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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

CARVYKTI® (ciltacabtagene autoleucel)

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CARVYKTI - Management of Severe Adverse Reactions

Last Updated: 08/20/2024

SUMMARY

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI. Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Consider laboratory testing to monitor for disseminated intravascular coagulation, hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function.¹
- If CRS is suspected, manage according to the recommendations in Table: CRS Grading and Management Guidance.¹
Neurologic toxicities, which may be severe, life-threatening, or fatal, occurred following treatment with CARVYKTI. Monitor patients for signs and symptoms of neurologic toxicities (immune effector cell associated neurotoxicity syndrome [ICANS] and other neurologic toxicities). Rule out other causes neurologic signs or symptoms. Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities.¹
- If ICANS is suspected, manage according to the recommendations in Table: Guideline for Management of ICANS.¹

PRODUCT LABELING

Cytokine Release Syndrome

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Consider laboratory testing to monitor for disseminated intravascular coagulation, hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. If CRS is suspected, manage according to the recommendations in Table: CRS Grading and Management Guidance.¹
Patients who experience CRS should be closely monitored for cardiac and other organ function until resolution of symptoms. Consider anti-seizure prophylaxis with levetiracetam in patients who experience CRS.¹
Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous telemetry and pulse oximetry.¹
For severe or life-threatening CRS, consider intensive care unit level monitoring and supportive therapy.¹
For CRS refractory to first line interventions such as tocilizumab or tocilizumab and corticosteroids, consider alternate treatment options (i.e., higher corticosteroid dose, alternative anti-cytokine agents, e.g., anti-interleukin [IL]1 and/or anti-tumor necrosis factor [TNF]α, anti-T cell therapies].¹
- Refractory CRS is characterized by fevers, end-organ toxicity (e.g., hypoxia, hypotension) not improving within 12 hours of first line interventions or development of hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (HLH/MAS).¹
If concurrent neurologic toxicity is suspected during CRS, administer¹:
- Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables: CRS Grading and Management Guidance and Guideline for Management of ICANS.
- Tocilizumab according to the CRS grade in Table: CRS Grading and Management Guidance.
- Anti-seizure medication according to the neurologic toxicity in Table: Guideline for Management of ICANS.

Neurologic Toxicities

Monitor patients for signs and symptoms of neurologic toxicities (ICANS and other neurologic toxicities). Rule out other causes of neurologic signs or symptoms. Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities.¹
If ICANS is suspected, manage according to the recommendations in Table: Guideline for Management of ICANS ¹
If concurrent CRS is suspected during the neurologic toxicity event, administer¹:
- Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables: CRS Grading and Management Guidance and Guideline for Management of ICANS.
- Tocilizumab according to CRS grade in Table: CRS Grading and Management Guidance.
- Anti-seizure medication according to neurologic toxicity in Table: Guideline for Management of ICANS.

CRS Grading and Management Guidance¹

CRS Grade^a	Tocilizumab^b/Corticosteroids^f
Grade 1 Temperature ≥38°C	In patients with: Early onset of fever (if onset less than 72 hours after infusion) Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg) may be considered. Corticosteroids: N/A
Grade 2 Symptoms require and respond to moderate intervention. Temperature ≥38°C^c with: Hypotension not requiring vasopressors, and/or, Hypoxia requiring oxygen via canula^e or blow-by, or, Grade 2 organ toxicity.^g	Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids up to 1 liter or increasing supplemental oxygen. Consider dexamethasone 10 mg IV every 12-24 hours. If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg IV every 12 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents.^d Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.
Grade 3 Symptoms require and respond to aggressive intervention. Temperature ≥38°C^c with: Hypotension requiring one vasopressor with or without vasopressin, and/or, Hypoxia requiring oxygen via high-flow nasal canula^e, facemask, non-rebreather mask, or Venturi mask, or, Grade 3 organ toxicity or Grade 4 transaminitis.	Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids up to 1 liter or increasing supplemental oxygen. Consider dexamethasone 10 mg IV every 12 hours.
	If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg IV every 12 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents.^d Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.
Grade 4 Life-threatening symptoms. Requirements for ventilator support, CVVHD. Temperature ≥38°C^c with: Hypotension requiring multiple vasopressors (excluding vasopressin), and/or, Hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation), or, Grade 4 organ toxicity (excluding transaminitis).	Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids up to 1 liter or increasing supplemental oxygen. Administer dexamethasone 20 mg IV every 6 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents^d. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. If no improvement within 24 hours, consider methylprednisolone (1-2 g IV, repeat every 24 hours if needed; taper as clinically indicated) or other immunosuppressants (e.g. other anti-T cell therapies).
Abbreviations: ASTCT, American Society for Transplantation and Cellular Therapy; BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; CRS, cytokine release syndrome; CVVHD, continuous veno-venous hemodialysis; IV, intravenously; kg, kilogram; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events. ^aBased on ASTCT 2019 grading system (Lee et.al, 2019), modified to include organ toxicity. ^bRefer to tocilizumab prescribing information for details. ^cAttributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia, as it may be masked by interventions such as antipyretics or anti-cytokine therapy (e.g., tocilizumab or steroids). Absence of fever does not impact CRS management decision. In this case, CRS management is driven by hypotension and/or hypoxia and by the more severe symptom not attributable to any other cause. ^dMonoclonal antibodies targeting cytokines may be considered based on institutional practice for unresponsive CRS. ^eLow-flow nasal cannula is ≤6 L/min; high-flow nasal cannula is >6 L/min. ^fContinue corticosteroids use until the event is Grade 1 or less; taper steroids if total corticosteroid exposure is greater than 3 days. ^gOrgan toxicity grading based on NCI CTCAE version 5.0.

Guideline for Management of ICANS¹

ICANS Grade^a	Corticosteroids
Grade 1 ICE score 7-9^b or depressed level of consciousness: awakens spontaneously.	Consider dexamethasone^c 10 mg IV every 12 to 24 hours for 2 to 3 days. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 2 ICE score-3-6^b or depressed level of consciousness: awakens to voice	Administer dexamethasone^c 10 mg IV every 12 hours for 2-3 days, or longer for persistent symptoms. Consider steroid taper if total corticosteroid exposure is greater than 3 days. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 3 ICE score-0-2^b (If ICE score is 0, but the patient is arousable (e.g., awake with global aphasia) and able to perform assessment) or depressed level of consciousness: awakens only to tactile stimulus, or seizures, either: any clinical seizure, focal or generalized, that resolves rapidly, or non-convulsive seizures on EEG that resolve with intervention, or raised ICP: focal/local edema on neuroimaging^d.	Administer dexamethasone^c 10 mg-20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate dexamethasone^c dose to at least 20 mg IV every 6 hours, OR escalate to high-dose methylprednisolone (1-2 g/day, repeat every 24 hours if needed; taper as clinically indicated) Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated).
Grade 4 ICE score-0^b (Patient is unarousable and unable to perform ICE assessment) or depressed level of consciousness either: patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or stupor or coma, or seizures, either: life-threatening prolonged seizure (>5 min), or repetitive clinical or electrical seizures without return to baseline in between, or motor findings^e: deep focal motor weakness such as hemiparesis or paraparesis, or raised ICP/cerebral edema, with signs/symptoms such as: diffuse cerebral edema on neuroimaging, or decerebrate or decorticate posturing, or cranial nerve VI palsy, or papilledema, or Cushing’s triad	Administer dexamethasone^c 20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (12 g/day, repeated every 24 hours if needed; taper as clinically indicated). Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. If raised ICP/cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g/day, repeat every 24 hours if needed; taper as clinically indicated), and consider neurology and/or neurosurgery consultation.
Abbreviations: ASTCT, American Society for Transplantation and Cellular Therapy; ICANS, immune effector cell associate neurotoxicity; ICE, Immune Effector Cell-Associated Encephalopathy; ICP, intracranial pressure; IV, intravenously; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events. Note: ICANS grade and management is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema), not attributable to any other cause. ^aASTCT 2019 criteria for grading Neurologic Toxicity (Lee et.al, 2019). ^bIf patient is arousable and able to perform ICE Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points. ^cAll references to dexamethasone administration are dexamethasone or equivalent. ^dIntracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may be graded according to NCI CTCAE v5.0. ^eTremors and myoclonus associated with immune effector cell therapies may be graded according to NCI CTCAE v5.0, but they do not influence ICANS grading.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 19 August 2024.

References

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1	CARVYKTI (ciltacabtagene autoleucel) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.;https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf.