i3 Health is pleased to make the Clinician's Resource Guide from this activity available for use as a nonaccredited self-study or teaching resource.

1. Clinical Tools and Resources for
Self-Study and Patient Education
CAR T-CELL THERAPY
REFERENCE GUIDE
The clinical tools and resources contained herein are provided as educational adjuncts
to the CE-approved online activity Understanding and Optimizing CAR T-Cell Therapy for
Patients with B-Cell Malignancies. To access the activity and earn CE credit, visit:
https://www.i3Health.com/CAR-T-Therapy
CONTENTS
I: Most Common Types of B-Cell MAlignancies...............................................................2
II: CAR T-Cell Therapy Workflow......................................................................................4
III: FDA-Approved CAR T-Cell Therapies.........................................................................5
IV: Adverse Events of CAR T-Cell Therapy.......................................................................6
V: PRinciples of Patient Monitoring..................................................................................7
VI: Cytokine Release Syndrome Guidelines .....................................................................8
VII: CAR T-Cell Related Neurotoxicity..............................................................................9
VIII: Neurotoxicity: Treatment by Grade ........................................................................10
IX: Mini-Mental State Examination (MMSE)....................................................................11

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I: MOST COMMON TYPES OF B-CELL MALIGNANCIES
Malignancy Type Characteristics
Diffuse large B-cell lymphoma
(DLBCL)
• Most common; accounts for 1 in 3 lymphomas
• Average age at diagnosis is around mid 60s
• Subtype: primary mediastinal B-cell lymphoma
o Occurs mostly in young women
Follicular lymphoma (FL)
• Slow growing
• Responds well to treatment but is hard to cure
• Average age at diagnosis is 60
B-cell acute lymphocytic
leukemia (ALL)
• Most common cancer in children aged >15 years
• Aggressive
Chronic lymphocytic leukemia
(CLL) / small lymphocytic
lymphoma (SLL)
• Closely related diseases
• Same type of cancer cell for both types
• CLL affects blood and bone marrow
• SLL affects lymph nodes and spleen
• Slow growing
Marginal zone lymphoma
• Accounts for 5%-10% of lymphomas
• Slow growing
• Three subtypes
o Extranodal marginal zone B-cell lymphoma/mucosa-
associated lymphoid tissue (MALT) lymphoma
o Nodal marginal zone B-cell lymphoma
o Splenic marginal zone B-cell lymphoma
Mantle cell lymphoma
• Accounts for 5% of lymphomas
• More common in men and patients over 60
• Grows faster than indolent lymphomas but doesn’t
respond to treatment as well as aggressive lymphomas
Burkitt lymphoma
• Rare; accounts for 1%-2% of all adult lymphomas
• More common in children and males
Lymphoplasmacytic
lymphoma (Waldenstrom
macroglobulinemia)
• Rare; accounts for 1%-2% of all lymphoma cases
• Lymphoma cells are small and are found in bone
marrow, lymph nodes, and spleen
Hairy cell leukemia
• Rare
• Small B lymphocytes with tiny hair-like projections
• Found in bone marrow, spleen, and blood
• Slow growing

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Malignancy Type Characteristics
Primary central nervous
system leukemia
• Rare; more common in elderly patients with weakened
immune systems
• Patients develop headaches, confusion, and sometimes
seizures
American Cancer Society (2019). Types of B-cell lymphoma. Available at: https://www.cancer.org/
National Cancer Institute (2018). Childhood acute lymphoblastic leukemia treatment (PDQ®)—health professional
version. Available at: https://www.cancer.gov

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II: CAR T-CELL THERAPY WORKFLOW
National Cancer Institute (2019). CAR T-cell therapy infographic. Available at: https://www.cancer.gov

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III: FDA-APPROVED CAR T-CELL THERAPIES
Treatment Description and Indications
Tisagenlecleucel
(Kymriah™)
• CD19-directed genetically modified autologous T-cell
immunotherapy
• FDA approved for patients ≤25 years of age with B-cell
precursor acute lymphoblastic leukemia (ALL) that is
refractory or in second or later relapse
• Also approved as third-line or later systemic therapy for
adults with several types of relapsed/refractory large B-cell
lymphoma:
o DLBCL-not otherwise specified (NOS)
o High-grade B-cell lymphoma
o DLBCL arising from FL
• Contraindicated in primary central nervous system (CNS)
lymphoma
Axicabtagene ciloleucel
(Yescarta™)
• CD19-directed genetically modified autologous T-cell
immunotherapy
• FDA approved as third-line or later systemic therapy for
adults with several types of relapsed/refractory large B-cell
lymphoma:
o DLBCL-NOS
o Primary mediastinal large B-cell lymphoma
o High-grade B-cell lymphoma
o DLBCL arising from FL
• Contraindicated in primary CNS lymphoma
Leukemia & Lymphoma Society (2019). Chimeric antigen receptor (CAR) T-cell therapy. Available at:
https://www.lls.org/

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IV: ADVERSE EVENTS OF CAR T-CELL THERAPY
Adverse Event Characteristics
Cytokine release
syndrome (CRS)
• Cytokines (chemical messengers that help the T cells carry out their
functions) are produced when the CAR T cells multiply in the body and kill
the cancer cells
• Symptoms range from mild flulike symptoms (nausea, fatigue, headache,
chills, fever) to more serious symptoms: low blood pressure, tachycardia,
capillary leakage, cardiac arrest, cardiac arrhythmias, cardiac failure,
hemophagocytic lymphohistiocytosis/macrophage activation syndrome
(HLH/MAS), hypoxia, renal insufficiency, poor lung oxygenation, multiple
organ failure
Neurologic
toxicities
• Frequency, severity, and nature of neurological effects vary between CAR T
products
• Symptoms: language impairment (aphasia), confusion, delirium, involuntary
muscle twitching, hallucinations, unresponsiveness, seizures
B-cell aplasia
• Because CAR T-cell therapy targeting antigens found on the surface of B
cells not only destroys cancerous B cells but also normal B cells, B-cell
aplasia (low numbers of B cells or absent B cells) is an expected result of
successful CD19-specific CAR T-cell treatment and has served as a useful
indicator of ongoing CAR T-cell activity
• This effect results in less ability to make the antibodies that protect against
infection
• Intravenous or subcutaneous immunoglobulin replacement therapy may be
given with the aim of preventing infection
Tumor lysis
syndrome (TLS)
• Group of metabolic complications that can occur due to the breakdown of
dying cells
• Usually occurs at the onset of toxic cancer treatments but can be delayed;
may occur ≥1 month after CAR T-cell therapy
• Can cause organ damage
• Can be a life-threatening complication of any treatment, including CAR T,
that causes breakdown of cancer cells
• Managed by standard supportive therapy
Anaphylaxis
• There is potential for a patient receiving CAR T-cell therapy to have an
overwhelming immune response against the CAR itself
• Symptoms: hives, facial swelling, low blood pressure, respiratory distress
• There have been few reports of acute anaphylaxis
• Thorough monitoring and immediate treatment of this life-threatening side
effect are critical
Leukemia & Lymphoma Society (2019). Chimeric antigen receptor (CAR) T-cell therapy. Available at:
https://www.lls.org

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V: PRINCIPLES OF PATIENT MONITORING
Patient Monitoring Before and During CAR T-Cell Infusion
• Perform central venous access, preferably with double or triple lumen catheter, for
intravenous (IV) fluid and other infusions in case of toxicities
• Perform cardiac monitoring at the onset of grade ≥2 CRS until resolution to grade £1
and additionally as clinically indicated
• Tumor lysis precautions are recommended for patients with large tumor burden and
aggressive histologies per institutional guidelines
• For CAR T-cell therapies known to cause neurotoxicity, start seizure prophylaxis (eg,
levetiracetam 500-700 mg orally every 12 hours for 30 days) on the day of infusion
• Consider baseline brain magnetic resonance imaging (MRI)
Patient Monitoring After CAR T-Cell Infusion
• Close monitoring in the hospital is preferable with current products used for adults,
but extremely close outpatient monitoring may be possible at centers with CAR T-
cell transplant or outpatient transplant experience
• Hospitalization is warranted for patients with CRS
• Monitor complete blood count (CBC), complete metabolic panel (including
magnesium and phosphorous), and coagulation profile
• Check baseline C-reactive protein (CRP) and ferritin; recheck at least 3 times per
week for 2 weeks post infusion. Consider daily checks during CRS. C-reactive protein
can normalize prior to the onset of neurotoxicity
• During the peak window of CRS risk, assessment for CRS should be done at least
twice daily or when the patient’s status changes
• During the peak window of neurotoxicity risk, neurotoxicity assessment should be
done at least twice daily or when the patient’s status changes. If neurologic concern
develops, assess cognitive function and motor weakness at least every 8 hours
National Comprehensive Cancer Network (2019). Clinical Practice Guidelines in Oncology: management of
immunotherapy-related toxicities. Version 1.2019. Available at: http://www.nccn.org

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VI: CYTOKINE RELEASE SYNDROME GUIDELINES
CRS Grade
Anti–IL-6
Therapy
Corticosteroids Additional Supportive Care
Grade 1:
Fever with or
without
constitutional
symptoms
For prolonged CRS
(>3 days) in patients
with significant
symptoms and/or
comorbidities,
consider
tocilizumab per
Grade 2
N/A
• Empiric broad-spectrum antibiotics
• If neutropenic, consider granulocyte
colony-stimulating factor (G-CSF)
• Maintenance IV fluids for hydration
• Symptomatic management of organ
toxicities
Grade 2:
Hypotension
responding to fluids;
hypoxia responding
to <40% O2
Tocilizumab 8
mg/kg IV over 1
hour (not to exceed
800 mg/dose).
Repeat in 8 hours if
no improvement;
no more than 3
doses in 24 hours,
with a maximum of
4 doses in total
For persistent
refractory
hypotension after 1-
2 doses of anti–IL-6
therapy:
dexamethasone 10
mg IV every 6 hours
(or equivalent)
• IV fluid bolus as needed
• For persistent refractory
hypotension after 2 fluid boluses
and anti–IL-6 therapy:
o Start vasopressors
o Consider transfer to ICU
o Consider echocardiogram
o Initiate hemodynamic
monitoring
• Symptomatic management of organ
toxicities
Grade 3:
Hypotension
managed with one
pressor; hypoxia
returning with ³40%
O2
Anti–IL-6 therapy
per Grade 2 if
maximum dose not
reached within 24-
hour period
Dexamethasone 10
mg IV every 6 hours
(or equivalent). If
refractory, manage
as grade 4
• Transfer to ICU, obtain
echocardiogram, and perform
hemodynamic monitoring
• Supplemental oxygen, including
high-flow oxygen delivery and
noninvasive positive pressure
ventilation
• IV fluid bolus and vasopressors as
needed
• Symptomatic management of organ
toxicities
Grade 4:
Life-threatening
consequences;
requires ventilator
support or
vasopressor-
refractory shock
Anti–IL-6 therapy
per Grade 2 if
maximum dose not
reached within 24-
hour period
Dexamethasone 10
mg IV every 6 hours
(or equivalent). If
refractory, consider
methylprednisolone
1,000 mg/day IV
• ICU care and hemodynamic
monitoring
• Mechanical ventilation as needed
• IV fluid bolus and vasopressors as
needed
• Symptomatic management of organ
toxicities
National Comprehensive Cancer Network (2019). Clinical Practice Guidelines in Oncology: management of
immunotherapy-related toxicities. Version 1.2019. Available at: http://www.nccn.org

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VII: CAR T-CELL RELATED NEUROTOXICITY
Assessment and Supportive Care Recommendations (All Grades)
• Neurologic assessment and grading, include cognitive assessment and motor weakness, at least
twice a day
• Neurology consultation at first sign of neurotoxicity
• For neurotoxicity ³ grade 2:
o MRI of the brain with and without contrast (or brain computed tomography (CT) if MRI is not
feasible)
o Electroencephalogram (EEG) for seizure activity
• Aspiration precautions
• IV hydration
• Use caution when prescribing medications that can cause CNS depression (aside from those
needed for seizure prophylaxis/treatment)
National Comprehensive Cancer Network (2019). Clinical Practice Guidelines in Oncology: management of
immunotherapy-related toxicities. Version 1.2019. Available at: http://www.nccn.org

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VIII: NEUROTOXICITY: TREATMENT BY GRADE
Neurologic Toxicity: Assessment and Supportive Care Recommendations (All Grades)
Grade No Concurrent CRS
Additional Therapy
if Concurrent CRS
Grade 1
Mild impact on activities of
daily living (ADLs)
• Supportive Care
Tocilizumab 8 mg/kg IV
over 1 hour
(≤800 mg/dose)
Grade 2
Moderate impact on ADLs
• Supportive Care
• Dexamethasone 10 mg IV x 1; can
repeat every 6 hours or
methylprednisolone 1 mg/kg IV every
12 hours if symptoms worsen
Anti–IL-6 therapy per
Grade 1
Grade 3
Severe impact on ADLs;
seizure; signs of elevated
intracranial pressure (eg,
papilledema, Cushing’s
triad, hypertension,
bradycardia)
• ICU care is recommended
• Dexamethasone 10 mg IV every 6 hours
or methylprednisolone 1 mg/kg IV
every 12 hours
• Consider repeat neuroimaging (CT or
MRI) every 2-3 days if patient has
persistent grade ³3 neurotoxicity
Anti–IL-6 therapy per
Grade 1
Grade 4
Patient in critical condition
and/or obtunded; cannot
perform assessment of
tasks; life-threatening
seizures or repetitive
seizures without return to
baseline
• ICU care; consider mechanical
ventilation for airway protection
• High-dose corticosteroids
• Consider repeat neuroimaging (CT or
MRI) every 2-3 days if patient has
persistent grade ³3 neurotoxicity
• Treat convulsive status epilepticus per
institutional guidelines
Anti–IL-6 therapy per
Grade 1
National Comprehensive Cancer Network (2019). Clinical Practice Guidelines in Oncology: management of
immunotherapy-related toxicities. Version 1.2019. Available at: http://www.nccn.org

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IX: MINI-MENTAL STATE EXAMINATION (MMSE)
Maximum
Score
Patient’s Score Questions
5
“What is the year? Season? Date? Day of the week?
Month?”
5
“Where are we now: State? County? Town/city? Hospital?
Floor?”
3
The examiner names three unrelated objects clearly and
slowly, then asks the patient to name all three of them. The
patient’s response is used for scoring. The examiner repeats
them until patient learns all of them, if possible. Number of
trials:
5
“I would like you to count backward from 100 by sevens.”
(93, 86, 79, 72, 65, …) Stop after five answers.
Alternative: “Spell WORLD backwards.” (D-L-R-O-W)
3
“Earlier I told you the names of three things. Can you tell me
what those were?”
2
Show the patient two simple objects, such as a wristwatch
and a pencil, and ask the patient to name them.
1 “Repeat the phrase: ‘No ifs, ands, or buts.’”
3
“Take the paper in your right hand, fold it in half, and put it
on the floor.” (The examiner gives the patient a piece of
blank paper.)
1
“Please read this and do what it says.” (Written instruction is
“Close your eyes.”)
1
“Make up and write a sentence about anything.” (This
sentence must contain a noun and a verb.)
1
“Please copy this picture.” (The examiner gives the patient a
blank piece of paper and asks him/her to draw the symbol
below. All 10 angles must be present and two must
intersect.)
30 Total
Rovner BW & Folstein MF (1987). Mini-mental state exam in clinical practice. Hosp Pract (Off Ed), 22(1A):99, 103,
106, 110.