Adverse Events & Safety | KYMRIAH® (tisagenlecleucel)

Safety Profile

A CONSISTENT SAFETY PROFILE THROUGH 24-MONTH FOLLOW-UP

Treatment with KYMRIAH^® (tisagenlecleucel) involves coordination of care with a KYMRIAH Treatment Center. After it is determined that your patient is eligible for and prescribed KYMRIAH, you and the treatment center will both contribute to your patient’s care, so ongoing communication is key. Following KYMRIAH infusion, routine long-term monitoring is required to treat potential KYMRIAH-associated side effects.

Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following infusion with KYMRIAH.^1,a With longer-term follow-up, no new adverse events were detected.² Key manifestations of CRS included fever, hypotension, hypoxia, tachycardia, and may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy.¹

Median time to first event, 3 days from infusion (range, 1-22; 1 patient with onset after Day 10) Median time to resolution, 8 days (range, 1-36)¹

Monitor patients 2 to 3 times during the first week and for at least 4 weeks following KYMRIAH infusion at the certified health care facility for signs and symptoms of CRS.¹

Ensure that at least 2 doses of tocilizumab are available on-site prior to infusion of KYMRIAH¹
Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time¹
Instruct patients to remain within proximity of the certified health care facility for at least 4 weeks following infusion¹
At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated¹

In the ELIANA trial: to manage CRS, 10 (16%) patients received 2 doses of tocilizumab and 3 (5%) patients received 3 doses of tocilizumab.¹

ALL, acute lymphoblastic leukemia; DLBCL, diffuse large B-cell lymphoma; USPI, United States Prescribing Information.

^aMedian follow-up from time of infusion¹.

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Neurological Events

After infusion with KYMRIAH, patients reported occurrence of neurological events (NEs). Onset of NEs can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. The majority of events occurred within 8 weeks of infusion. Most common NEs included: headache, encephalopathy, delirium, anxiety, sleep disorders, dizziness, tremor, peripheral neuropathy, seizures, mutism, aphasia.¹

Median time to first event, 6 days from infusion (range, 1-301).¹

^bMedian follow-up from time of infusion.¹

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

Selected Adverse Reactions (≥10%) Following Treatment (24-month follow-up)^1,c

Adverse Reaction	All Grades, (%)	Grades 3 or Higher, (%)
	(N=79)¹	(N=79)¹
Blood and lymphatic system disorders
Febrile neutropenia	34	34
Cardiac disorders
Tachycardia^d	24	4
Gastrointestinal disorders
Vomiting	32	1
Diarrhea	29	1
Nausea	27	3
Abdominal pain^e	18	3
Constipation	18	0
General disorders and administration site conditions
Fever	42	13
Pain^f	25	3
Fatigue^g	23	0
Edema^h	23	8
Immune system disorders
Cytokine release syndrome	77	48
Hypogammaglobulinemiaⁱ	53	13
Infections and infestations
Infections–pathogen unspecified	57	27
Viral infectious disorders	37	22
Bacterial infectious disorders	29	16
Fungal infectious disorders	15	9
Metabolism and nutrition disorders
Decreased appetite	38	15
Hypocalcemia	20	6
Hyperferritinemia^j	10	3
Musculoskeletal and connective tissue disorders
Musculoskeletal pain^k	32	4
Arthralgia	14	1
Nervous system disorders
Headache^l	35	3
Encephalopathy^m	30	9
Psychiatric disorders
Deliriumⁿ	19	4
Anxiety	17	3
Sleep disorder^o	11	0
Renal and urinary disorders
Acute kidney injury^p	22	14
Respiratory, thoracic, and mediastinal disorders
Cough^q	27	0
Hypoxia	25	20
Dyspnea^r	19	14
Pulmonary edema	15	9
Nasal congestion	11	0
Oropharyngeal pain	10	0
Pleural effusion	10	4
Tachypnea	10	5
Skin and subcutaneous tissue disorders
Rash^s	18	1
Vascular disorders
Hemorrhage^t	32	10
Hypotension	29	20
Hypertension	19	5

^cTable includes only nonlaboratory terms as reported in the Prescribing Information.

^dTachycardia includes sinus tachycardia and tachycardia.
^eAbdominal pain includes abdominal pain, abdominal pain upper.
^fPain includes pain and pain in extremity.
^gFatigue includes fatigue and malaise.
^hEdema includes face edema, fluid overload, generalized edema, localized edema, edema peripheral.
ⁱHypogammaglobulinemia includes hypogammaglobulinemia, immunoglobulins decreased, blood immunoglobulin G decreased, blood immunoglobulin A decreased, blood immunoglobulin M decreased, immunodeficiency, immunodeficiency common variable.
^jHyperferritinemia includes serum ferritin increased.
^kMusculoskeletal pain includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and non-cardiac chest pain.
^lHeadache includes headache and migraine.
^mEncephalopathy includes encephalopathy, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, and automatism. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms.
ⁿDelirium includes delirium, agitation, hallucination, hallucination visual, irritability, restlessness.
^oSleep disorder includes sleep disorder, insomnia, and nightmare.
^pAcute kidney injury includes acute kidney injury, anuria, azotemia, renal failure, qenal tubular dysfunction, renal tubular necrosis, and blood creatinine increased.
^qCough includes cough and productive cough.
^rDyspnea includes acute respiratory failure, dyspnea, respiratory distress, and respiratory failure.
^sRash includes dermatitis, rash, rash maculo-papular, rash papular, and rash pruritic.
^tHemorrhage includes anal hemorrhage, catheter site hemorrhage, cerebral hemorrhage, conjunctival hemorrhage, contusion, cystitis hemorrhagic, disseminated intravascular coagulation, epistaxis, gastrointestinal hemorrhage, gingival bleeding, hemarthrosis, hematemesis, hematuria, hemoptysis, heavy menstrual bleeding, melena, mouth hemorrhage, peritoneal hematoma, petechiae, pharyngeal hemorrhage, purpura, retinal hemorrhage, vaginal hemorrhage.

Select each adverse reaction listed below to view more information.

Cytokine Release Syndrome

CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 61 (77%) of the 79 patients with relapsed or refractory (r/r) ALL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 48% of patients. The median times to onset and resolution of CRS for patients with r/r ALL 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 r/r ALL who had CRS, 31 (51%) received tocilizumab; 10 (16%) patients received 2 doses of tocilizumab, 3 (5%) patients received 3 doses of tocilizumab, and 17 (28%) patients received addition of corticosteroids (eg, methylprednisolone).

Two deaths occurred in patients with r/r ALL within 30 days of KYMRIAH infusion. One patient died with CRS and progressive leukemia, and 1 patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Among patients with r/r ALL who had CRS, key manifestations included fever (93%), hypotension (69%), hypoxia (57%), and tachycardia (26%). CRS may be associated with hepatic, renal, and cardiac dysfunction; and coagulopathy.

Delay KYMRIAH infusion after lymphodepleting chemotherapy if patient has unresolved serious adverse reactions from preceding chemotherapies including pulmonary toxicity, cardiac toxicity, or hypotension, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden.

Risk factors for severe CRS are high pre-infusion tumor burden (>50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes.

Ensure that a minimum of 2 doses of tocilizumab are available on-site prior to infusion of KYMRIAH. Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care 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.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurological Toxicities

KYMRIAH REMS to Mitigate CRS and Neurological Toxicities

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

Hypersensitivity Reactions

Serious Infections

Prolonged Cytopenias

Hypogammaglobulinemia

Secondary Malignancies

Effects on Ability to Drive and Use Machines

Drug Interactions

Pregnancy, Lactation, Females and Males of Reproductive Potential

Adverse Reactions

The above listing does not include all potential side effects of KYMRIAH. Please be vigilant in monitoring all patients administered KYMRIAH for adverse reactions, and manage accordingly.

Cytokine Release Syndrome Treatment Algorithm

CRS is managed clinically according to the following algorithm.¹

CRS Grade⁶	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 one vasopressor or grade 2 organ toxicity	Antipyretics, oxygen, intravenous fluids and/or low dose vasopressors as needed.	Administer tocilizumab^u 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.^v	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.^v	Administer methylprednisolone 1000 mg intravenously one to two times per day for 3 days If not improving, consider methylprednisolone 1000 mg intravenously two to three times a day or alternate therapy.^v Continue corticosteroids until improvement to grade 1, and then taper as clinically appropriate.

^uRefer to tocilizumab Prescribing Information for details.¹

^vAlternative 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 anti-thymocyte globulin.¹

For information about the Treatment Process, continue to the next page

Safety Profile

Cytokine Release Syndrome

Neurological Toxicities

KYMRIAH REMS to Mitigate CRS and Neurological Toxicities

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

Hypersensitivity Reactions

Serious Infections

Prolonged Cytopenias

Hypogammaglobulinemia

Secondary Malignancies

Effects on Ability to Drive and Use Machines

Drug Interactions

Pregnancy, Lactation, Females and Males of Reproductive Potential

Adverse Reactions

Important Safety Information for KYMRIAH^® (tisagenlecleucel)

Indication