HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`KYMRIAH safely and effectively. See full prescribing information for
`KYMRIAH.
`KYMRIAH® (tisagenlecleucel) suspension for intravenous infusion
`Initial U.S. Approval: 2017
`
`WARNING: CYTOKINE RELEASE SYNDROME and
`NEUROLOGICAL TOXICITIES
`See full prescribing information for complete boxed warning.
` Cytokine Release Syndrome (CRS), including fatal or life-threatening
`reactions, occurred in patients receiving KYMRIAH. Do not
`administer KYMRIAH to patients with active infection or
`inflammatory disorders. Treat severe or life-threatening CRS with
`tocilizumab or tocilizumab and corticosteroids. (2.3, 2.4, 5.1)
` Neurological toxicities, which may be severe or life-threatening, can
`occur following treatment with KYMRIAH, including concurrently
`with CRS. Monitor for neurological events after treatment with
`KYMRIAH. Provide supportive care as needed. (5.2)
` KYMRIAH is available only through a restricted program under a
`Risk Evaluation and Mitigation Strategy (REMS) called the
`KYMRIAH REMS. (5.3)
`
` 5/2022
`
`-----------------------------RECENT MAJOR CHANGES-------------------------
`Indications and Usage, Adult Relapsed or Refractory (r/r) Follicular
`Lymphoma (FL) (1.3)
`Dosage and Administration Adult Relapsed or Refractory (r/r)
` 5/2022
`Follicular Lymphoma (FL) (2.2, 2.3)
` 5/2022
`Management of Severe Adverse Reactions (2.4)
` 5/2022
`
`Warnings and Precautions (5.1, 5.2, 5.4, 5.6, 5.7, 5.8)
`----------------------------INDICATIONS AND USAGE--------------------------
`KYMRIAH is a CD19-directed genetically modified autologous T-cell
`immunotherapy indicated for the treatment of:
`Patients up to 25 years of age with B-cell precursor acute lymphoblastic
`
`leukemia (ALL) that is refractory or in second or later relapse. (1.1)
` Adult patients with relapsed or refractory (r/r) large B-cell lymphoma
`after two or more lines of systemic therapy, including diffuse large B-cell
`lymphoma (DLBCL) not otherwise specified, high grade B-cell
`lymphoma and DLBCL arising from follicular lymphoma.
`Limitations of Use: KYMRIAH is not indicated for treatment of patients
`with primary central nervous system lymphoma. (1.2)
` Adult patients with relapsed or refractory follicular lymphoma (FL) after
`two or more lines of systemic therapy. This indication is approved under
`accelerated approval based on response rate and duration of response.
`Continued approval for this indication may be contingent upon
`verification and description of clinical benefit in confirmatory trial(s).
`(1.3)
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`For autologous use only. For intravenous use only.
` Administer a lymphodepleting regimen if needed before infusion of
`KYMRIAH. (2.3)
` Do NOT use a leukodepleting filter. (2.3)
` Verify the patient’s identity prior to infusion. (2.3)
`Premedicate with acetaminophen and an H1-antihistamine. (2.3)
`
` Confirm availability of tocilizumab prior to infusion. (2.3, 5.1)
` Dosing of KYMRIAH is based on the number of chimeric antigen
`receptor (CAR)-positive viable T cells.
`Pediatric and Young Adult B-cell ALL (up to 25 years of age)
`For patients 50 kg or less, administer 0.2 to 5.0 x 106 CAR-positive
`
`viable T cells per kg body weight intravenously. (2.1)
`
`
`
`
`
`
`
`For patients above 50 kg, administer 0.1 to 2.5 x 108 total CAR-
`positive viable T cells (non-weight based) intravenously. (2.1)
`Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and
`Follicular Lymphoma
` Administer 0.6 to 6.0 x 108 CAR-positive viable T cells
`intravenously. (2.2)
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`Pediatric and Young Adult B-cell ALL (up to 25 years of age)
`
`A single dose of KYMRIAH contains 0.2 to 5.0 x 106 CAR-positive viable T
`cells per kg of body weight for patients 50 kg or less, or 0.1 to 2.5 x 108 CAR-
`positive viable T cells for patients more than 50 kg, suspended in one to three
`patient-specific infusion bag(s) for intravenous infusion. (3)
`Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma and
`
`Follicular Lymphoma
`A single dose of KYMRIAH contains 0.6 to 6.0 x 108 CAR-positive viable T
`cells suspended in one to three patient-specific infusion bag(s) for intravenous
`infusion. (3)
`-------------------------------CONTRAINDICATIONS-----------------------------
`None. (4)
`------------------------WARNINGS AND PRECAUTIONS-----------------------
` Hypersensitivity Reactions: Monitor for hypersensitivity reactions during
`infusion. (5.5)
` Serious Infections: Monitor patients for signs and symptoms of infection;
`treat appropriately. (5.6)
` Prolonged Cytopenias: Patients may exhibit ≥ Grade 3 cytopenias for
`several weeks following KYMRIAH infusion. Prolonged neutropenia has
`been associated with increased risk of infection. (5.7)
` Hypogammaglobulinemia: Monitor and provide replacement therapy until
`resolution. Assess immunoglobulin levels in newborns of mothers treated
`with KYMRIAH. (5.8)
` Secondary Malignancies: In the event that a secondary malignancy occurs
`after treatment with KYMRIAH, contact Novartis Pharmaceuticals
`Corporation at 1-844-4KYMRIAH. (5.9)
` Effects on Ability to Drive and Use Machines: Advise patients to refrain
`from driving and engaging in hazardous occupations or activities, such as
`operating heavy or potentially dangerous machinery, for at least 8 weeks
`after receiving KYMRIAH. (5.10)
`------------------------------ADVERSE REACTIONS------------------------------
`Pediatric and Young Adult B-cell ALL (up to 25 years of age): The most
`common adverse reactions (incidence greater than 20%) are cytokine release
`syndrome, infections-pathogen unspecified, hypogammaglobulinemia, fever,
`decreased appetite, viral infectious disorders, headache, febrile neutropenia,
`hemorrhage, musculoskeletal pain, vomiting, encephalopathy, diarrhea,
`hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia,
`tachycardia, edema, fatigue, and acute kidney injury. (6.1)
`Adult Relapsed or Refractory Diffuse Large B-cell Lymphoma: The most
`common adverse reactions (incidence greater than 20%) are CRS, infections-
`pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema,
`hemorrhage, dyspnea, and headache. (6.1)
`Adult Relapsed or Refractory Follicular Lymphoma: The most common
`adverse reactions (incidence greater than 20%) are cytokine release syndrome,
`infections-pathogens unspecified, fatigue, musculoskeletal pain, headache,
`and diarrhea. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch.
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 5/2022
`
`UPenn Ex. 2079
`Miltenyi v. UPenn
`IPR2022-00855
`Page 1
`
`

`

`1.2
`
`2.2
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: CYTOKINE RELEASE SYNDROME and
`NEUROLOGICAL TOXICITIES
`1 
`INDICATIONS AND USAGE
`Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell
`1.1
`Acute Lymphoblastic Leukemia (ALL)
`Adult Relapsed or Refractory (r/r) Diffuse Large B-cell
`Lymphoma (DLBCL)
`Adult Relapsed or Refractory (r/r) Follicular Lymphoma (FL)
`1.3
`DOSAGE AND ADMINISTRATION
`2.1
`Dosage in Pediatric and Young Adult Relapsed or Refractory
`(r/r) B-cell Acute Lymphoblastic Leukemia (ALL)
`Dosage in Adult Relapsed or Refractory (r/r) Diffuse Large B-
`cell Lymphoma (DLBCL) and Follicular Lymphoma (FL)
`Administration
`2.3
`2.4 Management of Severe Adverse Reactions
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Cytokine Release Syndrome (CRS)
`5.2
`Neurological Toxicities
`5.3
`KYMRIAH REMS to Mitigate Cytokine Release Syndrome and
`Neurological Toxicities
`Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage
`Activation Syndrome (MAS)
`Hypersensitivity Reactions
`5.5
`Serious Infections
`5.6
`Prolonged Cytopenias
`5.7
`Hypogammaglobulinemia
`5.8
`Secondary Malignancies
`5.9
`5.10  Effects on Ability to Drive and Use Machines
`
`2
`
`3
`4
`5
`
`5.4
`
`6
`
`7
`8
`
`11
`12
`
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`6.3
`Immunogenicity
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1  Mechanism of Action
`12.2  Pharmacodynamics
`12.3  Pharmacokinetics/Cellular Kinetics
`NONCLINICAL TOXICOLOGY
`13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`14.1  Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic
`Leukemia (ALL)
`14.2  Adult Relapsed or Refractory (r/r) Diffuse Large B-cell
`Lymphoma (DLBCL)
`14.3  Adult Relapsed or Refractory (r/r) Follicular Lymphoma (FL)
`REFERENCES
`15
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`PATIENT COUNSELING INFORMATION
`17
`*Sections or subsections omitted from the full prescribing information are
`not listed.
`
`13
`
`14
`
`UPenn Ex. 2079
`Miltenyi v. UPenn
`IPR2022-00855
`Page 2
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES
` Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients
`receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory
`disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids [see
`Dosage and Administration (2.3, 2.4), Warnings and Precautions (5.1)].
` Neurological toxicities, which may be severe or life-threatening, can occur following treatment with
`KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with
`KYMRIAH. Provide supportive care as needed [see Warnings and Precautions (5.2)].
` KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation
`Strategy (REMS) called the KYMRIAH REMS [see Warnings and Precautions (5.3)].
`
`
`
`INDICATIONS AND USAGE
`1
`KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:
`Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)
`1.1
`Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or
`later relapse.
`1.2
`Adult Relapsed or Refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL)
`Adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy
`including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL
`arising from follicular lymphoma.
`Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.
`
`Adult Relapsed or Refractory (r/r) Follicular Lymphoma (FL)
`1.3
`Adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy.
`This indication is approved under accelerated approval based on response rate and duration of response [see Clinical
`Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical
`benefit in confirmatory trial(s).
`
`DOSAGE AND ADMINISTRATION
`2
`For autologous use only. For intravenous use only.
`2.1
`Dosage in Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia
`(ALL)
`KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive
`viable T cells.
`Based on the patient weight reported at the time of leukapheresis:
` Patients 50 kg or less: administer 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight.
` Patients above 50 kg: administer 0.1 to 2.5 x 108 CAR-positive viable T cells.
`Dosage in Adult Relapsed or Refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL) and Follicular
`2.2
`Lymphoma (FL)
`KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive
`viable T cells.
` For adult patients: administer 0.6 to 6.0 x 108 CAR-positive viable T cells.
`
`
`
`UPenn Ex. 2079
`Miltenyi v. UPenn
`IPR2022-00855
`Page 3
`
`

`

`
`2.3
`
`
`
`Administration
`Preparing Patient for KYMRIAH Administration with Lymphodepletion
` Confirm availability of KYMRIAH prior to starting the lymphodepleting regimen.
`Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)
` Lymphodepleting chemotherapy: Fludarabine (30 mg/m2 intravenously daily for 4 days) and
`cyclophosphamide (500 mg/m2 intravenously daily for 2 days starting with the first dose of fludarabine).
`
`Infuse KYMRIAH 2 to 14 days after completion of the lymphodepleting chemotherapy.
`Adult Relapsed or Refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL) and r/r Follicular Lymphoma
`(FL)
` Lymphodepleting chemotherapy: Fludarabine (25 mg/m2 intravenously daily for 3 days) and
`cyclophosphamide (250 mg/m2 intravenously daily for 3 days starting with the first dose of fludarabine).
` Alternate lymphodepleting chemotherapy: bendamustine 90 mg/m2 intravenously daily for 2 days if a patient
`experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a
`previous cyclophosphamide containing regimen.
`Infuse KYMRIAH 2 to 11 days (r/r DLBCL) or 2 to 6 days (r/r FL) after completion of the lymphodepleting
`chemotherapy.
` Lymphodepleting chemotherapy may be omitted if a patient is experiencing significant cytopenia, e.g., white
`blood cell (WBC) count is less than 1 x 109/L within 1 week prior to KYMRIAH infusion.
`Preparation of KYMRIAH for Infusion and Administration
`Delay the infusion of KYMRIAH if a patient has unresolved serious adverse reactions (including pulmonary reactions,
`cardiac reactions, or hypotension) from preceding chemotherapies, active uncontrolled infection, active graft versus host
`disease (GVHD), or worsening of leukemia burden following lymphodepleting chemotherapy [see Warnings and
`Precautions (5.1)].
`A KYMRIAH dose may be contained in one to three cryopreserved patient specific infusion bag(s). Verify the number of
`bags received for the dose of KYMRIAH with the Certificate of Conformance (CoC) and Certificate of Analysis (CoA).
`Coordinate the timing of thaw of KYMRIAH and infusion in the following manner. Confirm the infusion time in advance,
`and adjust the start time for thaw so that KYMRIAH is available for infusion when the recipient is ready. If more than one
`bag has been received for the treatment dose, thaw 1 bag at a time. Wait to thaw/infuse the next bag until it is determined
`that the previous bag is safely administered.
`Preparation of KYMRIAH for Infusion
`1. Ensure tocilizumab and emergency equipment are available prior to infusion and during the recovery period.
`2. Premedicate patient with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to
`60 minutes prior to KYMRIAH infusion. Avoid prophylactic use of systemic corticosteroids, as it may interfere
`with the activity of KYMRIAH.
`3. Confirm patient identity: Prior to KYMRIAH preparation, match the patient's identity with the patient identifiers
`on each KYMRIAH infusion bag(s). KYMRIAH is for autologous use only. Employ universal precautions to
`avoid potential transmission of infectious diseases when handling the product.
`Note: The patient identifier number may be preceded by the letters DIN or Aph ID.
`
`
`
`
`
`
`UPenn Ex. 2079
`Miltenyi v. UPenn
`IPR2022-00855
`Page 4
`
`

`

`
`
`Figure 1. KYMRIAH Infusion Bag
`
`
`4. Inspect the infusion bag(s) for any breaks or cracks prior to thawing. If a bag is compromised, do not infuse the
`contents. Call Novartis at 1-844-4KYMRIAH.
`5. Place the infusion bag inside a second, sterile bag in case of a leak and to protect ports from contamination.
`6. Thaw each infusion bag one at a time at 37°C using either a water bath or dry thaw method until there is no
`visible ice in the infusion bag. Remove bag from thawing device immediately; do not store product bag at 37°C.
`Once the infusion bag has been thawed and is at room temperature (20°C to 25°C), it should be infused within 30
`minutes. Do not wash, spin down, and/or resuspend KYMRIAH in new media prior to infusion.
`7. Inspect the contents of the thawed infusion bag for any visible cell clumps. If visible cell clumps remain, gently
`mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not
`infuse KYMRIAH if clumps are not dispersed, the infusion bag is damaged or leaking, or otherwise appears to be
`compromised. Call Novartis at 1-844-4KYMRIAH.
`Administration
`8. Confirm the patient’s identity with the patient identifiers on the infusion bag.
`9. Administer KYMRIAH as an intravenous infusion at 10 mL to 20 mL per minute, adjusted as appropriate for
`smaller children and smaller volumes. The volume in the infusion bag ranges from 10 mL to 50 mL. Do NOT use
`a leukocyte-depleting filter. If more than one bag is being infused for the treatment dose, wait to thaw/infuse the
`next bag until it is determined that the previous bag is safely administered.
`- Prime the tubing prior to infusion with sodium chloride 9 mg/mL (0.9%) solution for injection.
`-
`Infuse all contents of the infusion bag.
`- Rinse the infusion bag with 10 mL to 30 mL sodium chloride 9 mg/mL (0.9%) solution for injection while
`maintaining a closed tubing system to assure as many cells as possible are infused into the patient.
`- Cells from all the bag(s) must be infused to complete a single dose.
`KYMRIAH contains human cells genetically modified with a lentivirus. Follow local biosafety guidelines applicable for
`handling and disposal of such products.
`Monitoring
`- Administer KYMRIAH at a REMS-certified healthcare facility.
`- Monitor patients 2-3 times during the first week following KYMRIAH infusion at the certified healthcare
`facility for signs and symptoms of CRS and neurologic toxicities [see Warnings and Precautions (5.1,
`5.2)].
`Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following
`infusion.
`
`-
`
`
`
`UPenn Ex. 2079
`Miltenyi v. UPenn
`IPR2022-00855
`Page 5
`
`

`

`
`
`-
`Instruct patients to refrain from driving or hazardous activities for at least 8 weeks following infusion.
`2.4 Management of Severe Adverse Reactions
`Cytokine Release Syndrome
`Identify cytokine release syndrome (CRS) based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate
`for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the
`recommendations in Table 1 (Lee et al 2014). Alternative CRS management strategies may be implemented based on
`appropriate institutional or academic guidelines.
`
`Tocilizumab
`In patients with persistent (> 3
`days) or refractory fever,
`consider managing as Grade 2
`CRSb.
`
`Administer tocilizumabc
`intravenously over 1 hour:
` 8 mg/kg (max. 800 mg) if
`body weight ≥ 30 kg
` 12 mg/kg if body weight
`<30 kg
`If no improvement after first
`dose, repeat every 8 hours
`(limit to a maximum of 3
`dosages in 24 hours period;
`maximum total of 4 doses).
`
`Per Grade 2
`If not improving, consider
`alternative therapyd.
`
`Corticosteroids
`Not applicable
`
`If no improvement within 24
`hours of tocilizumab, administer a
`daily dose of 2 mg/kg/day
`methylprednisolone intravenously
`(or equivalent) until vasopressor
`and oxygen no longer needed,
`then taper.
`If not improving, manage as
`appropriate grade below.
`
`Per Grade 2
`If not improving, manage as
`Grade 4.
`
`
`Per Grade 2
`If not improving, consider
`alternative therapyd.
`
`Administer methylprednisolone
`1,000 mg intravenously one to
`two times per day for 3 days.
`If not improving, consider
`methylprednisolone 1,000 mg
`intravenously two to three times a
`day or alternate therapyd.
`Continue corticosteroids until
`improvement to Grade 1, and then
`taper as clinically appropriate.
`
`Table 1. CRS Grading and Management Guidance
`CRS Grade a
`Symptomatic treatment
`Grade 1
`Exclude other causes (e.g.,
`infection) and treat specific
`Mild symptoms requiring
`symptoms (e.g., with
`symptomatic treatment only
`antipyretics, antiemetics,
`(e.g., low grade fever,
`analgesics, etc.)
`fatigue, anorexia, etc.)
`Grade 2
`Antipyretics, oxygen,
`intravenous fluids and/or
`Symptoms require and
`low dose vasopressors as
`respond to moderate
`needed.
`intervention
`Oxygen requirement < 40%
`or
`Hypotension responsive to
`fluids or low dose of one
`vasopressor or
`Grade 2 organ toxicity
`
`Grade 3
`Symptoms require and
`respond to aggressive
`intervention
`Oxygen requirement ≥ 40%
`or
`Hypotension requiring high
`dose or multiple
`vasopressors or
`Grade 3 organ toxicity or
`Grade 4 transaminitis
`Grade 4
`Life-threatening symptoms
`Requirement for ventilator
`support or
`Grade 4 organ toxicity
`(excluding transaminitis)
`
`High-flow oxygen
`Intravenous fluids, and
`high-dose or multiple
`vasopressors
`Treat other organ toxicities
`as per local guidelines.
`
`Mechanical ventilation
`Intravenous fluids and high-
`dose vasopressor(s)
`Treat other organ toxicities
`as per local guidelines.
`
`aLee et al. 2014.
`bSantomasso et al. 2021.
`cRefer to tocilizumab Prescribing Information for details.
`dAlternative therapy includes anti-cytokine and anti-T cell therapies as per institutional policy and published guidelines such as (but not limited to)
`anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG.
`
`
`
`UPenn Ex. 2079
`Miltenyi v. UPenn
`IPR2022-00855
`Page 6
`
`

`

`
`Neurologic Toxicities
`Patients should be monitored for neurologic toxicities, including ICANS, following KYMRIAH infusion, particularly
`during and after resolution of CRS. Identify neurologic toxicities based on clinical presentation. Evaluate for and treat
`other causes of neurological symptoms. Consider non-sedating seizure prophylaxis (e.g., levetiracetam) for patients at
`higher risk of seizure, such as those with seizure history, CNS disease, concerning EEG findings, or neoplastic brain
`lesions. If neurologic toxicity is suspected, manage according to the recommendations in Table 2. Alternative neurologic
`toxicities management strategies may be implemented based on appropriate institutional, academic, or consensus
`guidelines.
`
`Table 2: Guidance for Grading and Management of ICANS
`ICANS Gradea
`No concurrent CRS
`
`Grade 1
`ICE scoreb: 7-9 with no depressed level
`of consciousness
`
`Offer supportive care with intravenous
`hydration and aspiration precautions.
`
`Grade 2
`ICE scoreb: 3-6
`
`and/or
`
`Mild somnolence awaking to voice
`
`Supportive care as above.
`
`Consider dexamethasone 10 mg intravenously
`every 6-12 hours or methylprednisolone
`equivalent (1 mg/kg intravenously every 12
`hours) until the event is Grade 1 or less. If
`improving, taper corticosteroids.
`
`Administer dexamethasone 10 mg
`intravenously every 6-12 hours or
`methylprednisolone equivalent (1 mg/kg
`intravenously every 12 hours)
`
`Grade 3
`ICE scoreb: 0-2*
`
`and/or
`
`Depressed level of consciousness
`awakening only to tactile stimulus
`
`and/or
`
`Any clinical seizure focal or
`generalized that resolves rapidly or
`nonconvulsive seizures on EEG that
`resolve with intervention
`
`and/or
`
`Focal or local edema on neuroimaging
`Grade 4
`ICE scoreb: 0* (patient is unarousable
`and unable to perform ICE)
`
`and/or
`
`Stupor or coma
`
`and/or
`
`Life-threatening prolonged seizure
`(> 5 minutes) or repetitive clinical or
`
`
`
`Concurrent CRS
`
`Administer tocilizumab at any grade CRS, as
`per dosage recommendation in Table 1.
`Caution with repeated tocilizumab doses in
`patients with ICANS. Consider adding
`corticosteroids to tocilizumab past the first
`dose c.
`
`Administer tocilizumab at any grade CRS, as
`per dosage recommendation in Table 1. If
`refractory to tocilizumab past the first dose,
`administer dexamethasone 10 mg
`intravenously every 6-12 hours or
`methylprednisolone equivalent (1 mg/kg
`intravenously every 12 hours) until the event
`is Grade 1 or less, then taper corticosteroids.
`Administer tocilizumab at any grade CRS, as
`per dosage recommendation in Table 1.
`Administer dexamethasone 10 mg
`intravenously every 6-12 hours or
`methylprednisolone equivalent (1 mg/kg
`intravenously every 12 hours). Continue
`corticosteroids until the event is Grade 1 or
`less, then taper corticosteroids. If not
`improving, manage as Grade 4.
`
`Consider mechanical ventilation for airway
`protection.
`
`Administer high-dose methylprednisolone
`intravenously 1,000 mg one to two times per
`day for 3 days.
`
`If not improving, consider 1,000 mg of
`methylprednisolone two to three times per day
`or alternate therapyd.
`
`Administer tocilizumab at any grade CRS, as
`per dosage recommendation in Table 1.
`Administer methylprednisolone 1,000 mg
`intravenously one to two times per day for 3
`days.
`If not improving, consider methylprednisolone
`1,000 mg intravenously two to three times per
`day or alternate therapyd.
`
`UPenn Ex. 2079
`Miltenyi v. UPenn
`IPR2022-00855
`Page 7
`
`

`

`
`
`ICANS Gradea
`
`electrical seizures without return to
`baseline in between
`
`and/or
`
`Diffuse cerebral edema on
`neuroimaging, decerebrate or
`decorticate posturing or papilledema,
`cranial nerve VI palsy, or Cushing’s
`triad
`
`No concurrent CRS
`
`Concurrent CRS
`
`Continue corticosteroids until improvement to
`Grade 1, and then taper as clinically
`appropriate.
`
`Continue corticosteroids until improvement to
`Grade 1, and then taper as clinically
`appropriate.
`
`Treat seizures, status epilepticus, and cerebral
`edema as per institutional guidelines.
`
`Treat seizures, status epilepticus, and cerebral
`edema as per institutional guidelines.
`
`aASTCT criteria for grading NT (Lee et al. 2019); NCI CTCAE criteria for grading NT used in clinical trials.
`bICE Assessment Tool: (1) Orientation: orientation to year, month, city, and hospital: 4 points. (2) Naming: ability to name three objects (e.g., point to
`clock, pen, and button): 3 points. (3) Following commands: ability to follow simple commands (e.g., show me 2 fingers or close your eyes and stick out
`your tongue): 1 point. (4) Writing: ability to write a standard sentence (e.g., Our national bird is the bald eagle): 1 point. (5) Attention: ability to count
`backward from 100 by 10: 1 point.
`cSantomasso et. al. 2021.
`dAlternate therapy may include anakinra, siltuximab, ruxolitinib, cyclophosphamide, antithymocyte globulin, or intrathecal hydrocortisone (50 mg) plus
`methotrexate (12 mg).
`*A patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be
`classified as Grade 4 ICANS if unarousable.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Pediatric and Young Adult r/r B-cell ALL (up to 25 years of age): A single dose of KYMRIAH contains 0.2 to 5.0 x
`106 CAR-positive viable T cells per kg of body weight for patients 50 kg and below or 0.1 to 2.5 x 108 CAR-positive
`viable T cells for patients above 50 kg, suspended in one to three patient-specific infusion bag(s) [see How
`Supplied/Storage and Handling (16)].
`Adult r/r DLBCL and r/r FL: A single dose of KYMRIAH contains 0.6 to 6.0 x 108 CAR-positive viable T cells, which
`may be suspended in one to three patient-specific infusion bag(s) [see How Supplied/Storage and Handling (16)].
`See the CoA for actual cell count. The volume in the infusion bag ranges from 10 mL to 50 mL.
`
`CONTRAINDICATIONS
`
`4
`None.
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Cytokine Release Syndrome (CRS)
`5.1
`CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 61
`(77%) of the 79 pediatric and young adult patients with r/r ALL receiving KYMRIAH, including ≥ Grade 3 CRS (Penn
`grading system1) occurring in 48% of patients. The median times to onset and resolution of CRS were 3 days (range: 1-22;
`1 patient with onset after Day 10) and 8 days (range: 1-36), respectively. Of the 61 patients with CRS, 31 (51%) received
`tocilizumab. Ten (16%) patients received two doses of tocilizumab and 3 (5%) patients received three doses of
`tocilizumab; 17 (28%) patients received addition of corticosteroids (e.g., methylprednisolone).
`CRS occurred in 85 (74%) of the 115 adult patients with r/r DLBCL receiving KYMRIAH, including ≥ Grade 3 CRS
`(Penn grading system1) occurring in 23% of patients. The median times to onset and resolution of CRS were 3 days
`(range: 1-51; 1 patient with onset after Day 10) and 7 days (range: 2-30), respectively. Of the 85 patients with CRS, 19
`(22%) received systemic tocilizumab or corticosteroids. Seven (8%) patients received a single dose of tocilizumab and 11
`(13%) patients received two doses of tocilizumab; 11 (13%) patients received corticosteroids in addition to tocilizumab.
`One patient received corticosteroids for CRS without concomitant tocilizumab, and two patients received corticosteroids
`for persistent neurotoxicity after resolution of CRS.
`CRS occurred in 51 (53%) of the 97 adult patients with r/r FL receiving KYMRIAH; all were Grade 1 or 2 CRS (Lee
`grading system2). The median times to onset and resolution of CRS were 4 days (range: 1-14) and 4 days (range: 1-13),
`
`
`UPenn Ex. 2079
`Miltenyi v. UPenn
`IPR2022-00855
`Page 8
`
`

`

`
`respectively. Of the 51 patients with CRS, 15 (29%) received systemic anticytokine treatment with tocilizumab. Three
`(6%) patients required 3 dosages of tocilizumab, 4 (8%) patients required 2 dosages and 8 (16%) patients required single
`dose of tocilizumab. Two (4%) patients received corticosteroids in addition to tocilizumab.
`Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive
`leukemia, and one patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure
`when an intracranial hemorrhage occurred. Of the 3 r/r DLBCL patients who died within 30 days of infusion, all had CRS
`in the setting of stable to progressive underlying disease, one of whom developed bowel necrosis.
`Among patients with CRS, key manifestations include fever (93% in r/r ALL; 85% in r/r DLBCL; 92% in r/r FL),
`hypotension (69% in r/r ALL; 45% in r/r DLBCL; 40% in r/r FL), hypoxia (57% in r/r ALL; 35% in r/r DLBCL; 19% in
`r/r FL), and tachycardia (26% in r/r ALL; 13% in r/r DLBCL; 2% in r/r FL). CRS may be associated with hepatic, renal,
`and cardiac dysfunction, and coagulopathy.
`Delay the infusion of KYMRIAH after lymphodepleting chemotherapy if the patient has unresolved serious adverse
`reactions from preceding chemotherapies (including pulmonary toxicity, cardiac toxicity, or hypotension), active
`uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden [see Dosage and
`Administration (2.3)].
`Risk factors for severe CRS in the pediatric and young adult r/r B-cell ALL population are high pre-infusion tumor burden
`(greater than 50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting
`chemotherapy, active infections, and/or inflammatory processes.
`Ensure that a minimum of two doses of tocilizumab are available on site prior to infusion of KYMRIAH.
`Monitor patients 2-3 times during the first week following KYMRIAH infusion at the REMS-certified healthcare facility
`for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with
`KYMRIAH. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with
`supportive care, tocilizumab and/or corticosteroids as indicated [see Dosage and Administration (2.3, 2.4)].
`Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient
`Counseling Information (17)].
`5.2
`Neurological Toxicities
`Neurological toxicities, including severe or life-threatening reactions, occurred following treatment with KYMRIAH.
`Neurologic toxicities occurred in 56 (71%) of the 79 patients with r/r ALL, including ≥ Grade 3 in 22%. The median times
`to the first event and duration were 6 days from infusion (range: 1-301) and 7 days, respectively.
`Neurologic toxicities occurred in 69 (60%) of the 115 patients with r/r DLBCL, including ≥ Grade 3 in 19%. The median
`times to the first event and duration were 5 days (range: 1-368) and 17 days, respectively.
`Neurologic toxicities occurred in 42 (43%) of the 97 patients with r/r FL, including ≥ Grade 3 in 6%. T