CAR T Safety and Management

Clinical Trials

Well-characterized and manageable safety profile^1-8

Toxicities are managed per established guidance^9,10*

The safety profile of CAR T therapies is well characterized, with no new unexpected serious adverse events or neurologic toxicities found in long-term follow-ups^1,2,11
- After CAR T therapy, most delayed hematological toxicities improved a few months after treatment¹²
Primary toxicities associated with CAR T therapy include CRS and neurologic toxicities⁹
- CRS is considered an “on-target” side effect of CAR T therapy¹³
- Often, CRS and neurologic toxicities were low, Grade 1 or 2. However, severe reactions have occurred in some patients receiving CAR T^1,2,14
- Most CRS and neurologic toxicities occur within the first few weeks and are treated at the CAR T treatment center. Patients are monitored for any signs or symptoms for at least 4 weeks after infusion as delayed AEs may occur^9,15,16
Other common adverse events associated with CAR T include neutropenia, thrombocytopenia, anemia, and LFT elevations^12,17

The management of therapy-related toxicities has evolved with processes and strategies in place to address potential adverse events that may arise.^18,19

Safety PROFILE OF CAR T THERAPY IN CLINICAL TRIALS^†

Any grade	LBCL²⁰	FL^7,21	ALL²	MM^22,23
CRS	78%	49-78%	82%	76%
Neurotoxicity	41%	37-56%	29%	10.5%
Grade ≥3	LBCL^1,20	FL^7,21	ALL²	MM²²
CRS	6-18%	0-6%	26%	11%
Neurotoxicity	16-19%	3-15%	12%	8%

	Any grade
	CRS	Neurotoxicity
LBCL²⁰	78%	41%
FL^7,21	49-78%	37-56%
ALL²	82%	29%
MM^22,23	76%	10.5%
	Grade ≥3
	CRS	Neurotoxicity
LBCL^1,20	6-18%	16-19%
FL^7,21	0-6%	3-15%
ALL²	26%	12%
MM²²	11%	8%

Real-World Data

Real-world evidence improves our understanding of CAR T

SAFETY PROFILE OF CAR T THERAPY IN CLINICAL PRACTICE^†

Any grade	LBCL^24-29	ALL³⁰	MM³¹
CRS	45-93%	55%	82%
Neurotoxicity	15-70%	27%	15%
Grade ≥3	LBCL^24-29	ALL³⁰	MM³¹
CRS	5-10%	16%	4%
Neurotoxicity	1-35%	9%	5%

	Any grade
	CRS	Neurotoxicity
LBCL^24-29	45-93%	15-70%
ALL³⁰	55%	27%
MM³¹	82%	15%
	Grade ≥3
	CRS	Neurotoxicity
LBCL^24-29	5-10%	1-35%
ALL³⁰	16%	9%
MM³¹	4%	5%

AE Management

CAR T treatment centers are well equipped to manage the most common AEs: CRS and neurotoxicity⁹

CRS AND NEUROTOXICITY: GENERAL ONSET AND DURATION^10,32,33‡

CRS and neurotoxicity: General onset and duration Days post CAR T-cell infusion. CRS median onset day 2-3, Neurotoxicity median onset day 5-6, CRS median duration is 7-8 days, Neurotoxicity median duration is 5-11 days, Delayed neurotoxicity can occur at 3-4 weeks or later

^‡Presentation and duration may vary based on the individual patient and product.

	Day 1-3³⁴		Within Week 1³⁷
CRS	High fever is a common first sign and typically occurs before other more serious side effects^19,34	Median time to onset is 2 to 3 days and rarely later than 14 days after treatment^35,36	CRS usually occurs within the first week. Severe CRS can manifest as early as 1 day after infusion^35,37,38
CRS	Common signs and symptoms include: Fever, tachycardia, hypotension, depressed cardiac function, dyspnea, and hypoxia. Additional constitutional symptoms may include fatigue, headache, and myalgia.^19,36,37
	Week 1¹⁹		Week 3-4³³
Neurotoxicity	Can occur concurrently with high fever and other CRS symptoms, but can also occur after CRS^19,33,37	Potentially more severe symptoms can occur after CRS symptoms subside, usually more than 5 days after CAR T treatment^19,33	In ~10% of patients, delayed neurotoxicity can arise 3 to 4 weeks after treatment or later³³
Neurotoxicity	Some of the earliest manifestations include: Tremors, dysgraphia, impaired attention, apraxia, and mild lethargy. Bradycardia, hypertension and respiratory depression, and coma can also occur.³⁶

CRS
Day 1-3³⁴	High fever is a common first sign and typically occurs before other more serious side effects^19,34
Day 1-3³⁴	Median time to onset is 2 to 3 days and rarely later than 14 days after treatment^35,36
Within Week 1³⁷	CRS usually occurs within the first week. Severe CRS can manifest as early as 1 day after infusion^35,37,38
Common signs and symptoms include: Fever, tachycardia, hypotension, depressed cardiac function, dyspnea, and hypoxia. Additional constitutional symptoms may include fatigue, headache, and myalgia.^19,36,37
Neurotoxicity
Week 1¹⁹	Can occur concurrently with high fever and other CRS symptoms, but can also occur after CRS^19,33,37
Week 1¹⁹	Potentially more severe symptoms can occur after CRS symptoms subside, usually more than 5 days after CAR T treatment^19,33
Week 3-4³⁷	In ~10% of patients, delayed neurotoxicity can arise 3 to 4 weeks after treatment or later³³
Some of the earliest manifestations include: Tremors, dysgraphia, impaired attention, apraxia, and mild lethargy. Bradycardia, hypertension and respiratory depression, and coma can also occur.³⁶

Incidence, onset, and duration of CRS and neurotoxicity vary among individual patients and can be longer than what is listed.

Monitor for late effects of CAR T therapy

Once patients have completed CAR T therapy and are discharged from the treatment center, they return to their primary oncologist for care. Patients will enter into an observation phase that involves long-term follow-up to monitor for toxicities.⁹

Potential late effects	Considerations for management^§
Cytopenia^32,39(ie, anemia, thrombocytopenia, and neutropenia)	Until blood counts normalize, consider obtaining a CBC with differential at least every 30 days after CAR T infusion In some cases, growth factor support and corticosteroids may be used
Hypogamma-globulinemia³²	Until IgG levels reach >400 mg/dL, consider obtaining monthly levels, starting 30 days after CAR T infusion Treatment with immunoglobulin replacement may be necessary to restore and maintain IgG levels
B-cell aplasia^39,40	Consider monitoring for low B-cell counts and immunoglobulin levels monthly following CAR T infusion, as these are signs of B-cell aplasia To help prevent infections, the main complications of B-cell aplasia, IVIG therapy may be needed Flu and COVID vaccines are recommended, as well as antiviral and PJP prophylaxis per institutional standards Antifungals should also be considered for high-risk patients, including those receiving corticosteroids for CRS or neurotoxicity
Infections^32,39	Consider obtaining and/or conducting: Medical history Physical exam CBC Bacterial cultures and evaluate for other infections (fungal and viral) Treatment should be given according to the infectious source Supportive care, empiric antibiotics, antifungal agents, as well as antiviral and PJP prophylaxis may be considered as needed for appropriate patients
Neurologic events^32,39	Consider evaluating for neuropsychiatric dysfunction in patients exhibiting signs or symptoms, starting 30 days after CAR T infusion Supportive care, specific adverse event management, and routine monitoring with laboratory tests may be considered for appropriate patients as needed
Secondary malignancies³²	There have been rare reports of secondary malignancies after CAR T therapy Cancer surveillance with periodic monitoring of blood counts may be appropriate for certain patients based on age or sex

Potential late effects
Cytopenia^32,39 (ie, anemia, thrombocytopenia, and neutropenia) Considerations for management^§ Until blood counts normalize, consider obtaining a CBC with differential at least every 30 days after CAR T infusion In some cases, growth factor support and corticosteroids may be used
Hypogamma-globulinemia³² Considerations for management^§ Until IgG levels reach >400 mg/dL, consider obtaining monthly levels, starting 30 days after CAR T infusion Treatment with immunoglobulin replacement may be necessary to restore and maintain IgG levels
B-cell aplasia^39,40 Considerations for management^§ Consider monitoring for low B-cell counts and immunoglobulin levels monthly following CAR T infusion, as these are signs of B-cell aplasia To help prevent infections, the main complications of B-cell aplasia, IVIG therapy may be needed Flu and COVID vaccines are recommended, as well as antiviral and PJP prophylaxis per institutional standards Antifungals should also be considered for high-risk patients, including those receiving corticosteroids for CRS or neurotoxicity
Infections^32,39 Considerations for management^§ Consider obtaining and/or conducting: Medical history Physical exam CBC Bacterial cultures and evaluate for other infections (fungal and viral) Treatment should be given according to the infectious source Supportive care, empiric antibiotics, antifungal agents, as well as antiviral and PJP prophylaxis may be considered as needed for appropriate patients
Neurologic events^32,39 Considerations for management^§ Consider evaluating for neuropsychiatric dysfunction in patients exhibiting signs or symptoms, starting 30 days after CAR T infusion Supportive care, specific adverse event management, and routine monitoring with laboratory tests may be considered for appropriate patients as needed
Secondary malignancies³² Considerations for management^§ There have been rare reports of secondary malignancies after CAR T therapy Cancer surveillance with periodic monitoring of blood counts may be appropriate for certain patients based on age or sex

Potential late effects

Cytopenia^32,39 (ie, anemia, thrombocytopenia, and neutropenia)