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Management of Toxicities Associated with Novel T-Cell Therapies – Adult/Pediatric – Emergency Department/Inpatient

Management of Toxicities Associated with Novel T-Cell Therapies – Adult/Pediatric – Emergency Department/Inpatient - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Medications


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Management of Toxicities Associated with Novel
T-Cell Therapies – Adult/Pediatric – Emergency
Department/Inpatient
Clinical Practice Guideline
Note: Active Table of Contents – Click each header below to jump to the section of interest
Table of Contents
INTRODUCTION ............................................................................................................. 3
SCOPE ............................................................................................................................ 3
DEFINITIONS ................................................................................................................. 3
RECOMMENDATIONS ................................................................................................... 5
METHODOLOGY .......................................................................................................... 14
APPENDIX A. ............................................................................................................... 17
APPENDIX B. ............................................................................................................... 19
APPENDIX C. ............................................................................................................... 20
APPENDIX D. ............................................................................................................... 21
REFERENCES .............................................................................................................. 22
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Content Expert(s):
Adult Management
Name: Jason Jared, PharmD, BCOP – Pharmacy
Phone Number: (608) 263-1290
Email Address: jjared@uwhealth.org

Pediatric Management
Name: Christian Capitini, MD – Pediatric Hematology/Oncology
Phone Number: (608) 262-2415
Email Address: ccapitini@pediatrics.wisc.edu

Contact for Changes:
Name: Philip Trapskin, PharmD, BCPS
Phone Number: (608) 263-1328
Email Address: PTrapskin@uwhealth.org

Guideline Author(s):
Jason Jared, PharmD, BCOP – Pharmacy
Cameron Ninos, PharmD – Pharmacy
Catherine Renna, PharmD - Pharmacy

Workgroup Members:
Christian Capitini, MD – Pediatric Hematology/Oncology
Aric Hall, MD – Adult Hematology/Oncology
Jason Jared, PharmD, BCOP – Pharmacy
Daniel Kapp, PharmD – Drug Policy Program
Cameron Ninos, PharmD – Pharmacy
Catherine Renna, PharmD – Pharmacy

Reviewers:
Christian Capitini, MD – Pediatric Hematology/Oncology
Aric Hall, MD – Adult Hematology/Oncology
Bone Marrow Transplant DOT
Chemotherapy Council Subcommittee
Emergency Medicine: Dr. Brian Sharp

Committee Approval(s):
Chemotherapy Council Subcommittee (11/10/2017)
Pharmacy & Therapeutics Committee (12/21/2017)









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Introduction
Novel immunotherapy agents are designed to enhance a patient’s immune response to specific
targets. Multiple mechanisms exist to achieve this specificity; chimeric antigen receptor T cell
(CAR-T) therapies are engineered by linking autologous T cells to a tumor-specific antigen to
induce supraphysiologic cytotoxicity against tumor cells, whereas bispecific T cell engagers
(e.g., blinatumomab) utilize antibodies to bring T cells and tumor cells in proximity to each
other.1 Anti-CD19 CAR-T therapies tisagenlecleucel and axicabtagene ciloleucel are indicated
for the treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (ALL) in
pediatric and young adults and relapsed lymphoma in adult patients, respectively.2

Due to the increased activation of the immune system with CAR-T therapy, the major adverse
effects of treatment include autoimmune and cytokine-associated toxicities. Cytokine release
syndrome (CRS) is a systemic inflammatory syndrome related to the increased levels of several
cytokines, including IL-2, IL-5, IL-6, IL-8, IL-10, IFNγ, and TNFα, as well as granulocyte
macrophage-colony stimulating factor (GM-CSF). The cytokine primarily implicated in CRS
toxicity is IL-6 that initiates a proinflammatory response at elevated levels. Cytokine release
syndrome can be a life-threatening toxicity requiring urgent medical attention and supportive
care based on the presenting signs and symptoms.3 Independent of CRS, patients may also
experience a CAR-T-related encephalopathy syndrome (CRES) requiring separate monitoring
and management strategies.4
Scope
Intended Users: Physicians, Advanced Practice Providers, Pharmacists, Nurses, Technical
Support

Objectives: To guide the management of cytokine release syndrome and neurotoxicity
associated with chimeric antigen receptor T-cell therapy and other novel T-cell therapies in adult
and pediatric patients to promote prompt and appropriate evidence-based interventions

Target Population: Adult and pediatric patients with toxicities associated with novel T-cell
therapies including chimeric antigen receptor (CAR) T-cell therapies and Bispecific T-cell
Engager (BiTE) therapies

Clinical Questions Considered:
ξ What patient assessments should occur when evaluating a patient with suspected CRS
and/or CRES?
ξ How is CRS and CRES categorized and what are the appropriate treatments for each
category?
ξ When should tocilizumab be used for the treatment of CRS and/or CRES?
ξ When should siltuximab be used for the treatment of CRS and/or CRES?

Definitions
1. CTCAE: Common Terminology Criteria for Adverse Events
2. CAR-T: Chimeric antigen receptor T cell
3. CRS: Cytokine release syndrome
4. CRES: CAR-T-related encephalopathy syndrome
5. Patients at high risk for CRS include any of the following:4
a. High tumor burden
b. Score ≥ 3 using the Hematopoietic Cell Transplantation Comorbidity Index5
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c. Age ≥ 60 years
d. CRS onset less than 3 days from cell infusion
6. Organ specific toxicity is defined according to CTCAE V4 (Appendix A) with the
exception of transaminitis as indicated in Table 1.
7. Neurologic toxicity is defined according to CTCAE V4 (Appendix A)






















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Recommendations

Cytokine Release Syndrome (CRS):
1. CRS monitoring and grading
1.1. Patients may be monitored closely for CRS symptoms for a specified period following
treatment to ensure prompt symptom management4,6 (UW Health GRADE low quality
evidence, weak recommendation)
1.2. CRS grading may be determined using the criteria in Tables 1–24 (UW Health GRADE
low quality evidence, weak recommendation)
1.3. CRS grade may be evaluated at least once daily and as needed any time there is a
change in patient status4 (UW Health GRADE low quality evidence, weak
recommendation)

Table 1. Grading of Cytokine Release Syndrome4,7,8
Category Sign/Symptom CRS Grade
1A 2B 3B 4B
Vital Signs
Temperature
≥38°C Yes Any Any Any
SBP <90 mmHg or
age appropriate
normal range
No No
Responds to IV
fluids or low-dose
vasopressorD
Life-threatening/
Requires high-
dose or multiple
vasopressorsD
Supplemental
oxygen to
maintain O2
saturation >90%
No FiO2 <40%
FiO2 ≥40% and/or
requiring
supplemental
oxygen
Requires ventilator
support
Organ
ToxicityC See Appendix A Grade 1 Grade 2
Grade 3 except
grade 4
transaminitis
Grade 4E

Abbreviations: CRS, cytokine release syndrome; SBP, systolic blood pressure; FiO2, fraction of inspired oxygen; BiPAP, bilevel
positive airway pressure
Footnotes:
AGrade 1 CRS may manifest as a fever and/or grade 1 organ toxicity
BFor grades 2, 3, or 4 CRS: any one of the criteria other than temperature is sufficient
CSee Appendix A for grading of organ toxicity
DSee Table 2 for definition of high-dose vasopressors
EGrade 4 transaminitis is categorized as grade 3 CRS


Table 2. High-Dose Vasopressor Definition (Adults and Pediatrics)4
Vasopressor Dose Given τ 3 hours
Norepinephrine τ 0.2 mcg/kg/min
Dopamine τ 10 mcg/kg/min
Phenylephrine τ 200 mcg/min
Epinephrine τ 0.1 mcg/kg/min
If on vasopressin High-dose if vasopressin use and norepinephrine equivalent
dose of τ 0.10 mcg/kg/min (using VASST formulaA)
If on combination vasopressors (not
vasopressin)
Norepinephrine equivalent dose of τ 20 mcg/min (using
VASST formulaA)
Footnotes:
AVASST formula: norepinephrine equivalent dose = [norepinephrine (mcg/minute)] + [dopamine
(mcg/kg/min) ψ 2] + [epinephrine (mcg/min)] + [phenylephrine (mcg/min) ψ 10]


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2. Baseline interventions and monitoring that may be considered before and during
novel T-cell therapy infusions include:4 (UW Health GRADE very low quality evidence,
weak recommendation)
 Central venous access for intravenous fluid and other infusions in case of toxicities
 Cardiac monitoring by telemetry at baseline and during hospitalization for CRS if
indicated based upon significant cardiac history
 Tumor lysis precautions for bulky tumors as recommended by UW Oncologic
Emergencies Guideline
3. Monitoring of the patient during CRS-related admission may include the following:4
(UW Health GRADE very low quality evidence, weak recommendation)
 Vital signs every 4 hours
 Oral and intravenous fluid input and urine output
 Daily bodyweight
 Daily blood count, complete metabolic profiling, and coagulation profiling
 Daily C-reactive protein and ferritin
 Assessment and grading of CRS at least once daily and when the patient’s status
changes
 Neutropenic patients with a temperature ≥38°C should be managed according to the
appropriate adult or pediatric fever and neutropenia UW Health institution guideline
based upon patient age
4. Management of CRS: Treatment of symptoms is dependent upon the specific organ system
affected4 (UW Health GRADE low quality evidence, weak recommendation)

4.1. Grade 1 CRS
4.1.1. Acetaminophen should be used as needed for fever4 (UW Health GRADE low
quality evidence, weak recommendation)
4.1.2. Ibuprofen can be considered if fever is not controlled with acetaminophen4 (UW
Health GRADE low quality evidence, weak recommendation)
4.1.2.1. Ibuprofen should be used with caution or avoided if the patient is
thrombocytopenic4,6 (UW Health GRADE low quality evidence, weak
recommendation)
4.1.3. Patients with fever and tachycardia may have vital signs monitored at least every
4 hours4,6 (UW Health GRADE low quality evidence, weak recommendation)
4.1.4. Assess for infection with blood, urine culture, and chest x-ray as clinically
indicated4 (UW Health GRADE low quality evidence, weak recommendation)
4.1.4.1. Management of neutropenic fever may follow adult and pediatric UW
Health institution guidelines4 (UW Health GRADE low quality evidence,
weak recommendation)
4.1.4.2. Filgrastim is contraindicated with CAR-T cell therapy and should be
avoided for at least 30 days post-infusion as it may worsen CRS2 (UW
Health GRADE low quality of evidence, strong recommendation)
4.1.5. Intravenous (IV) fluids, bolus and/or maintenance, may be used as needed
based upon clinical judgment4 (UW Health GRADE very low quality evidence,
weak recommendation)
4.1.6. Constitutional symptoms and organ toxicities may be treated symptomatically4
(UW Health GRADE very low quality evidence, weak recommendation)




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4.2. Grade 2 CRS
4.2.1. Fever and constitutional symptoms may be managed according to Grade 1 CRS
recommendations4 (UW Health GRADE low quality evidence, weak
recommendation)
4.2.2. Hypotension Management
4.2.2.1. IV fluid challenge may be initiated as first-line management of
hypotension. However, early experience with CAR-T therapy toxicity
management suggests a higher rate of intubation in patients receiving
large volume fluid resuscitation; consider vasopressor treatment earlier
in the course of management than would otherwise be standard in
distributive shock (UW Health GRADE low quality evidence, weak
recommendation)4,6
 Pediatric patients should receive 0.9% NaCl fluid bolus of 10–20
mL/kg (maximum 1,000 mL)
 Adult patients should receive 0.9% NaCl fluid bolus of 500–1000 mL
to maintain SBP greater than 90 mmHg
4.2.2.2. Patients with persistent hypotension after 1 bolus of IV fluids may be
initiated on vasopressors and transferred to intensive care unit4,6 (UW
Health GRADE low quality evidence, strong recommendation)
 Norepinephrine is the preferred first-line vasopressor4,6 (UW Health
GRADE low quality evidence, strong recommendation)
 ECHO may be obtained4 (UW Health GRADE low quality evidence,
weak recommendation)
4.2.3. Hypoxia Management
4.2.3.1. Supplemental oxygen may be started to maintain oxygen saturation
>90%4 (UW Health GRADE low quality evidence, strong
recommendation)
4.2.4. Organ toxicities may be managed per standard-of-care4 (UW Health GRADE low
quality evidence, strong recommendation)

4.3. Grade 3 CRS
4.3.1. Fever and constitutional symptoms may be managed according to Grade 1 CRS
recommendations4 (UW Health GRADE low quality evidence, weak
recommendation)
4.3.2. Hypotension may be managed according to Grade 2 CRS recommendations4
(UW Health GRADE low quality evidence, weak recommendation)
4.3.3. Tocilizumab use should be considered with the following guidance4,9 (UW
Health GRADE moderate quality evidence, strong recommendation)
 For patients <30 kg, tocilizumab 12 mg/kg IV may be administered
 For patients ≥30 kg, tocilizumab 8 mg/kg up to a maximum of 800 mg
per dose may be administered
 If no clinical improvement in the signs and symptoms of CRS occurs
after the first dose, up to 3 additional doses of tocilizumab may be
administered
 The interval between consecutive doses should be at least 8 hours6
 Tocilizumab should be administered intravenously over 1 hour9
4.3.4. Corticosteroids may be considered in patients at high-risk for CRS or if
hypotension persists after 1-2 doses of tocilizumab4 (UW Health GRADE
low quality evidence, weak recommendation)
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 Corticosteroids should only be administered after consultation with a bone
marrow transplant attending physician
 Corticosteroid administration should only be considered after the failure of IL-
6 directed therapy due to steroid-mediated killing of T-cells4
 For pediatric patients, methylprednisolone 1 mg/kg up to a maximum of 100
mg IV every 12 hours may be administered10
 For adult patients, dexamethasone 10 mg IV every 6 hours may be
administered4
4.3.5. Hypoxia may be managed according to Grade 2 CRS recommendations4 (UW
Health GRADE low quality evidence, weak recommendation)
4.3.6. Organ toxicities may be managed per standard of care4 (UW Health GRADE low
quality evidence, weak recommendation)
4.3.6.1. Tocilizumab should be considered as in hypotension4 (UW Health
GRADE low quality evidence, strong recommendation)
4.3.6.2. Corticosteroids may be considered as in hypotension4 (UW Health
GRADE low quality evidence, strong recommendation)

4.4. Grade 4 CRS
4.4.1. Fever and constitutional symptoms may be managed according to Grade 1 CRS
recommendations4 (UW Health GRADE low quality evidence, weak
recommendation)
4.4.2. Hypotension and hypoxia may be managed according to Grade 3 CRS
recommendations4 (UW Health GRADE low quality evidence, weak
recommendation)
4.4.3. Hypoxia may be managed according to Grade 3 CRS recommendations4 (UW
Health GRADE low quality evidence, weak recommendation)
4.4.3.1. Mechanical ventilation may be considered for Grade 4 hypoxia4 (UW
Health GRADE low quality evidence, weak recommendation)
4.4.3.2. Tocilizumab should be considered as in hypotension4 (UW Health
GRADE low quality evidence, strong recommendation)
4.4.3.3. Corticosteroids may be considered as in hypotension4 (UW Health
GRADE low quality evidence, strong recommendation)
4.4.4. Organ toxicities may be managed per standard of care4 (UW Health GRADE low
quality evidence, weak recommendation
4.4.4.1. Tocilizumab should be considered as in hypotension4 (UW Health
GRADE low quality evidence, strong recommendation)
4.4.4.2. Corticosteroids may be considered as in hypotension4 (UW Health
GRADE low quality evidence, strong recommendation)
4.4.5. Siltuximab may be considered after at least 2 doses of tocilizumab and
corticosteroids if minimal to no improvement in patient condition4 (UW Health
GRADE very low quality evidence, weak recommendation)









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Table 3. Management of CRS and Organ Toxicity4
CRS
Grade Symptoms Management
1
Fever or grade 1
organ toxicity
- Administer acetaminophen as needed for fever
- Assess for infection with blood and urine cultures. Chest x-ray if there are
respiratory symptoms
- Administer antibiotics in febrile neutropenic patients
- Administer IV fluids as needed
- Manage constitutional symptoms and organ toxicities symptomatically
2
Hypotension
- Manage fever and constitutional symptoms as in Grade 1 CRS
- Administer IV fluid bolus once if needed
 Pediatrics: 0.9% NaCl fluid bolus of 10–20 mL/kg (maximum 1,000 mL)
 Adults: 0.9% NaCl fluid bolus of 500-1000 mL
Hypoxia - Manage fever and constitutional symptoms as in Grade 1 CRS
- Initiate supplemental oxygen as needed to maintain SpO2 >90%
Grade 2 organ
toxicity
- Manage fever and constitutional symptoms as in Grade 1 CRS
- Manage organ toxicity as per standard of care
3
Hypotension
- Manage fever and constitutional symptoms as in Grade 1 CRS
- Manage hypotension as in Grade 2 CRS
- Transfer to ICU and obtain ECHO if not done already
- Consider early transfer to ICU
- Initiate norepinephrine for persistent hypotension
- Consider tocilizumab (<30 kg: 12 mg/kg; ≥30 kg: 8 mg/kg up to a maximum of
800 mg per dose) IV over 1 hour every 12 hours as needed for up to 3 doses
as first-line therapy if high dose vasopressors needed
- Consider corticosteroids in patients if hypotension persists after 1-2 doses of
tocilizumab
o Adults: dexamethasone 10 mg IV every 6 hours
o Pediatrics: methylprednisolone 1 mg/kg up to 100 mg IV every 12 hours
o Corticosteroids should only be administered after approval from bone
marrow transplant attending physician
Hypoxia - Manage fever and constitutional symptoms as in Grade 1 CRS
- Initiate supplemental oxygen as needed to maintain SpO2 >90%
Grade 3 organ
toxicity or grade
4 transaminitis
- Manage fever and constitutional symptoms as in Grade 1 CRS
- Manage organ toxicity as per standard of care
- Consider tocilizumab as in hypotension
- Consider corticosteroids if minimal to no improvement after 1-2 doses of
tocilizumab ***Corticosteroids should only be administered after approval from
bone marrow transplant attending physician***
4
Hypotension
- Manage as in Grade 3 CRS
- Consider Siltuximab after 2 doses of tocilizumab and corticosteroids with
minimal to no improvement in patient condition3 (UW Health GRADE very low
quality evidence, weak recommendation)
Hypoxia
- Mechanical ventilation to maintain SpO2 >90%
- Administer tocilizumab as in Grade 3 CRS
- Consider corticosteroids if minimal to no improvement after 1-2 doses of
tocilizumab
o Corticosteroids should only be administered after approval from bone
marrow transplant attending physician
- Consider Siltuximab after 2 doses of tocilizumab and corticosteroids with
minimal to no improvement in patient condition
Grade 4 organ
toxicity
(excluding
transaminitis)
- Manage as in Grade 3 CRS
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10


CAR-T-Cell Related Encephalopathy Syndrome (CRES):
1. Neurotoxicity monitoring and grading
1.1. Patients may be monitored closely for neurotoxicity symptoms for a specified period
following treatment to ensure prompt symptom management4,6 (UW Health GRADE low
quality evidence, weak recommendation)
1.2. Neurotoxicity grades may be determined using CTCAE (See Appendix A)2,4,6 (UW
Health GRADE low quality evidence, weak recommendation)
1.3. In adults, neurotoxicity may be evaluated using the CAR-T-cell therapy associated
toxicity 10-point neurological assessment (CARTOX-10) (See Table 3)4 (UW Health
GRADE low quality evidence, weak recommendation)
1.3.1. Grade 1 or 2 papilledema with CSF opening pressure < 20 mmHg may be
classified as severe neurotoxicity4 (UW Health GRADE low quality evidence,
weak recommendation)
1.3.2. The following may be classified as critical neurotoxicity4 (UW Health GRADE low
quality evidence, weak recommendation)
 Obtunded/stuporous
 New motor weakness, Convulsive status epilepticus
 Grade 3, 4, or 5 papilledema
 CSF OP ≥ 20 mmHg
 Cerebral edema on neuro-imaging

Table 4. CARTOX-10 Neurologic Examination Scoring and Interpretation4
Evaluation
Method of evaluation Points Assigned
Orientation to year, month, city, hospital, President 5 points
Ability to write a standard sentence
(e.g., “National bird is the bald eagle”) 1 point
Name 3 objects (e.g., clock, pen, button) 3 points
Count backwards from 100 by tens 1 point
Interpretation
Severity Score
Normal 10
Mild 7 – 9
Moderate 3 – 6
Severe 1 -2

2. Management of neurotoxicity
2.1. In adults, seizure prophylaxis may be considered with levetiracetam 750 mg PO every
12 hours (renally adjusted) for 30 days following CAR-T-cell infusion4 (UW Health
GRADE low quality evidence, weak recommendation)
2.2. Neurotoxicity may be managed according to CARTOX-10 neurologic examination
scoring and interpretation (See Table 3). This should not replace medical or
professional judgement of physicians or other healthcare providers4 (UW Health
GRADE low quality evidence, weak recommendation)
2.3. Grade 1 neurotoxicity: may be managed according to Table 52,4,6 (UW Health GRADE
low quality evidence, weak recommendation)
2.3.1. Supportive care may be initiated including aspiration precautions4 (UW Health
GRADE low quality evidence, weak recommendation)
2.3.2. Neurological exams and imaging may be obtained4 (UW Health GRADE low
quality evidence, weak recommendation)
2.3.3. Manage seizures per standard of care (UW Health GRADE low quality evidence,
weak recommendation)
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2.3.4. Tocilizumab may be considered if other symptoms are associated with Grade 2
CRS or higher4 (UW Health GRADE low quality evidence, weak
recommendation)
 Tocilizumab should not be administered for CRES in patients without
symptoms of CRS 4 (UW Health GRADE low quality evidence, weak
recommendation)
 For patients <30 kg, tocilizumab 12 mg/kg IV may be administered
 For patients ≥30 kg, tocilizumab 8 mg/kg up to a maximum of 800 mg
per dose may be administered
 If no clinical improvement in the signs and symptoms of CRS occurs
after the first dose, up to 3 additional doses of tocilizumab may be
administered
 The interval between consecutive doses should be at least 12 hours
 Tocilizumab should be administered intravenously over 1 hour9

2.4. Grade 2 neurotoxicity
2.4.1. May manage according to Grade 1 neurotoxicity4 (UW Health GRADE low quality
evidence, weak recommendation)
2.4.2. Tocilizumab may be considered only in patients with concominat CRS4,9 (UW
Health GRADE moderate quality evidence, strong recommendation
2.4.3. Tocilizumab should not be administered for CRES in patients without symptoms
of CRS4,9 (UW Health GRADE low quality evidence, weak recommendation)

2.5. Grade 3 neurotoxicity
2.5.1. Managed according to Grade 2 neurotoxicity4 (UW Health GRADE low quality
evidence, weak recommendation)
2.5.2. Corticosteroids may be considered for worsening symptoms4 (UW Health
GRADE low quality evidence, weak recommendation)
 Corticosteroids should only be administered after consultation with a bone
marrow transplant attending physician
 Corticosteroid administration should only be considered after the failure of IL-6
directed therapy due to steroid-mediated induction of T-cell apoptosis4
 For pediatric patients, methylprednisolone 1 mg/kg up to a maximum of 100
mg IV every 12 hours may be administered10
 For adult patients, dexamethasone 10 mg IV every 6 hours may be
administered4 (UW Health GRADE low quality evidence, weak
recommendation)
 Corticosteroids may be continued until reversal of toxicity and tapered over 1-
2 weeks4 (UW Health GRADE low quality evidence, weak recommendation)
 Grade 1-2 papilledema with cerebrospinal fluid opening pressure <20 mmHg
may be treated as per standard of care4 (UW Health GRADE low quality
evidence, weak recommendation

2.6. Grade 4 neurotoxicity
2.6.1. Managed according to Grade 3 neurotoxicity4 (UW Health GRADE low quality
evidence, weak recommendation)
2.6.2. High-dose corticosteroids may be considered4 (UW Health GRADE low quality
evidence, weak recommendation)
 For pediatric patients, methylprednisolone 30 mg/kg IV up to 1000 mg once
daily for 3 days followed by rapid taper
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 For adult patients, methylprednisolone 1000 mg IV once daily for 3 days followed
by rapid taper (250 mg every 12 hours for 2 days, 125 mg every 12 hours for 2
days, and 60 mg every 12 hours for 2 days)
 Corticosteroids may be continued until reversal of toxicity and tapered over 2
weeks4 (UW Health GRADE low quality evidence, weak recommendation)
2.6.3. For convulsive seizures, treat per standard of care (UW Health GRADE low
quality evidence, strong recommendation)
2.6.4. Grade 3-5 papilledema with cerebrospinal fluid opening pressure <20 mmHg or
cerebral edema may be treated as per standard of care4 (UW Health GRADE low
quality evidence, weak recommendation)

2.7. Therapy Escalation
2.7.1. Siltuximab may be considered if after 2 doses of tocilizumab there is minimal to
no improvement in patient condition4 (UW Health GRADE very low quality
evidence, weak recommendation)

Table 5. Management of CRES2,4,6
Grade Management
1
- Vigilant supportive care; aspiration precautions
- Daily simplified neurologic examination as per standard of care
- Fundus exam to assess for papilledema
- Daily 30 minute EEG if seizure detected
- Continue levetiracetam (if previously initiated)
- If EEG shows non-convulsive status epilepticus, treat as per standard of care
2
- Manage as per Grade 1
- Consider early transfer to ICU
- Consider tocilizumab if associated with CRS (<30 kg: 12 mg/kg; ≥30 kg: 8 mg/kg up to a
maximum of 800 mg per dose) IV over 1 hour every 12 hours as needed for up to 3 doses
3
- Manage as per Grade 2
- Consider tocilizumab if associated with CRS (<30 kg: 12 mg/kg; ≥30 kg: 8 mg/kg up to a
maximum of 800 mg per dose) IV over 1 hour every 12 hours as needed for up to 3 doses
- Consider corticosteroids if neurotoxicity persists after 1-2 doses of tocilizumab
o Adults: dexamethasone 10 mg IV every 6 hours
o Pediatrics: methylprednisolone 1 mg/kg up to 100 mg IV every 12 hours
- Corticosteroids should only be administered after approval from bone marrow transplant
attending physician
- Continue corticosteroids until reversal of toxicity is seen and taper over 1-2 weeks
- Consider early ICU transfer if associated with Grade 2 or greater CRS
- Low grade (1&2) papilledema with CSF OP less than 20 mmHg, treat as per standard of
care
4
- Manage as per Grade 3
- ICU monitoring
- High-dose corticosteroids [e.g. methylprednisolone IV 1,000 mg/day x 3 days followed by
rapid taper (250 mg every 12 hours x 2 days, 125 mg every 12 hours x 2 days, and 60 mg
every 12 hours x 2 days)]
- Continue until reversal of toxicity is seen and taper over 2 weeks
- For convulsive status epilepticus, treat as per standard of care
- High grade (3, 4, & 5) papilledema with CSF OP greater than or equal to 20 mmHg, or
cerebral edema, treat as per standard of care


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13


Disclaimer
Clinical practice guidelines assist clinicians by providing a framework for the evaluation and
treatment of patients. This guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is
understood that some patients will not fit the clinical condition contemplated by a guideline and
that a guideline will rarely establish the only appropriate approach to a problem.


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Methodology
Development Process
Each guideline is reviewed and updated a minimum of every 3 years. All guidelines are
developed using the guiding principles, standard processes, and styling outlined in the UW
Health Clinical Practice Guideline Resource Guide. This includes expectations for workgroup
composition and recruitment strategies, disclosure and management of conflict of interest for
participating workgroup members, literature review techniques, evidence grading resources,
required approval bodies, and suggestions for communication and implementation.

Methods Used to Collect the Evidence:
The following criteria were used by the guideline author(s) and workgroup members to conduct
electronic database searches in the collection of evidence for review.

Literature Sources:
ξ Electronic database search (e.g., PubMed)
ξ Databases of systematic reviews (e.g., Cochrane Library)
ξ Hand-searching journals, external guidelines, and conference publications

Time Period: All published articles through 2017

Search Terms:
ξ [("CAR-T" OR "chimeric antigen receptor T-cell therapy") AND ("CRS" OR "cytokine
release syndrome")] and [("CAR-T" OR "chimeric antigen receptor T-cell therapy") AND
("neurotoxicity" OR “CRES”)

Methods to Select the Evidence:
Searches were limited to clinical trials, review articles, case series, human subjects, and articles
available in English. Expert opinion and clinical experience were also considered during
discussions of the evidence.

Methods Used to Formulate the Recommendations:
The workgroup members agreed to adopt recommendations developed by external
organizations and/or created recommendations internally via a consensus process using
discussion of the literature and expert experience/opinion. If issues or controversies arose
where consensus could not be reached, the topic was escalated appropriately per the guiding
principles outlined in the UW Health Clinical Practice Guideline Resource Guide.

Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations:
Recommendations developed by external organizations maintained the evidence grade
assigned within the original source document and were adopted for use at UW Health.

Internally developed recommendations, or those adopted from external sources without an
assigned evidence grade, were evaluated by the guideline workgroup using an algorithm
adapted from the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) methodology (see Figure 1).
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Figure 1. GRADE Methodology adapted by UW Health

Rating Scheme for the Strength of the Evidence/Recommendations:

GRADE Ranking of Evidence
High We are confident that the effect in the study reflects the actual effect.
Moderate We are quite confident that the effect in the study is close to the true effect, but it
is also possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.

GRADE Ratings for Recommendations For or Against Practice
Strong The net benefit of the treatment is clear, patient values and circumstances
are unlikely to affect the decision.
Weak/conditional
Recommendation may be conditional upon patient values and
preferences, the resources available, or the setting in which the
intervention will be implemented.


Recognition of Potential Health Care Disparities: Disparities in the treatment of patients with
malignancies exist. The availability of novel diagnostic and therapeutic measures (e.g., CAR-T
therapies) and the opportunity to participate in clinical trials may be affected by multiple factors
(e.g., geographical location, socioeconomic status). Distrust of the health care system, stigmas
related to cancer and death, literacy and language barriers, and poor expectations regarding the
outcome from cancer care may also influence treatment outcomes.11
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16


Companion Documents
1. Neutropenic Fever – Adult Guideline
2. Fever and Neutropenia – Pediatric Guideline
3. Granulocyte-Colony Stimulating Factor – Adult/Pediatric Guideline
4. Oncologic Emergencies – Adult/Pediatric Guideline
5. Status Epilepticus – Pediatrics Guideline

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17


Appendix A.
CTCAE Grading of Common Organ Toxicities7
Adverse Event Grade 1 Grade 2 Grade 3 Grade 4
Ca
rd
ia
c
Sinus tachycardia Asymptomatic, No
intervention needed
Symptomatic, non-
urgent intervention
indicated
Urgent intervention
indicated
-
Arrhythmia or heart
block
Asymptomatic, No
intervention needed
Symptomatic, non-
urgent intervention
indicated
Urgent intervention
indicated
Life-threatening
Ejection fraction
decreasedA -
EF 40-50% or 10-19%
drop from baseline
EF 20-39% or greater
than or equal to 20%
drop from baseline
EF less than 20%
Re
sp
ir
at
or
y Pleural Effusion Asymptomatic, No
intervention needed
Symptomatic,
intervention indicated
(diuretics or
thoracentesis)
Symptomatic with
respiratory distress;
needs surgical
intervention (chest tube
or pleurodesis)
-
Pulmonary edema Minimal dyspnea on
exertion
Moderate dyspnea on
exertion; medical
intervention indicated;
limits instrumental ADL
Dyspnea at rest; oxygen
indicated; limits self-care
ADL
Life-threatening; urgent
intervention or ventilatory
support indicated
Ga
st
ro
in
te
st
i
na
l
Nausea
Loss of appetite without
alteration in eating
habits
Oral intake decreased
without dehydration or
weight loss
Inadequate oral caloric
or fluid intake; receiving
tube feeding or TPN
-
Vomiting 1-2 episodes/24 hours 3-5 episodes/24 hours
Greater than 6
episodes/24 hours;
receiving tube feeding or
TPN
Life-threatening
Diarrhea Increase of 1-3
stools/day over baseline
Increase of 4-6
stools/day over
baseline
Increase of greater than
6 stools/day over
baseline; limits self-care
ADL
Life-threatening
He
pa
tic
Transaminitis
(Increased AST or
ALT)
Greater than ULN to 3 x
ULN
Greater than 3 x ULN
to 5 x ULN
Greater than 5 x ULN to
20 x ULN Greater than 20 x ULN
Total bilirubin
increased
Greater than ULN to 1.5
x ULN
Greater than 1.5 x ULN
to 3 x ULN
Greater than 3 x ULN to
10 x ULN Greater than 10 x ULN
Re
na
l
Urine output
decreased - -
Oliguria (less than 80
mL/8 hours)
Anuria (less than 240
mL/24 hours)
Acute kidney injury Creatinine 1.5-2 x above
baseline
Creatinine 2-3 x above
baseline
Creatinine greater than
3 x baseline or greater
than 4 mg/dL
Life-threatening; dialysis
indicated
Co
ag
ul
op
at
hy

Disseminated
Intravascular
Coagulation
-
Laboratory findings
with no bleeding
Laboratory findings with
bleeding

Life-threatening; urgent
intervention indicated
S
ki
n
Rash Acneiform
Papules and/or pustules
covering less than 10%
BSA, which may or may
not be associated with
symptoms of pruritus or
tenderness
Papules and/or
pustules covering 10 -
30% BSA, which may
or may not be
associated with
symptoms of pruritus or
tenderness; associated
with psychosocial
impact; limiting
instrumental ADL
Papules and/or pustules
covering greater than
30% BSA, which may or
may not be associated
with symptoms of
pruritus or tenderness;
limiting self-care ADL;
associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering any percent BSA,
which may or may not be
associated with symptoms
of pruritus or tenderness
and are associated with
extensive superinfection
with IV antibiotics
indicated; life threatening
consequences
Rash Maculo-
papular
Macules/papules
covering less than 10%
BSA with or without
symptoms (e.g., pruritus,
burning, tightness)
Macules/papules
covering 10-30% BSA
with or without
symptoms (e.g.,
pruritus, burning,
tightness); limiting
instrumental ADL
Macules/papules
covering greater than
30% BSA with or without
associated symptoms;
limiting self-care ADL
-
Abbreviations: CTCAE, common terminology criteria for adverse events; EF, Ejection fraction; ADL, activities of daily living; AST, aspartate
aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal; BSA, body surface area
Footnotes:
AEjection fraction may be increased with cytokine release syndrome but is not graded
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Neurotoxicity Grading4,7
Sign/symptom Grade 1 Grade 2 Grade 3 Grade 4
Somnolence Mild drowsiness/
sleepiness
Moderate
somnolence, limiting
instrumental ADL
Obtundation or stupor
Life-threatening
needing urgent
intervention or
mechanical
ventilation

Confusion Mild disorientation/
confusion
Moderate
disorientation,
limiting instrumental
ADL
Severe disorientation,
limiting self-care ADL
Encephalopathy Mild limiting of ADL
Limiting instrumental
ADL
Limiting self-care
ADL
Dysphasia No impairment in
communicating
Moderate
impairment in ability
to communicate
spontaneously
Severe receptive or
expressive
dysphasia, impairing
ability to read, write
or communicate
intelligibly
-
Seizure
Brief partial
seizure; no loss of
consciousness
Brief generalized
seizure
Multiple seizures
despite medical
intervention
Life-
threatening;
prolonged
repetitive
seizures
Incontinence or
motor weakness - -
Bowel / bladder
incontinence;
Weakness limiting
self-care ADL,
disabling
-
Tremor Mild symptoms
Moderate
symptoms; limiting
instrumental ADL
Severe symptoms;
limiting self-care ADL -
Abbreviations: ADL, activities of daily living

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Appendix B.
Approach to the assessment and management of acute toxicities associated with
chimeric antigen receptor (CAR)-T-cell therapy










































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20



Appendix C.
Kymriah (tisagenlecleucel) REMS Requirements (11/2017):12

ξ Authorized representative must complete KYMRIAH REMS Live training program and
successfully completes KYMRIAH REMS Program Knowledge Assessment
ξ Ensure all relevant staff are trained and successfully complete knowledge assessment and
maintain records of training
ξ Utilize processes and procedures to ensure that:
o New staff is trained
o Staff retrained if KYMRIAH has not been dispensed once annually from certification
o Prior to dispensing KYMRIAH:
 Verify 2 doses of tocilizumab are available onsite and ready for immediate
administration
 Provide patients and their guardians with KYMRIAH REMS Program Patient
Wallet Card to inform them:
ξ Signs and symptoms of CRS and neurological toxicities that require
immediate medical attention.
ξ Importance of staying within 2 hours of the certified hospital and their
associated clinic for at least 4 weeks after receiving KYMRIAH
treatment, unless otherwise indicated by the doctor.
ξ Conditions of certification
o Recertify in the KYMRIAH REMS Program if the hospital and their associated clinics
designate a new authorized representative.
o Report any adverse events suggestive of CRS or neurological toxicities.
o Maintain documentation that all processes and procedures are in place and are
being followed for the KYMRIAH REMS Program and provide that documentation
upon request to Novartis, FDA, or a third party acting on behalf of Novartis.
o Comply with audits by Novartis, FDA, or a third party acting on behalf of Novartis to
ensure that all training, processes and procedures are in place and are being
followed for the KYMRIAH REMS Program.
o Dispense KYMRIAH only after verifying that a minimum of two doses of tocilizumab
are available on-site for each patient for administration within 2 hours.












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21


Appendix D.
Yescarta (axicabtagene ciloleucel) REMS Requirements (11/2017):13

ξ Authorized representative must complete YESCARTA REMS training program which
includes review of full prescribing information, program live training, and adverse reaction
management guide and successfully completes YESCARTA REMS Program Knowledge
Assessment
ξ Authorized representative must complete the hospital enrollment form
ξ Ensure all relevant staff involved in the prescribing, dispensing, or administration of
YESCARTA are trained and successfully complete knowledge assessment and maintain
records of training
ξ Maintain training records of all staff
ξ Utilize processes and procedures to ensure that:
o New staff is trained
o Staff retrained if YESCARTA has not been dispensed once annually from
certification
o Prior to dispensing YESCARTA:
 Verify 2 doses of tocilizumab are available onsite for each patient and ready
for immediate administration (within 2 hours)
 Provide patients and their guardians with YESCARTA REMS Program
Patient Wallet Card to inform them:
ξ Signs and symptoms of CRS and neurological toxicities that require
immediate medical attention.
ξ Importance of staying within 2 hours of the certified hospital and their
associated clinic for at least 4 weeks after receiving YESCARTA
treatment, unless otherwise indicated by the doctor.
















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22


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4. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy -
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Copyright © 2018 Univ ersity of Wisconsin Hospitals and Clinics Authority
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