FL Safety Profile | KYMRIAH® (tisagenlecleucel)

Safety Profile

Cytokine Release Syndrome

Key manifestations of CRS¹
May include:

Fever
Hypotension
Hypoxia
Tachycardia

May be associated with:

Hepatic, renal, and cardiac dysfunction
Coagulopathy
Nearly all CRS events observed in the ELARA study occurred within the first 8 weeks post-infusion⁴
Ensure that at least 2 doses of tocilizumab are available on site prior to infusion of KYMRIAH¹
- Of the 51 patients who had CRS, 15 (29%) received systemic tocilizumab, and 2 (4%) received corticosteroids in addition to tocilizumab
CRS management in ELARA allowed for the use of tocilizumab and corticosteroids as early as grade 2^1,5
- In ELARA, all CRS events resolved with appropriate management^4,6
Monitor patients daily during the first week and for at least 2 weeks following KYMRIAH infusion for signs and symptoms of CRS. Instruct patients to remain within proximity of a health care facility for at least 2 weeks following infusion¹

Neurological Events

RATES OF NEs IN ELARA WERE MAINLY GRADE 1 OR 2^1,2

Key manifestations of NEs may include¹:

Headache
Encephalopathy
Delirium
Anxiety
Sleep disorders
Dizziness
Tremor
Peripheral neuropathy
Seizures
Aphasia
The most common NE observed with KYMRIAH was headache (25%)¹
Onset of NEs can be concurrent with CRS, following resolution of CRS, or in the absence of CRS¹
Majority of NEs required no specific protocol-defined intervention other than supportive care⁴
- All NEs resolved with appropriate management⁶
- There were no fatalities attributed to NEs²

The reported rates of NEs vary between the ASH 2024 analysis and the USPI due to differences in the criteria and clinical manifestations by which they are defined.

The 53-month analysis (ASH 2024) reported the data only for serious NEs, rather than all NEs. These NEs included: encephalopathy, dyskinesia, muscular weakness, and tremor but excluded headache.²

NE, neurological event.

Warnings and Precautions

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGICAL TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES

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
Neurological toxicities, including severe or life-threatening reactions, occurred following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care and/or corticosteroids as needed
T cell malignancies have occurred following treatment of hematological malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including KYMRIAH

Adverse Reactions

The most common adverse reactions (incidence ≥20%) in ELARA were CRS, infections-pathogens unspecified, fatigue, musculoskeletal pain, headache, and diarrhea.

Selected adverse reactions anytime after infusion reported in ≥10% following treatment with KYMRIAH in adult patients with r/r FL in the 21-month analysis from the USPI^1,3

Adverse reactions		All grades, %	Grade ≥3
Blood and lymphatic disorders	Febrile neutropenia	13	13
Gastrointestinal disorders	Diarrhea	24	2
	Nausea	16	2
	Constipation	16	0
	Abdominal pain^a	10	1
General disorders and administration site conditions	Fatigue^a	27	3
General disorders and administration site conditions	Fever	19	1
Immune system disorders	Cytokine release syndrome	53	0
Immune system disorders	Hypogammaglobulinemia^a	18	1
Infections and infestations	Infections - pathogen unspecified	38	12
Infections and infestations	Viral infectious disorders^b	18	5
Musculoskeletal and connective tissue disorders	Musculoskeletal pain^a	25	1
Musculoskeletal and connective tissue disorders	Arthralgia	10	0
Nervous system disorders	Headache^a	25	2
Respiratory, thoracic, and mediastinal disorders	Cough^a	19	0
Skin and subcutaneous tissue disorders	Rash^a	10	0

^aIncludes multiple related composite terms.
^bIncludes 1 case of progressive multifocal leukoencephalopathy due to John Cunningham virus reactivation.

CRS Treatment Algorithm

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the treatment algorithm below. Alternative CRS management strategies may be implemented based on appropriate institutional or academic guidelines.¹

CRS Grade⁵	Symptomatic treatment	Tocilizumab	Corticosteroids
Grade 1 Mild symptoms requiring symptomatic treatment only (eg, low-grade fever, fatigue, anorexia, etc.)	Exclude other causes (eg, infection) and treat specific symptoms (eg, with antipyretics, antiemetics, analgesics, etc.)	In patients with persistent (>3 days) or refractory fever, consider managing as grade 2 CRS⁷	Not applicable
Grade 2 Symptoms require and respond to moderate intervention: oxygen requirement <40%, or hypotension responsive to fluids, or low dose of 1 vasopressor, or grade 2 organ toxicity	Antipyretics, oxygen, intravenous fluids and/or low-dose vasopressors as needed	Administer tocilizumabⁱ 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 doses in 24 hours; maximum total of 4 doses).	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.
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	High-flow oxygen, intravenous fluids, and high-dose or multiple vasopressors; treat other organ toxicities as per local guidelines	Per grade 2 If not improving, consider alternative therapy.^j	Per grade 2 If not improving, manage as grade 4.
Grade 4 Life-threatening symptoms requirement for ventilator support or grade 4 organ toxicity (excluding transaminitis)	Mechanical ventilation, intravenous fluids, and high-dose vasopressor(s); treat other organ toxicities as per local guidelines	Per grade 2 If not improving, consider alternative therapy.^j	Administer methylprednisolone 1000 mg intravenously 1 to 2 times per day for 3 days. If not improving, consider methylprednisolone 1000 mg intravenously 2 to 3 times a day or alternate therapy.^j Continue corticosteroids until improvement to grade 1, and then taper as clinically appropriate.

ⁱRefer to tocilizumab Prescribing Information for details.
^jAlternative therapy includes anticytokine and anti-T cell therapies as per institutional policy and published guidelines, such as (but not limited to) anakinra, siltuximab, ruxolitinib, cyclophosphamide, intravenous immunoglobulin, and antithymocyte globulin.

For more information about the treatment process, continue to the next page

Safety Profile

Important Safety Information for KYMRIAH^® (tisagenlecleucel)

Indication