Safety Profile
A CONSISTENT SAFETY PROFILE THROUGH 32.6-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.1,2,a,b With long-term follow-up, no new adverse events were detected.3 Key manifestations of CRS were fever, hypotension, hypoxia, tachycardia that may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy.1
Median time to onset, 3 days from infusion (range, 1-51); Median time to resolution, 7 days (range, 2-30)1,b
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 a minimum of 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
aThe reported rates of CRS vary between the 32.6-month analysis and the USPI due to differences in the criteria and clinical manifestations by which they are defined.
b1 Of the 85 patients with r/r DLBCL who had CRS, 19 (22%) received systemic tocilizumab or corticosteroids. Seven (8%) patients received a single dose of tocilizumab and 11 (13%) patients received 2 doses of tocilizumab.1
cMedian follow-up from time of infusion.
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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.1,2 Key manifestations of NEs were: headache, encephalopathy, delirium, anxiety, sleep disorders, dizziness, tremor, peripheral neuropathy, seizures, and aphasia.
Median time to first event, 5 days from infusion (range, 1-368); Median duration, 17 days1
dPatients with events starting ≤8 weeks after infusion (N=23 patients).2
eThere were no deaths attributed to NEs, including no fatal cases of cerebral edema.2,3
fMedian follow-up from time of infusion.
gAmong patients who had a neurological toxicity, 84% occurred within 8 weeks following KYMRIAH infusion.1
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Warnings and Precautions
WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGICAL TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES |
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Select each adverse reaction listed below to view more information.
CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 85 (74%) of the 115 patients with r/r DLBCL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 23% of patients with r/r DLBCL. In KYMRIAH clinical trials, the median times to onset and resolution 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 r/r DLBCL who had CRS, 19 (22%) received systemic tocilizumab or corticosteroids. Seven (8%) received a single dose of tocilizumab, 11 (13%) received 2 doses of tocilizumab, and 11 (13%) received corticosteroids in addition to tocilizumab. One patient with r/r DLBCL received corticosteroids for CRS without concomitant tocilizumab, and 2 patients received corticosteroids for persistent neurotoxicity after resolution of CRS.
Three deaths occurred in patients with r/r DLBCL within 30 days of KYMRIAH infusion. Of these 3 patients, all had a history of CRS in the setting of stable to progressive underlying disease, 1 of whom developed bowel necrosis. Among patients with r/r DLBCL who had CRS, key manifestations included fever (85%), hypotension (45%), hypoxia (35%), and tachycardia (13%). 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, active uncontrolled infection, or active graft vs host disease.
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.
Adverse Reactions
THE SAFETY PROFILE OF KYMRIAH REMAINS CONSISTENT AFTER 26 MONTHS OF FOLLOW-UP
In the JULIET trial, 115 adults with r/r DLBCL received a single intravenous dose of KYMRIAH by 26 months of follow-up. The most common adverse reactions (>20%) were cytokine release syndrome, infections-pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema, bleeding episodes, dyspnea, and headache.1
| Adverse Reaction | All Grades (%) | Grades 3 or Higher (%) |
|---|---|---|
| (N=115)1 | (N=115)1 | |
Blood and lymphatic system disorders | ||
Febrile neutropenia | 17 | 17 |
Cardiac disorders | ||
Tachycardiah | 13 | 3 |
Arrhythmiai | 10 | 5 |
Gastrointestinal disorders | ||
Diarrhea | 31 | 1 |
Nausea | 29 | 1 |
Constipation | 17 | 1 |
Abdominal painj | 10 | 2 |
General disorders and administration site conditions | ||
Fever | 35 | 5 |
Fatiguek | 27 | 6 |
Edemal | 27 | 3 |
Painm | 14 | 3 |
Chills | 12 | 0 |
Immune system disorders | ||
Cytokine release syndrome | 74 | 23 |
Hypogammaglobulinemian | 17 | 6 |
Infections and infestations | ||
Infections–pathogen unspecified | 48 | 26 |
Bacterial infectious disorders | 17 | 8 |
Fungal infectious disorders | 11 | 5 |
Viral infectious disorders | 11 | 2 |
Investigations | ||
Weight decreased | 12 | 4 |
Metabolism and nutrition disorders | ||
Decreased appetite | 14 | 4 |
Musculoskeletal and connective tissue disorders | ||
Arthralgia | 14 | 0 |
Musculoskeletal paino | 13 | 1 |
Nervous system disorders | ||
Headachep | 21 | 1 |
Encephalopathyq | 16 | 11 |
Peripheral neuropathyr | 12 | 3 |
Dizzinesss | 12 | 2 |
Psychiatric disorders | ||
Anxiety | 10 | 1 |
Sleep disordert | 10 | 0 |
Renal and urinary disorders | ||
Acute kidney injuryu | 17 | 6 |
Respiratory, thoracic, and mediastinal disorders | ||
Dyspneav | 21 | 6 |
Coughw | 17 | 0 |
Skin and subcutaneous tissues disorders | ||
Rashx | 11 | 0 |
Vascular disorders | ||
Hypotensiony | 25 | 9 |
Hemorrhagez | 22 | 8 |
hTachycardia includes sinus tachycardia and tachycardia.
iArrhythmia includes atrial fibrillation, cardiac arrest, supraventricular tachycardia and ventricular extrasystoles.
jAbdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain upper.
kFatigue includes fatigue and malaise.
lEdema includes face edema, fluid overload, fluid retention, generalized edema, localized edema, edema peripheral, peripheral swelling.
mPain includes pain and pain in extremity.
nHypogammaglobulinemia includes blood immunoglobulin G decreased, immunodeficiency, immunoglobulins decreased and hypogammaglobulinemia.
oMusculoskeletal pain includes back pain, flank pain, musculoskeletal chest pain, neck pain, and non-cardiac chest pain.
pHeadache includes headache and migraine.
qEncephalopathy includes cognitive disorder, confusional state, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, metabolic encephalopathy, and thinking abnormal. Encephalopathy is a dominant feature of immune effector cell-associated neurotoxicity syndrome (ICANS), along with other symptoms.
rPeripheral neuropathy includes paresthesia, hypoesthesia, hyperesthesia, peripheral sensory neuropathy, neuropathy peripheral, cranial nerve paralysis, demyelinating polyneuropathy, Horner’s syndrome, polyneuropathy, and sciatica.
sDizziness includes dizziness, presyncope, and syncope.
tSleep disorder includes insomnia and sleep disorder.
uAcute kidney injury includes acute kidney injury, blood creatinine abnormal, and blood creatinine increased.
vDyspnea includes dyspnea, dyspnea exertional, respiratory distress, and respiratory failure.
wCough includes cough, productive cough, and upper-airway cough syndrome.
xRash includes dermatitis, dermatitis acneiform, dermatitis contact, rash, rash maculo-papular, rash papular, and rash pruritic.
yHypotension includes hypotension and orthostatic hypotension.
zHemorrhage includes anal hemorrhage, blood urine present, cerebral hemorrhage, contusion, cystitis hemorrhagic, disseminated intravascular coagulation, duodenal ulcer hemorrhage, epistaxis, eye contusion, gastrointestinal hemorrhage, hematemesis, hematochezia, hematuria, large intestinal hemorrhage, melena, mouth hemorrhage, petechiae, pharyngeal hemorrhage, post procedural hemorrhage, pulmonary hemorrhage, purpura, retinal hemorrhage, traumatic hematoma, tumor hemorrhage, upper gastrointestinal hemorrhage.
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 Grade4 | Symptomatic treatment | Tocilizumab | Corticosteroids |
|---|---|---|---|
Grade 1 | 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 CRS5 | Not applicable. |
Grade 2 | Antipyretics, oxygen, intravenous fluids and/or low dose vasopressors as needed | Administer tocilizumabaa intravenously over 1 hour:
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 | 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.bb | Per grade 2 If not improving, manage as grade 4. |
Grade 4 | 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.bb | 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 therapybb Continue corticosteroids until |
aaRefer to tocilizumab Prescribing Information for details.
bbAlternative 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.