Management of Adverse Events with Newer Therapeutic Approaches
Matthew J. Frigault, MDAssistant Director, Cellular Immunotherapy ProgramBone Marrow Transplant Massachusetts General Hospital, Boston, MA
• Description of Cytokine Release Syndrome (CRS)• Description of Immune Effector Cell Associated Neurotoxicity
Syndrome (ICANS) and Grading • Frequency of CRS/ICANS in Pivotal Studies • Mechanisms of Toxicity
§ Construct Specific Differences § Pathophysiology
Agenda
Cytokine-Release Syndrome (CRS)
Lee. Blood. 2014;124:188.
• Typical onset 2-3 days, duration 7-8 days• Can range in severity from low-grade
constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan system failure
• On a spectrum with macrophage activation syndrome
• Rarely, severe CRS can evolve into fulminant hemophagocytic lymphohistiocytosis
• Characterized by high levels of TNF-α, IFN-γ, IL-1, IL-2, IL-6, GM-CSF, IL-8, and IL-10
• Correlates with peak T-cell expansion• Managed with tocilizumab.
30002500200015001000500
500400300200100
0
pg/m
L
CRP mg/L (< 3 m
g/L)
300250200150100100806040200
30
0 2 4 8 10
12
14
20Tocilizumab
Day After T-Cell Infusion
Fever
Neurologic symptoms
Vasopressor 2Vasopressor 1
± IL-6IFN-yOtherCRP
Immune Effector Cell–Associated Neurotoxicity Syndrome (ICANS)
Gust. Cancer Discov. 2017;7:1404. Cancer Discov. 2018;8:4.
• Typical onset 4-12 days, typical duration 14-17 days• Toxic encephalopathy with symptoms of mild headaches, confusion, and
delirium; expressive aphasia; occasional seizures; and rarely, cerebral edema• Can occur in the presence of absence of systemic CRS• Patients with severe neurotoxicity demonstrated evidence of endothelial
activation, including disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier permeability• T-cells known to traffic into the CNS; however, no T-cells were found within the
brain parenchyma of patients with ALL who died of severe CRS following infusion of JCAR015• Managed with steroids
ASTCT Grading of CRS and ICANS
Lee. Biol Blood Marrow Transplant. 2019;25:625.
ASTCT Guidelines for Grading of CRSParameter Grade 1 Grade 2 Grade 3 Grade 4Fever Temp ≥ 38°C Temp ≥ 38°C Temp ≥ 38°C Temp ≥ 38°CwithHypotension None Not requiring
vasopressorsRequiring a vasopressor
with or without vasopressin
Requiring multiple vasopressors (excluding
vasopressin)and/orHypoxia None Requiring low-
flow nasal cannula or blow-
by
Requiring high-flow nasal cannula,
facemask, nonrebreather mask, or
Venturi mask
Requiring positive pressure (eg, CPAP,
BiPAP, intubation, and mechanical ventilation)
Lee. Biol Blood Marrow Transplant. 2019;25:625.
New ASTCT Guidelines for Grading of ICANSNeurotoxicity Domain
Grade 1 Grade 2 Grade 3 Grade 4
ICE score* 7-9 3-6 0-2 0 (pt is unarousable)
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; stupor or coma
Seizure 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 mins) 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
*an ICE score of 0 may be classified as grade 3 ICANS if patient is awake with global aphasia; otherwise classified as grade 4 ICANS if unarousable.
Lee. Biol Blood Marrow Transplant. 2019;25:625.
New ASTCT Guidelines for Grading of ICANS: ICE ScoreParameter Score (Points)Orientation: year, month, city, hospital 4Naming: ability to name 3 objects (eg, point to clock, pen, button)
3
Following commands: ability to follow simple commands (eg, “show me 2 fingers” or “close your eyes and stick out your tongue”)
1
Writing: ability to write a standard sentence (eg, “our national bird is the bald eagle”)
1
Attention: ability to count backwards from 100 by 10 1
Scoring: 10, no impairment7-9, grade 1 ICANS3-6, grade 2 ICANS
0-2, grade 3 ICANS0, patient unarousable and unable to perform ICE
assessment, grade 4 ICANS
Frequency of CRS/ICANS in Pivotal Studies
1. Neelapu. NEJM. 2017;377:2531. 2. Schuster. NEJM. 2019;380:45. 3. Maude. NEJM. 2018;378:439.
Frequency of CRS and Neurotoxicity FDA-Approved CAR T-Cell Therapies
Parameter Axicabtagene Ciloleucel1 Tisagenlecleucel2,3
Setting DLBCL DLBCL B-ALLTrial ZUMA-1 JULIET ELIANAToxicity grading criteria Lee 2014 Penn Grading Scale Penn Grading ScaleAny-grade CRS, % 93 58 77Grade ≥ 3 CRS, % 13 22 47Any-grade neurotoxicity, % 64 21 40
Grade ≥ 3 neurotoxicity, % 28 12 13
Tocilizumab use, % 43 14 48
1. Abramson. Blood 134(Supplement_1): 241-241. 2. Raje. NEJM 380(18): 1726-1737.
Frequency of CRS and Neurotoxicity Investigational Products Pending FDA Approval
Parameter Lisocabtagenemareleucel1
Idecabtagenevicleucel2
Setting DLBCL MMTrial TRANSCEND KarMMaToxicity grading criteria Lee 2014 Lee 2014Any-grade CRS, % 42 76Grade ≥ 3 CRS, % 2 6Any-grade neurotoxicity, % 30 42
Grade ≥ 3 neurotoxicity, % 10 3
Tocilizumab use, % 19 28
Mechanisms of Toxicity
Contribution of Signaling Domains
1. Kawalekar. Immunity. 2016;44:380. 2. Milone. Mol Ther. 2009;17:1453.
• CD28• Correlated with effector memory T-cell differentiation known to provide immediate protection in vitro1
• Metabolic profile supports rapid expansion (glycolic metabolism)1• Involved in early and rapid expansion with limited long-term persistence in vivo2
• 4-1BB• Induces central memory T-cell differentiation for enduring protection and immunosurveillance in vitro1
• Metabolic profile supports gradual sustained expansion (oxidative metabolism)1• Enhances expansion and long-term persistence of CAR T-cells in vitro and in vivo1,2
Biological Considerations of CAR-T Constructs: Costimulatory Domains
Brudno. Nature Medicine. 2020. (26) 270-280
Pre Post
Context of Co-Stimulatory Domains
Grade ≥ 3 CRS: 2/20 (vs 13%)Grade ≥ 3 ICANS: 1/20 (vs 28%)
Mechanisms of Toxicity
Pathophysiology
CRS: Macrophage Activation Syndrome
Teachey. Cancer Discov. 2016;6:664.
• Correlates with robust production of inflammatory cytokines
• Correlates with CAR-T expansion
• MAS appears to accompany CRS in a subset of patients
• Characterized by high fevers, hepatosplenomegaly, liver dysfunction, renal failure, coagulopathy, hypofibrinogenemia, and profound hyperferritinemia
• Histologic evidence of hemophagocytosis noted on bone marrow biopsy at peak of CRS
• Similar cytokine profiles
CRS MAS
Hay. Blood. 2017;130:2295
Mechanisms of Toxicity: Correlative Cytokines
IFN-γ IL-6 MCP-1
*P < .0001†P < .005‡P < .001
Grade 0 CRSGrade 1-3 CRSGrade ≥ 4 CRS
Pre-
chem
oPr
e-in
fusi
on0-
36h
2-5d
6-8d
9-12
d
13-1
8d 18-
23d
24-3
0d
4
3
2
1
0
MCP
-1 (l
og10
pg/m
L) *
† ‡*
Pre-
chem
oPr
e-in
fusi
on0-
36h
2-5d
6-8d
9-12
d
13-1
8d 18-
23d
24-3
0d
4
3
2
1
0
IL-6
(log
10pg
/mL)
Pre-
chem
oPr
e-in
fusi
on0-
36h
2-5d
6-8d
9-12
d
13-1
8d 18-
23d
24-3
0d
4
3
2
1
0IFN
-γ(lo
g 10
pg/m
L)
††*
**
**
**
Hay. Blood. 2017;130:2295.
Mechanisms of Toxicity: Cytopenias and Inflammatory MarkersANC
CRP
Platelets
Ferritin
*P < .005 †P < .001‡P < .0001
Grade 0 CRSGrade 1-3 CRSGrade ≥ 4 CRS
76543210N
eutr
ophi
ls (1
000/
μL)
300250200150100
500
CRP
(mg/
L)
Pre-chemo
Pre-infusio
n0-36h
2-5d6-8d
9-12d13-18d
18-23d24-30d
400200200
150
100
50
0
Plat
elet
s (10
00/μ
L)
5
4
3
2Ferr
itin
(log 1
0 ng
/mL)
Pre-chemo
Pre-infusio
n0-36h
2-5d6-8d
9-12d13-18d
18-23d24-30d
* *
*
†
††
* *
†
‡
‡
‡‡ ‡
‡ ‡ ‡‡
‡
Gust. Cancer Discov. 2017;7:1404.
Mechanisms of Toxicity: Endothelial Permeability
*P < .01†P < .05
IFN
-γ(p
g/m
L)
Before Infusion During Neurotoxicity
Before Infusion During Neurotoxicity
102
101
100
10-1
*
*
SerumCSF
IL-6
(pg/
mL) 103
102
101
100
*†
104
Higher levels of systemic cytokines found in cerebrospinal fluid collected after vs before T-cell infusion in patients with acute neurotoxicity
Gust. Cancer Discov. 2017;7:1404
Mechanisms of Toxicity: Endothelial Activation
VWF
Antig
en (f
old
norm
al)
% LM
W V
WF
Mul
timer
s
Grade 0-3 Neurotoxicity
Grade 4/5 Neurotoxicity
106
105
104
103
ANG2
(pg/
mL)
P = .0003
Grade 0-3 Neurotoxicity
Grade 4/5 Neurotoxicity
5
2
1
0
P = .004
3
4
Grade 0-3 Neurotoxicity
Grade 4/5 Neurotoxicity
90
60
50
40
P = .0120
70
80
Higher serum levels of endothelial activation markers observed in patients with high-grade vs low-grade neurotoxicity approximately 7 d after CAR T-cell infusion
Toxicity Management
Standard of Care
Pre-infusion/LD chemo
Principles of Management
• Appropriate screening per institutional standards• Baseline labs
• CRP, ferritin• CBC, CMP, Coags• TLS labs
• +/- Initiation of AEDs• Appropriate bacterial/fungal/viral
prophylaxis per institutional standards
Post-infusion/LD chemo• Monitor CBC, CMP, and coags
• Monitor for TLS
• Monitor CRP and ferritin
• Daily assessments for at least 7 days
– FDA requirement for Yescarta
– Fevers? Hypotension? Hypoxia?
– Mental status?
Pre-infusion/LD chemo
MD Anderson. CAR cell therapy toxicity assessment and management. 2017. Neelapu. Nat Rev Clin Oncol. 2018;15:47.
Principles of Toxicity Management by Grade
Grade CRS Neurotoxicity CRS + Neurotoxicity1 Supportive care Supportive care Supportive care
2 Tocilizumab Steroids (dexamethasone or methylprednisolone)
Tocilizumab + steroids (dexamethasone)
3 Tocilizumab Steroids (dexamethasone) Tocilizumab + steroids (dexamethasone)
4Tocilizumab + high-dose
steroidsICU/critical care
High-dose steroids (methylprednisolone)
ICU/critical care
Tocilizumab + high-dose steroids (methylprednisolone)
ICU/critical care
Toxicity Management
Macrophage Activation Syndrome
• Prophylactic tocilizumab given on D+2 following CAR-T cell infusion.
• CSF collected pre-LD chemo and D+5
• Prophylactic tocilizumab decreased the rates of ≥ 3 CRS but not rates of grade ≥ 3 NE
• Increased levels of IL-6, IFNg were observed with tocilizumab prophylaxis
• One grade 5 NE was observed
Prophylactic Tocilizumab?
Locke et al. Proc ASH 2017 Poster 1547
Locke et al. Proc ASH 2017 Poster 1547
CSF Cytokines Elevated following CAR-T
Role of Myeloid Activation/MAS: Animal Models
Norelli et al. Nat Med 2018. Giavridis et al Nat Medicine 2018
Myeloid cells are recruited in the setting of CRS in novel animal models
Monocytes appear to be the primary producers of IL-1 and IL-6
SGM3 mice
SCID-beige mice
Norelli. Nat Med. 2018;24:739.
IL-1 blockade, but not IL6, prevents the development of neurotoxicity in an animal model of CRS/NT
Role of Myeloid Cells/MAS: Animal Models
IL-1 As a Therapeutic Target: Clinical TrialsStudy Name Phase N Population Prophylaxis/Treatment
A Study of Anakinra to Prevent or Treat Severe Side Effects for Patients Receiving CAR-T Cell Therapy§ NCT04148430 (MSKCC)
II 90 Adult pts with CD19+ B-cell ALL or NHL receiving CAR T-cell infusions
Treatment
Anakinra In Car-T Cell Mediated Neurotoxicity§ NCT04150913 (MGH)
II 20 Adult pts with R/R NHL receiving axicabtagene
Prophylaxis
Anakinra in Preventing Severe Chimeric Antigen Receptor T-Cell Related Encephalopathy Syndrome in Patients With Recurrent or Refractory Large B-cell Lymphoma§ NCT04205838 (UCLA)
II 36Adult pts with R/R NHL receiving
axicabtagene Treatment
Toxicity Management
Early Steroid Use
Topp et al. BBMT (26): 3
Zuma 1: Cohort 4
Bridging therapy allowed on cohort 4: Dexamethasone, high-dose methylprednisolone + rituximab, or bendamustine + rituximab
Topp et al. BBMT (26): 3
Baseline Characteristics
Topp et al. BBMT (26): 3
Zuma 1: Cohort 4
Toxicity Management
Additional/Pending Trials
1. Mestermann. STM 2019 11(499) 2. Sterner Blood 2019. 133(7):697-709
Study Name Agent Phase Agent Population Mechanism
A Safety and Efficacy Study of Defibrotide in the Prevention of Chimeric Antigen Receptor-T-cell-associated Neurotoxicity§ NCT03954106 (DFCI)
Defibrotide II 35 DLBCL receiving axicabtagene ciloleucel
Reduced Endothelial Activation
A Study of Itacitinib for the Prevention of Cytokine Release Syndrome Induced by Immune Effector Cell Therapy• NCT04071366 (multiple)
Itacitanib II 62 All commercial CAR-T Reduced Inflammatory Cytokines
- Dasatinib1 - - Animal Models Only Inactivation of CD3z Signaling
- Lenzilumab2 - - Animal Models Only GM-CSF Blockade
