SAFETY

YESCARTA®WELL-CHARACTERIZED SAFETY AND ESTABLISHED MANAGEMENT GUIDANCE

After your patient receives their YESCARTA infusion, monitoring will take place at the YESCARTA Authorized Treatment Center where there are approved safety protocols and physicians who are specially trained in YESCARTA administration and adverse event management. The YESCARTA Authorized Treatment Center will work with primary hematologists/oncologists to stay connected about treatment decisions, patient progress, and follow-up care. Though infusion and monitoring take place at the treatment center, long-term monitoring should continue in the community setting.

The safety of YESCARTA in 3L relapsed/refractory (r/r) follicular lymphoma (FL) was evaluated in the ZUMA-5 pivotal trial.

MOST CYTOKINE RELEASE SYNDROME AND NEUROLOGIC EVENTS IN ZUMA-5 OCCURRED EARLY, WERE GENERALLY REVERSIBLE, AND WERE MANAGED PER ESTABLISHED GUIDANCE.1,2

CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA.1

8
%
GRADE 3 INCIDENCE
84
%
OVERALL INCIDENCE
4
DAYS
MEDIAN TIME TO ONSET
(range: 1 to 20 days)
6
DAYS
MEDIAN DURATION
(range: 1 to 27 days)

MANAGEMENT OF CRS1

At the Authorized Treatment Center, ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids will be instituted as indicated. 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 recommendations in Section 2.3 of the full Prescribing Information.

Grade 1

Symptoms require symptomatic treatment only (eg, fever, nausea, fatigue, headache, myalgia, malaise).

Tocilizumab

N/A

Corticosteroids

N/A

Grade 2

Symptoms require and respond to moderate intervention.

Oxygen requirement less than 40% FiO2 or hypotension responsive to fluids or low-dose of one vasopressor or

Grade 2 organ toxicity.

Tocilizumab

Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).

If no clinical improvement in the signs and symptoms of CRS after the first dose, repeat tocilizumab every 8 hours as needed.

Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses.

Corticosteroids

Manage per Grade 3 if no improvement within 24 hours after starting tocilizumab.

Grade 3

Symptoms require and respond to aggressive intervention.

Oxygen requirement greater than or equal to 40% FiO2 or hypotension requiring high-dose or multiple vasopressors or

Grade 3 organ toxicity or Grade 4 transaminitis.

Tocilizumab

Per Grade 2

Corticosteroids

Administer methylprednisolone 1 mg/kg intravenously twice daily or equivalent dexamethasone (eg, 10 mg intravenously every 6 hours).

Continue corticosteroids use until the event is Grade 1 or less, then taper over 3 days.

Grade 4

Life-threatening symptoms.

Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD) or

Grade 4 organ toxicity (excluding transaminitis).

Tocilizumab

Per Grade 2

Corticosteroids

Administer methylprednisolone 1000 mg intravenously per day for 3 days; if improves, then manage as above (Grade 3).

CRS Grade Tocilizumab Corticosteroids

Grade 1

Symptoms require symptomatic treatment only (eg, fever, nausea, fatigue, headache, myalgia, malaise).

N/A

N/A

Grade 2

Symptoms require and respond to moderate intervention.

Oxygen requirement less than 40% FiO2 or hypotension responsive to fluids or low-dose of one vasopressor or

Grade 2 organ toxicity.

Administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).

If no clinical improvement in the signs and symptoms of CRS after the first dose, repeat tocilizumab every 8 hours as needed.

Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses.

Manage per Grade 3 if no improvement within 24 hours after starting tocilizumab.

Grade 3

Symptoms require and respond to aggressive intervention.

Oxygen requirement greater than or equal to 40% FiO2 or hypotension requiring high-dose or multiple vasopressors or

Grade 3 organ toxicity or Grade 4 transaminitis.

Per Grade 2

Administer methylprednisolone 1 mg/kg intravenously twice daily or equivalent dexamethasone (eg, 10 mg intravenously every 6 hours).

Continue corticosteroids use until the event is Grade 1 or less, then taper over 3 days.

Grade 4

Life-threatening symptoms.

Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD) or

Grade 4 organ toxicity (excluding transaminitis).

Per Grade 2

Administer methylprednisolone 1000 mg intravenously per day for 3 days; if improves, then manage as above.

Patients who experience Grade 2 CRS (eg, hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or life-threatening CRS, consider intensive care supportive therapy.1

ZUMA-5 STUDY DESIGN1,3

  • ZUMA-5: A phase 2, multicenter, single-arm, open-label study evaluating the efficacy and safety of YESCARTA in adults with r/r FL after 2 lines of therapy
  • 146 patients received YESCARTA and were evaluated for safety
    • 81 patients with FL were evaluated for efficacy
  • Patients received lymphodepleting chemotherapy: 500 mg/m2 intravenous (IV) cyclophosphamide and 30 mg/m2 IV fludarabine (–5, –4, and –3 days before infusion)
  • YESCARTA was administered as a single infusion to a target dose of 2 x 106 viable CAR T cells/kg body weight
  • Primary endpoint: ORR (CR + PR)
  • Median age: 62 years (range: 34 to 79 years)

NEUROLOGIC TOXICITIES

Neurologic toxicities, which were fatal or life-threatening, occurred following treatment with YESCARTA.1

21
%
GRADE 3 INCIDENCE
77
%
OVERALL INCIDENCE
74
%
OCCURRENCE WITHIN FIRST 7 DAYS OF INFUSION
6
DAYS
MEDIAN TIME TO ONSET
(range: 1 to 79 days)
16
DAYS
MEDIAN DURATION

MANAGEMENT OF NEUROLOGIC TOXICITIES1

When managing neurologic toxicities at the Authorized Treatment Center, rule out other causes of neurologic symptoms. Patients who experience Grade 2 neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. Consider nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis for any Grade 2 neurologic toxicities.

See Section 2.3 of the full Prescribing Information for additional monitoring and management guidance relating to neurologic toxicities.

Grade 2

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance table above for management of Grade 2 CRS.

If no improvement within 24 hours after starting tocilizumab, administer dexamethasone 10 mg intravenously every 6 hours if not already taking other corticosteroids. Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days.


Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

No Concurrent CRS

Administer dexamethasone 10 mg intravenously every 6 hours.

Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days.


Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

Grade 3

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance table above for management of Grade 2 CRS.

In addition, administer dexamethasone 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days.


Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

No Concurrent CRS

Administer dexamethasone 10 mg intravenously every 6 hours.

Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days.


Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

Grade 4

Concurrent CRS

Administer tocilizumab per CRS Grading and Management Guidance table above for management of Grade 2 CRS.

Administer methylprednisolone 1000 mg intravenously per day with first dose of tocilizumab and continue methylprednisolone 1000 mg intravenously per day for 2 more days; if improves, then manage as above (Grade 3).


Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

No Concurrent CRS

Administer methylprednisolone 1000 mg intravenously per day for 3 days; if improves, then manage as above (Grade 3).


Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

Grading Assessment Concurrent CRS No Concurrent CRS

Grade 2

Administer tocilizumab per CRS Grading and Management Guidance table above for management of Grade 2 CRS.

If no improvement within 24 hours after starting tocilizumab, administer dexamethasone 10 mg intravenously every 6 hours if not already taking other corticosteroids. Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days.

Administer dexamethasone 10 mg intravenously every 6 hours.

Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days.

Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

Grade 3

Administer tocilizumab per CRS Grading and Management Guidance table above for management of Grade 2 CRS.

In addition, administer dexamethasone 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days.

Administer dexamethasone 10 mg intravenously every 6 hours.

Continue dexamethasone use until the event is Grade 1 or less, then taper over 3 days.

Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

Grade 4

Administer tocilizumab per CRS Grading and Management Guidance table above for management of Grade 2 CRS.

Administer methylprednisolone 1000 mg intravenously per day with first dose of tocilizumab and continue methylprednisolone 1000 mg intravenously per day for 2 more days; if improves, then manage as above.

Administer methylprednisolone 1000 mg intravenously per day for 3 days; if improves, then manage as above.

Consider non-sedating, anti-seizure medicines (eg, levetiracetam) for seizure prophylaxis.

ZUMA-5 STUDY DESIGN1,3

  • ZUMA-5: A phase 2, multicenter, single-arm, open-label study evaluating the efficacy and safety of YESCARTA in adults with r/r FL after 2 lines of therapy
  • 146 patients received YESCARTA and were evaluated for safety
    • 81 patients with FL were evaluated for efficacy
  • Patients received lymphodepleting chemotherapy: 500 mg/m2 intravenous (IV) cyclophosphamide and 30 mg/m2 IV fludarabine (–5, –4, and –3 days before infusion)
  • YESCARTA was administered as a single infusion to a target dose of 2 x 106 viable CAR T cells/kg body weight
  • Primary endpoint: ORR (CR + PR)
  • Median age: 62 years (range: 34 to 79 years)

PATIENT MONITORING AT AUTHORIZED TREATMENT CENTERS1

Monitoring takes place at the YESCARTA Authorized Treatment Centers where there are approved safety protocols and physicians who are specially trained in YESCARTA administration and adverse event management. Long-term monitoring should continue in the community setting.

7
DAYS
4
WEEKS
7
DAYS

Patients will be monitored at least daily for 7 days at the Authorized Treatment Center following infusion for signs and symptoms of CRS and neurologic toxicities.

4
WEEKS

Patients will be instructed to remain within proximity of the Authorized Treatment Center for at least 4 weeks following infusion. Monitor patients for signs or symptoms of CRS or neurologic toxicities for 4 weeks after infusion. Patients will be counseled to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicities occur at any time.

ZUMA-5 STUDY DESIGN1,3

  • ZUMA-5: A phase 2, multicenter, single-arm, open-label study evaluating the efficacy and safety of YESCARTA in adults with r/r FL after 2 lines of therapy
  • 146 patients received YESCARTA and were evaluated for safety
    • 81 patients with FL were evaluated for efficacy
  • Patients received lymphodepleting chemotherapy: 500 mg/m2 intravenous (IV) cyclophosphamide and 30 mg/m2 IV fludarabine (–5, –4, and –3 days before infusion)
  • YESCARTA was administered as a single infusion to a target dose of 2 x 106 viable CAR T cells/kg body weight
  • Primary endpoint: ORR (CR + PR)
  • Median age: 62 years (range: 34 to 79 years)

ADVERSE REACTIONS IN ZUMA-51

The most common non-laboratory adverse reactions (incidence 20%) included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

Serious adverse reactions occurred in 48% of patients. Serious adverse reactions in >2% of patients included febrile neutropenia, encephalopathy, fever, CRS, infections with pathogen unspecified, pneumonia, hypoxia, and hypotension.

The most common (10%) Grade 3 or higher reactions included febrile neutropenia, encephalopathy, and infections with pathogen unspecified. Fatal adverse reactions occurred in 1% of patients and included CRS and fungal infection.

Adverse Reaction Any Grade (%) Grade 3 (%)
Blood and Lymphatic System Disorders
Febrile neutropeniaa 41 41
Cardiac Disorders
Tachycardiab 44 1
Arrhythmiac 21 2
Gastrointestinal Disorders
Nausea 40 0
Diarrhead 29 1
Constipation 28 0
Vomiting 24 1
Abdominal paine 16 0
General Disorders and Administration Site Conditions
Fever 85 8
Fatiguef 49 1
Chills 29 0
Edemag 13 1
Immune System Disorders
Cytokine release syndrome 84 8
Immunoglobulins decreasedh 18 1
Infections and Infestations
Infections with pathogen unspecified 45 14
Pneumoniai 13 8
Fungal infections 12 2
Viral infections 13 2
Metabolism and Nutrition Disorders
Decreased appetitej 26 1
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paink 40 1
Motor dysfunctionl 18 2
Nervous System Disorders
Encephalopathym 49 16
Headache 45 1
Tremor 31 1
Dizzinessn 20 0
Aphasia 14 4
Neuropathy peripheralo 12 0
Ataxiap 10 0
Psychiatric Disorders
Deliriumq 16 5
Insomnia 16 0
Affective disorderr 10 1
Respiratory, Thoracic and Mediastinal Disorders
Coughs 25 0
Hypoxia 23 8
Dyspneat 12 1
Nasal congestion 10 0
Skin and Subcutaneous Tissue Disorders
Rashu 19 3
Vascular Disorders
Hypotensionv 51 4
Hypertension 13 6
Thrombosisw 12 4

aFebrile neutropenia includes febrile neutropenia, fever overlapping with neutropenia.

bTachycardia includes tachycardia, sinus tachycardia.

cArrhythmia includes atrial fibrillation, atrioventricular block first degree, bradycardia, sinus bradycardia, supraventricular tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventricular tachycardia, electrocardiogram QT prolonged, electrocardiogram T wave inversion.

dDiarrhea includes diarrhea, colitis, enteritis.

eAbdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, dyspepsia, epigastric discomfort.

fFatigue includes asthenia, fatigue, decreased activity, malaise.

gEdema includes edema, face edema, generalized edema, localized edema, edema peripheral, peripheral swelling, pulmonary edema, swelling face.

hImmunoglobulins decreased includes hypogammaglobulinemia, blood immunoglobulin G decreased.

iPneumonia includes pneumonia streptococcal, pneumonia, lung infiltration. Pneumonia is also summarized under infections with pathogen unspecified.

jDecreased appetite includes decreased appetite, hypophagia.

kMusculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, myalgia, neck pain, osteoarthritis, pain in extremity.

lMotor dysfunction includes motor dysfunction, muscle rigidity, muscle spasms, muscle strain, muscular weakness.

mEncephalopathy includes agraphia, amnesia, aphonia, apraxia, CAR T-cell-related encephalopathy syndrome, cognitive disorder, disturbance in attention, dysarthria, dysgraphia, dyskinesia, encephalopathy, lethargy, loss of consciousness, memory impairment, somnolence, speech disorder, confusional state, mental status changes, immune effector cell-associated neurotoxicity, neurotoxicity, toxic encephalopathy.

nDizziness includes dizziness, presyncope, syncope, vertigo.

oNeuropathy peripheral includes allodynia, cervical radiculopathy, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy.

pAtaxia includes ataxia, balance disorder, gait disturbance, vestibular disorder.

qDelirium includes agitation, delirium, hallucination, restlessness.

rAffective disorder includes anxiety, depression, impulsive behavior, mania, panic attack.

sCough includes cough, productive cough, upper-airway cough syndrome.

tDyspnea includes dyspnea, dyspnea exertional.

uRash includes dermatitis bullous, erythema, pruritus, rash, rash macular, rash maculo-papular, Stevens-Johnson syndrome, urticaria.

vHypotension includes capillary leak syndrome, hypotension, hypoperfusion, orthostatic hypotension.

wThrombosis includes deep vein thrombosis, embolism, peripheral ischemia, pulmonary embolism, thrombosis in device, vascular occlusion, jugular vein thrombosis.

ZUMA-5 STUDY DESIGN1,3

  • ZUMA-5: A phase 2, multicenter, single-arm, open-label study evaluating the efficacy and safety of YESCARTA in adults with r/r FL after 2 lines of therapy
  • 146 patients received YESCARTA and were evaluated for safety
    • 81 patients with FL were evaluated for efficacy
  • Patients received lymphodepleting chemotherapy: 500 mg/m2 intravenous (IV) cyclophosphamide and 30 mg/m2 IV fludarabine (–5, –4, and –3 days before infusion)
  • YESCARTA was administered as a single infusion to a target dose of 2 x 106 viable CAR T cells/kg body weight
  • Primary endpoint: ORR (CR + PR)
  • Median age: 62 years (range: 34 to 79 years)

INDICATION

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
  • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.
  • YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.

CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade ≥3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade ≥3 in 13%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade ≥3 in 8% (11/146). Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL. Key manifestations of CRS (≥10%) in all patients combined included fever (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving YESCARTA, including Grade ≥3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade ≥3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including Grade ≥3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days for patients with iNHL. 98% of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (≥10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema, have occurred. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). The most common neurologic toxicities were consistent with the overall LBCL population treated with YESCARTA. Following YESCARTA infusion, monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS: Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 47% (119/254) of all patients with NHL. Grade 3 infections occurred in 19% of patients, Grade 3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common non-laboratory adverse reactions (incidence 20%) in patients with iNHL included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

INDICATION

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
  • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.
  • YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.

CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade ≥3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade ≥3 in 13%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade ≥3 in 8% (11/146). Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL. Key manifestations of CRS (≥10%) in all patients combined included fever (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving YESCARTA, including Grade ≥3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade ≥3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including Grade ≥3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days for patients with iNHL. 98% of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (≥10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema, have occurred. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). The most common neurologic toxicities were consistent with the overall LBCL population treated with YESCARTA. Following YESCARTA infusion, monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS: Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 47% (119/254) of all patients with NHL. Grade 3 infections occurred in 19% of patients, Grade 3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common non-laboratory adverse reactions (incidence 20%) in patients with iNHL included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

INDICATION

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
  • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.
  • YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.

CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade ≥3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade ≥3 in 13%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade ≥3 in 8% (11/146). Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL. Key manifestations of CRS (≥10%) in all patients combined included fever (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving YESCARTA, including Grade ≥3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade ≥3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including Grade ≥3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days for patients with iNHL. 98% of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (≥10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema, have occurred. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). The most common neurologic toxicities were consistent with the overall LBCL population treated with YESCARTA. Following YESCARTA infusion, monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS: Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 47% (119/254) of all patients with NHL. Grade 3 infections occurred in 19% of patients, Grade 3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated. In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common non-laboratory adverse reactions (incidence 20%) in patients with iNHL included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Authorized Treatment Centers are independently owned and operated. Kite does not endorse any Authorized Treatment Center.

3L=third line; CAR T=chimeric antigen receptor T cell; CR=complete remission; ORR=objective response rate; PR=partial remission.

References: 1. YESCARTA® (axicabtagene ciloleucel). Prescribing information. Kite Pharma, Inc; 2021. 2. Data on file. Kite Pharma, Inc; 2020. 3. A phase 2 multicenter study of axicabtagene ciloleucel in subjects with relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Clinicaltrials.gov. Published April 7, 2017. Updated February 25, 2021. Accessed March 5, 2021. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT03105336