FL Safety Profile | KYMRIAH® (tisagenlecleucel)

Safety Profile

Cytokine Release Syndrome

KYMRIAH DEMONSTRATED NO GRADE ≥3 CRS IN ELARA^1,2

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 2 to 3 times during the first week and for at least 4 weeks following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of CRS. Instruct patients to remain within proximity of the certified health care facility for at least 4 weeks following infusion¹

^aRefers to first CRS episode only.²

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
The majority of the KYMRIAH-related 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 29-month analysis (ASH 2022) reported serious neurological adverse events, which included ICANS, encephalopathy, dyskinesia, muscular weakness, and tremor, but excluded headaches.²

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, 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
T cell malignancies have occurred following treatment of hematological malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including KYMRIAH
KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS

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^b	10	1
General disorders and administration site conditions	Fatigue^c	27	3
General disorders and administration site conditions	Fever	19	1
Immune system disorders	Cytokine release syndrome	53	0
Immune system disorders	Hypogammaglobulinemia^d	18	1
Infections and infestations	Infections - pathogen unspecified	38	12
Infections and infestations	Viral infectious disorders	18	5
Musculoskeletal and connective tissue disorders	Musculoskeletal pain^e	25	1
Musculoskeletal and connective tissue disorders	Arthralgia	10	0
Nervous system disorders	Headache^f	25	2
Respiratory, thoracic, and mediastinal disorders	Cough^g	19	0
Skin and subcutaneous tissue disorders	Rash^h	10	0

^bAbdominal pain included abdominal pain and abdominal pain upper.
^cFatigue included asthenia, fatigue, and malaise.
^dHypogammaglobulinemia included blood immunoglobulin G decreased and hypogammaglobulinemia.
^eMusculoskeletal pain included back pain, bone pain, flank pain, muscle discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and non-cardiac chest pain.
^fHeadache included headache and migraine.
^gCough included cough and productive cough.
^hRash included rash, rash maculo-papular, and rash papular.

Cytokine Release Syndrome 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 (e.g., low grade fever, fatigue, anorexia, etc.)	Exclude other causes (e.g., infection) and treat specific symptoms (e.g., 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 one 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 dosages in 24 hours period; 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 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 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 anti-cytokine 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