Safety Profile
A CONSISTENT SAFETY PROFILE THROUGH 24-MONTH FOLLOW-UP
Treatment with KYMRIAH® (tisagenlecleucel) involves coordination of care with a certified 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, and 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 daily during the first week and for at least 2 weeks following KYMRIAH infusion for signs and symptoms of CRS.1
Confirm 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 a health care facility for at least 2 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 |
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Adverse Reactions
Adverse Reactions in ≥ 10% of Pediatric and Young Adults Patients With r/r B-cell ALL
Adverse Reaction | All Grades (%) | Grade 3 or Higher (%) |
(N=79)1 | (N=79)1 | |
Blood and lymphatic system disorders | ||
Febrile neutropenia | 34 | 34 |
| Cardiac disorders | ||
| Tachycardiaa | 24 | 4 |
| Gastrointestinal disorders | ||
| Vomiting | 32 | 1 |
| Diarrhea | 29 | 1 |
| Nausea | 27 | 3 |
| Abdominal paina | 18 | 3 |
| Constipation | 18 | 0 |
| General disorders and administration site conditions | ||
| Fever | 42 | 13 |
| Paina | 25 | 3 |
| Fatiguea | 23 | 0 |
| Edemaa | 23 | 8 |
| Immune system disorders | ||
| Cytokine release syndrome | 77 | 48 |
| Hypogammaglobulinemiaa | 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 |
| Hyperferritinemiaa | 10 | 3 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal paina | 32 | 4 |
| Arthralgia | 14 | 1 |
| Nervous system disorders | ||
| Headachea | 35 | 3 |
| Encephalopathyb | 30 | 9 |
| Psychiatric disorders | ||
| Deliriuma | 19 | 4 |
| Anxiety | 17 | 3 |
| Sleep disordera | 11 | 0 |
| Renal and urinary disorders | ||
| Acute kidney injurya | 22 | 14 |
| Respiratory, thoracic, and mediastinal disorders | ||
| Cougha | 27 | 0 |
| Hypoxia | 25 | 20 |
| Dyspneac | 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 | ||
| Rasha | 18 | 1 |
| Vascular disorders | ||
| Hemorrhagea | 32 | 10 |
| Hypotension | 29 | 20 |
| Hypertension | 19 | 5 |
aIncludes multiple related composite terms.
bEncephalopathy 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.
cDyspnea includes acute respiratory failure, dyspnea, respiratory distress, and respiratory failure.
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 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.
Confirm that a minimum of 2 doses of tocilizumab are available on-site prior to infusion of KYMRIAH. Monitor patients daily during the first week following KYMRIAH infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 2 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.
The above listing does not include all potential side effects of KYMRIAH. Please be vigilant in monitoring for adverse reactions in all patients administered KYMRIAH, and manage accordingly.
CRS Treatment Algorithm
CRS is managed clinically according to the following algorithm.1
CRS Grade6 | Symptomatic treatment | Tocilizumab | Corticosteroids |
|---|---|---|---|
Grade 1 | 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 | Antipyretics, oxygen, intravenous fluids and/or low dose vasopressors as needed. | Administer tocilizumabd intravenously over 1 hour:
If no improvement after first dose, repeat every 8 hours (limit to a maximum of 3 doses in a 24-hour 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. |
Grade 3 | High-flow oxygen, intravenous fluids, and high-dose or multiple vasopressors. Treat other organ toxicities as per local guidelines | Per grade 2 | Per grade 2 |
Grade 4
| Mechanical ventilation, intravenous fluids and high-dose vasopressor(s). Treat other organ toxicities as per local guidelines | Per grade 2 | Administer methylprednisolone 1000 mg intravenously 1 to 2 times per day for 3 days |
dRefer to tocilizumab Prescribing Information for details.1
eAlternative therapy includes anticytokine and anti-T cell therapies, such as (but not limited to) anakinra, siltuximab, ruxolitinib, cyclophosphamide, intravenous immunoglobulin, and anti-thymocyte globulin, as per institutional policy and published guidelines.1