Cytokine release syndrome (CRS)^1,2

CRS, including fatal or life-threatening reactions, occurred after ciltacabtagene autoleucel infusion

• Median time to onset of cytokine release syndrome (CRS): 7 days (range, 1-12 days)
• Median duration of CRS: 4 days (range, 1-40 days) with one patient extending out to 97 days
• Some patients required tocilizumab, corticosteroids, and/or anakinra for management of CRS
• Sixty-nine of 97 patients (71%) received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four patients (45%) received only tocilizumab; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids
• Ensure that a minimum of 2 doses of tocilizumab are available for each patient prior to CARVYKTI® (ciltacabtagene autoleucel) infusion and during recovery period, if needed for treatment of CRS
• In patients with early onset of fever (if onset less than 72 hours after infusion), tocilizumab should be considered
• At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids, depending on CRS grade (See Table 1 in Prescribing Information)
• Evaluation for hemophagocytic lymphohistiocytosis should be considered in patients with severe or unresponsive CRS

• The onset of ICANS occurred during CRS in 16 patients, before the onset of CRS in 3 patients, and after the CRS event in 3 patients
• Median time to first onset of ICANS: 8 days (range 1-28 days)
• Median duration of ICANS in all patients―including those with fatal ICANS, ICANS ongoing at time of death from other causes, or ongoing at last known alive date―was 7.5 days (range, 2-927 days)
• ICANS resolved in 17 of 22 patients (77%), and the median time to resolution was 6 days (range, 2-143 days)
• All 22 patients with ICANS had CRS
• Counsel patients to seek immediate medical attention should signs and symptoms of neurotoxicity occur after recovery from CRS and/or ICANS
• Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities

Parkinsonism

• Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS)
• Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs
• The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range 15-108) from infusion of ciltacabtagene autoleucel
• Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease, for the improvement or resolution of parkinsonism symptoms following CARVYKTI® treatment

Guillain-Barré syndrome (GBS)

• A fatal outcome following GBS has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances and polyradiculoneuritis
• Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS

Immune mediated myelitis

• Grade 3 myelitis has occurred 25 days following treatment with CARVYKTI® in another ongoing study. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immune globulin. Myelitis was ongoing at the time of death from other cause

Peripheral neuropathy

• Six patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor or sensorimotor neuropathies. Median time of onset of symptoms was 62 days (range 4-136 days), median duration of peripheral neuropathies was 256 days (range 2-465 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel
• Monitor patients for signs and symptoms of peripheral neuropathies

Cranial nerve palsies

• Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1. All three patients had 7^th cranial nerve palsy; one patient had 5^th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3^rd and 6^th cranial nerve palsy, bilateral 7^th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel
• Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms