kg IV every 12h or

if refractory to IL-6 antagonist• Consider ICU transfer if associated with Grade 2 or greater CRS

Neelapu SS, et al. Nat Rev Clin Oncol. 2018 Jan;15(1):47-62.

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Grade Management

Grade 3 • Supportive care and neurological work-up as per Grade 1 • ICU transfer is recommended• IL-6 antagonist if associated with concurrent CRS as per Grade 2 and if not administered previously• If NOT associated with CRS, corticosteroids as above or for worsening symptoms despite anti-IL-6 therapy; Continue

corticosteroids until improvement to grade 1 and then taper• Stage 1 or 2 papilledema with CSF op < 20 mm Hg, treat as per algorithm in Appendix 6• Consider repeat neuro-imaging (CT or MRI) q 2-3 days if persistent neurotoxicity ≥ Grade 3 CRES

Grade 4 • Supportive care and neurological work-up as per grade 1 • ICU monitoring; Consider mechanical ventilation for airway protection• IL-6 antagonist and repeat neuro-imaging as per Grade 3• High-dose corticosteroids (e.g. methylprednisolone IV 1 g/day x 3 days followed by rapid taper at 250 mg q12 h x 2

days, 125 mg q12 h x 2 days, and 60 mg q12 h x 2 days); Continue corticosteroids until improvement to Grade 1 and then taper

• For convulsive status epilepticus, treat as per algorithm in Appendix 5• Stage 3, 4, or 5 papilledema, CSF op ≥ 20 mm Hg, or cerebral edema, treat as per algorithm in Appendix 6

Management of Neurotoxicity (cont.)

Neelapu SS, et al. Nat Rev Clin Oncol. 2018 Jan;15(1):47-62.

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Gust J, et al. Cancer Discov. 2017 Dec; 7(12):1404-1419.

Endothelial Activation and BBB Disruption Drive Neurotoxicity

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June 2018

June 2018

Rooney C, Sauer T. Nat Med. 2018 Jun;24(6):705-706.

Role of IL-1 in CRS and/or Neurotoxicity

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• CAR T-cell expansion and inflammatory cytokines are associated with CRS and/or neurotoxicity

• Use of tocilizumab and steroids for management of toxicities did not appear to impact efficacy after axi-cel therapy

• Prophylactic tocilizumab decreased severe CRS but did not impact neurotoxicity

• Training of all healthcare providers involved in the management of patients is necessary for safe administration of CAR T-cell therapy

• Agents to target myeloid cells, IL-1 blockade, and/or to stabilize endothelial cells may further improve safety in the future

• ASBMT Consensus Grading System for CRS and neurotoxicity has been proposed

Summary and Future Directions

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Abstract # Brief title Authors Presentation time91 Real world experience with Axi-cel Nastoupil LJ, et al. Saturday, 9:30 am

96 Safety of axi-cel in elderly DLBCL patients Sano D, et al. Saturday, 10:45 am

223 Late effects of CD19 CAR T-cell therapy Cordeiro A, et al Saturday, 4:00 pm

2967 Safety and efficacy at 2 years on ZUMA-1 Neelapu S, et al Sunday, 6:00 pm

576Elevated expansion of axi-cel by immunotyping and association with toxicity

Spiegel JY, et al. Monday, 8:15 am

697Hu19-CD828Z CAR T-cells and low levels of neurologic toxicity

Kochenderfer JN, et al. Monday, 10:30 am

895Updated efficacy and safety analysis of tisagenlecleucel

Grupp SA, et al. Monday, 4:30 pm

961 Anti-GM-CSF reduces CRS and neurotoxicity Sterner RM, et al Monday, 4:30 pm

4190 Consensus grading of CRS in JULIET Schuster SJ, et al Monday, 6:00 pm

4183 Grading of neurotoxicity in JULIET Maziarz RT, et al Monday, 6:00 pm

ASH 2018: Abstracts of Interest on CAR-T Toxicity