Cytokine Release Syndrome and Neurotoxicity: Ongoing...
Transcript of Cytokine Release Syndrome and Neurotoxicity: Ongoing...
Cytokine Release Syndrome and Neurotoxicity: Ongoing Efforts to Enhance Safety Sattva S. Neelapu, MD
• 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
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.
• 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
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.
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
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
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
• Proliferate
• Make cytokines
• Kill the target cells
CAR T cell
CAR T-Cell Response to Antigen
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
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
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
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
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
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
Maude SL. Blood. 2017 Nov 23;130(21):2238-2240.
Pathophysiology of CRS
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
• 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.
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.
• 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
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
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
* 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.
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
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
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
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.
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.
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.
Gust J, et al. Cancer Discov. 2017 Dec; 7(12):1404-1419.
Endothelial Activation and BBB Disruption Drive Neurotoxicity
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
• 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
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