Important Safety Information


WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not admini…+
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Indication
KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.

Safety Profile

Setting Expectations

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions occurred in patients receiving KYMRIAH® (tisagenlecleucel). Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab, or tocilizumab and corticosteroids. Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed. KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS.

Cytokine Release Syndrome

CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 78 (74%) of the 106 adult patients with r/r diffuse large B-cell lymphoma (DLBCL) receiving KYMRIAH, including grade ≥3 (Penn grading system)2 in 23% of patients with r/r DLBCL. The median time to onset was 3 days (range: 1 to 51), and in only two patients was onset after day 10. The median time to resolution of CRS was 8 days (range: 1 to 36).

Of the 78 patients with r/r DLBCL who had CRS, 16 (21%) received systemic tocilizumab or corticosteroids. Six (8%) patients received a single dose of tocilizumab, 10 (13%) patients received two doses of tocilizumab, and 10 (13%) patients received corticosteroids in addition to tocilizumab. Two patients with r/r DLBCL received corticosteroids for CRS without concomitant tocilizumab, and two patients received corticosteroids for persistent neurotoxicity after resolution of CRS.

Five deaths occurred within 30 days of KYMRIAH infusion. Of the 3 r/r DLBCL patients who died within 30 days of infusion, all had CRS in the setting of stable to progressive underlying disease, one of whom developed bowel necrosis. Among patients with CRS, key manifestations include fever (92% in r/r DLBCL), hypotension (47% in r/r DLBCL), hypoxia (35% in r/r DLBCL) and tachycardia (14% in r/r DLBCL). CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy.

Delay the infusion of KYMRIAH after lymphodepleting chemotherapy if the patient has unresolved serious adverse reactions from preceding chemotherapies (including pulmonary toxicity, cardiac toxicity, or hypotension), active uncontrolled infection, or active graft versus host disease (GVHD).

Ensure that two doses of tocilizumab are available on site prior to infusion of KYMRIAH. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with KYMRIAH. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.

Risk factors for developing severe CRS in adult r/r DLBCL are not known.

Neurological Toxicities

Neurological toxicities including severe or life-threatening reactions, occurred in 62 (58%) of the 106 patients with r/r DLBCL following treatment with KYMRIAH, including ≥grade 3 in 18% of patients with r/r DLBCL. Among patients who had a neurological toxicity, 88% occurred within 8 weeks following KYMRIAH infusion.

Median time to the first event was 6 days from infusion (range: 1-359), and the median duration was 14 days for patients with r/r DLBCL. Resolution occurred within 3 weeks in 61% of patients with r/r DLBCL. Encephalopathy lasting up to 50 days was noted.

The onset of neurological toxicity can be concurrent with CRS, following resolution of CRS or in the absence of CRS.

The most common neurological toxicities observed with KYMRIAH include headache (21% in r/r DLBCL), encephalopathy (16% in r/r DLBCL), delirium (6% in r/r DLBCL), anxiety (9% in r/r DLBCL), sleep disorders (9% in r/r DLBCL), dizziness (11% in r/r DLBCL), tremor (7% in r/r DLBCL) and peripheral neuropathy (8% in r/r DLBCL). Other manifestations included seizures, mutism and aphasia.

Monitor patients for neurological events and exclude other causes for neurological symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events.

Hypersensitivity Reactions

Allergic reactions may occur with infusion of KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) or dextran 40 in KYMRIAH.

Serious Infections

Infections, including life-threatening or fatal infections, occurred in 95 (55%) of 174 patients with r/r ALL or r/r DLBCL after KYMRIAH infusion. Fifty-eight patients (33%) experienced grade ≥3 infections, including a fatal infection in 1 patient (1%) with r/r DLBCL. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Patients with active uncontrolled infection should not start KYMRIAH treatment until the infection is resolved. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately.

Febrile neutropenia (grade ≥3) was also observed in 17% of patients with r/r DLBCL after KYMRIAH infusion 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.

Viral Reactivation

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 KYMRIAH infusion.

In the JULIET study (Study 2), grade ≥3 cytopenias not resolved by Day 28 following KYMRIAH treatment included thrombocytopenia (40%) and neutropenia (25%) among 106 treated patients.

Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.

Hypogammaglobulinemia

Hypogammaglobulinemia and agammaglobulinemia (IgG) related to B-cell aplasia can occur in patients with a complete remission (CR) after KYMRIAH infusion.

Hypogammaglobulinemia was reported in 14% of patients with r/r DLBCL.

Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines.

Immunization with Live Vaccine

The safety of immunization with live viral vaccines during or following KYMRIAH 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 KYMRIAH treatment, and until immune recovery following treatment with KYMRIAH.

Pregnant women who have received KYMRIAH may have hypogammaglobulinemia. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH.

Secondary Malignancies

Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their cancer. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Novartis Pharmaceuticals Corporation at 1-844-4KYMRIAH to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurological events, including altered mental status or seizures, patients receiving KYMRIAH are at risk for altered or decreased consciousness or coordination in the 8 weeks following KYMRIAH 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

In the JULIET study (Study 2) 106 adults with r/r DLBCL received a single intravenous dose of KYMRIAH. The most common adverse reactions (incidence >20%) were CRS, infections-pathogen unspecified, diarrhea, nausea, pyrexia, fatigue, hypotension, edema, and headache.

The study population characteristics were: median age of 56 years (range: 22 to 76 years), 79% DLBCL; a median of 3 prior lines of therapy (range: 1-6), 49% had a prior autologous hematopoietic stem cell transplantation, and 33% had received prior radiation therapy. Ninety-nine patients (93%) received lymphodepleting chemotherapy prior to KYMRIAH, that included fludarabine (n=77) or bendamustine (n=22).

The adverse reactions with greater than or equal to 10% incidence for any grade are summarized below.

Selected Adverse Reactions AnyTime After Infusion Reported in ≥10% Following Treatment with KYMRIAH in Adult r/r DLBCL (N=106)

Adverse ReactionAll Grades
(%)
Grades 3 or Higher
(%)

Blood and lymphatic system disorders

Febrile neutropenia

17 17

Cardiac disorders

Tachycardiaa

13 3

Gastrointestinal disorders

Diarrhea

31 1

Nausea

27 1

Constipation

16 1

General disorders and administration site conditions

Pyrexia

34 6

Fatigueb

26 7

Edemac

23 2

Paind

15 3

Chills

13 0

Immune system disorders

Cytokine release syndrome

74 23

Hypogammaglobulinemiae

14 4

Infections and infestations

Infections–pathogen unspecified

42 25

Investigations

Weight decreased

11 3

Metabolism and nutrition disorders

Decreased appetite

12 4

Musculoskeletal and connective tissue disorders

Arthralgia

10 0

Nervous system disorders

Headachef

21 0

Encephalopathyg

16 11

Dizzinessh

11 1

Renal and Urinary Disorders

Acute kidney injuryi

17 6

Respiratory, thoracic, and mediastinal disorders

Coughj

19 0

Dyspneak

18 6

Vascular disorders

Hypotensionl

26 8
aTachycardia includes tachycardia and sinus tachycardia.
bFatigue includes fatigue and malaise.
cEdema includes face edema, generalized edema, localized edema, edema peripheral, and peripheral swelling.
dPain includes pain and pain in extremity.
eHypogammaglobulinemia includes blood immunoglobulin G decreased, immunoglobulins decreased, and hypogammaglobulinemia.
fHeadache includes headache and migraine.
gEncephalopathy includes encephalopathy, cognitive disorder, confusional state, disturbance in attention, lethargy, mental status changes, somnolence, memory impairment, metabolic encephalopathy, and thinking abnormal.
hDizziness includes dizziness, presyncope, and syncope.
iAcute kidney injury includes acute kidney injury and blood creatinine increased.
jCough includes cough, productive cough, and upper-airway cough syndrome.
kDyspnea includes dyspnea, dyspnea exertional, respiratory distress, and respiratory failure.
lHypotension includes hypotension and orthostatic hypotension.

Cytokine Release Syndrome Treatment Algorithm

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 treatment algorithm below.

Treatment of CRS

CRS SeverityManagement
Prodromal Syndrome:
Low-grade fever, fatigue, anorexia
Observe in person; exclude infection; administer antibiotics per local guidelines if neutropenic; provide symptomatic support.
CRS requiring mild intervention (one or more of the following):
  • High fever
  • Hypoxia
  • Mild hypotension
Administer antipyretics, oxygen, intravenous fluids, and/or low-dose vasopressors as needed.
CRS requiring moderate to aggressive intervention (one or more of the following):
  • Hemodynamic instability despite intravenous fluids and vasopressor support
  • Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen requirement including high-flow oxygen, and/or need for mechanical ventilation
  • Rapid clinical deterioration
  • Administer high-dose or multiple vasopressors, oxygen, mechanical ventilation, and/or other supportive care as needed
  • Administer tocilizumab
    • Patient weight less than 30 kg: 12 mg/kg intravenously over 1 hour
    • Patient weight greater than or equal to 30 kg: 8 mg/kg intravenously over 1 hour (maximum dose 800 mg)

Repeat tocilizumab as needed at a minimum interval of 8 hours if there is no clinical improvement.

If no response to second dose of tocilizumab, consider a third dose of tocilizumab or pursue alternative measures for treatment of CRS.

Limit to a maximum total of 4 tocilizumab doses.

  • If no clinical improvement within 12 to 18 hours of the first tocilizumab dose, or worsening at any time, administer methylprednisolone 2 mg/kg as an initial dose, then 2 mg/kg per day until vasopressors and high flow oxygen are no longer needed, then taper


References: 1.
Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 2. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139. doi: 10.1126/scitranslmed.aac5415.

Indication

KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitation of Use: KYMRIAH is not indicated for treatment of patients with primary central nervous system lymphoma.

Important Safety Information for KYMRIAH® (tisagenlecleucel)

WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab, or tocilizumab and corticosteroids
  • Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed
  • KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS

Warnings and Precautions

Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 78 (74%) of the 106 patients with r/r DLBCL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 23% of patients with r/r DLBCL. In KYMRIAH clinical trials, the median time to onset was 3 days (range: 1-51), and in only 2 patients was onset after Day 10. The median time to resolution was 8 days (range: 1-36).

Of the 78 patients with r/r DLBCL who had CRS, 16 (21%) received systemic tocilizumab or corticosteroids. Six (8%) received a single dose of tocilizumab, 10 (13%) received 2 doses of tocilizumab, and 10 (13%) received corticosteroids in addition to tocilizumab. Two patients with r/r DLBCL received corticosteroids for CRS without concomitant tocilizumab, and 2 patients received corticosteroids for persistent neurotoxicity after resolution of CRS.

Three deaths occurred in patients with r/r DLBCL within 30 days of KYMRIAH infusion. Of these 3 patients, all had history of CRS in the setting of stable to progressive underlying disease, 1 of whom developed bowel necrosis. Among r/r DLBCL patients with CRS, key manifestations included fever (90%), hypotension (47%), hypoxia (35%), and tachycardia (14%). 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, active uncontrolled infection, or active graft vs host disease.

Ensure 2 doses of tocilizumab are available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS 2-3 times during the first week, then for at least 4 weeks after treatment. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated. Risk factors for developing severe CRS in r/r DLBCL are unknown.

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 62 (58%) of the 106 patients with r/r DLBCL following treatment with KYMRIAH, including ≥ grade 3 in 18% of patients. Among KYMRIAH clinical trial patients who had a neurological toxicity, 88% occurred within 8 weeks following KYMRIAH infusion. Median time to the first event was 6 days from infusion (range: 1-359), and the median duration was 14 days for patients with r/r DLBCL. Resolution occurred within 3 weeks in 61% of patients with r/r DLBCL. Encephalopathy lasting up to 50 days was noted. The onset of neurological toxicity can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

The most common neurological toxicities observed in patients with r/r DLBCL included headache (21%), encephalopathy (16%), delirium (6%), anxiety (9%), sleep disorders (9%), dizziness (11%), tremor (7%), and peripheral neuropathy (8%). Other manifestations included seizures, mutism, and aphasia.

Monitor patients for neurological events, specifically 2-3 times during the first week following KYMRIAH infusion, and exclude other causes for neurological symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events.

KYMRIAH REMS to Mitigate CRS and Neurological Toxicities: Because of the risk of CRS and neurological toxicities, KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH.

Hypersensitivity Reactions: Allergic reactions may occur with KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH.

Serious Infections: Infections, including life-threatening or fatal infections, occurred in 95 (55%) of 174 KYMRIAH clinical trial patients after KYMRIAH infusion. Fifty-eight patients (33%) experienced grade ≥3 infections, including fatal infections in 1 patient (1%) with r/r DLBCL. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Patients with active uncontrolled infection should not start KYMRIAH treatment until the infection is resolved. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately.

Febrile neutropenia (≥ grade 3) was also observed in 17% of patients with r/r DLBCL after KYMRIAH infusion 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.

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 cell collection for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. In patients with r/r DLBCL, grade ≥3 cytopenias not resolved by Day 28 following KYMRIAH treatment included thrombocytopenia (40%) and neutropenia (25%) among 106 treated patients. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.

Hypogammaglobulinemia: Hypogammaglobulinemia and agammaglobulinemia (IgG) related to B-cell aplasia can occur in patients with a complete remission after KYMRIAH infusion. Hypogammaglobulinemia was reported in 14% of patients with r/r DLBCL. Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines.

The safety of immunization with live viral vaccines during or following KYMRIAH 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 KYMRIAH treatment, and until immune recovery following treatment with KYMRIAH.

Pregnant women who have received KYMRIAH may have hypogammaglobulinemia. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH.

Secondary Malignancies: Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their cancer. Monitor lifelong for secondary malignancies. If a secondary malignancy occurs, call 1-844-4KYMRIAH to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurological events, including altered mental status or seizures, patients receiving KYMRIAH are at risk for altered or decreased consciousness or coordination in the 8 weeks following 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.

Drug Interactions
HIV and the lentivirus used to make KYMRIAH have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false positive results in patients who have received KYMRIAH.

Pregnancy, Lactation, Females and Males of Reproductive Potential
No data are available of KYMRIAH use in pregnant or lactating women. Therefore, KYMRIAH is not recommended for women who are pregnant or breastfeeding. Pregnancy after KYMRIAH administration should be discussed with the treating physician. Pregnancy status of females of reproductive potential should be verified with a pregnancy test prior to starting treatment with KYMRIAH. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682.

Adverse Reactions
The most common adverse reactions (>20%) reported in patients with r/r DLBCL were cytokine release syndrome, infections-pathogen unspecified, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache. 

Please see full Prescribing Information for KYMRIAH, including Boxed WARNING, and Medication Guide.