Boxed WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGICAL TOXICITIES, and SECONDARY HEMATOLOGICAL MALIGNANCIES

• 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
• T cell malignancies have occurred following treatment of hematological malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including KYMRIAH
• 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 61 (77%) of the 79 pediatric and young adult patients with r/r ALL, including ≥ grade 3 (Penn Grading System) in 48% of patients. The median times to onset and resolution of CRS were 3 days (range: 1-22; 1 patient with onset after Day 10) and 8 days (range: 1-36), respectively. Of the 61 patients with CRS, 31 (51%) received tocilizumab. Ten (16%) patients received 2 doses of tocilizumab and 3 (5%) patients received 3 doses of tocilizumab; 17 (28%) patients received addition of corticosteroids (eg, methylprednisolone).

CRS occurred in 85 (74%) of the 115 adult patients with r/r DLBCL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 23% of patients. The median times to onset and resolution of CRS were 3 days (range: 1-51; 1 patient with onset after Day 10) and 7 days (range: 2-30), respectively. Of the 85 patients with CRS, 19 (22%) received systemic tocilizumab or corticosteroids. Seven (8%) patients received a single dose of tocilizumab and 11 (13%) patients received 2 doses of tocilizumab; 11 (13%) patients received corticosteroids in addition to tocilizumab. One patient received corticosteroids for CRS without concomitant tocilizumab, and 2 patients received corticosteroids for persistent neurotoxicity after resolution of CRS.

CRS occurred in 51 (53%) of the 97 adult patients with r/r FL receiving KYMRIAH; all were grade 1 or 2 CRS (Lee Grading System). The median times to onset and resolution of CRS were 4 days (range: 1-14) and 4 days (range: 1-13), respectively. Of the 51 patients with CRS, 15 (29%) received systemic anticytokine treatment with tocilizumab. Three (6%) patients required 3 doses of tocilizumab, 4 (8%) patients required 2 doses and 8 (16%) patients required a single dose of tocilizumab. Two (4%) patients received corticosteroids in addition to tocilizumab.

Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive leukemia, and 1 patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Of the 3 patients with r/r DLBCL who died within 30 days of infusion, all had a history of CRS in the setting of stable to progressive underlying disease, 1 of whom developed bowel necrosis.

Among patients with CRS, key manifestations included fever (93% r/r ALL; 85% r/r DLBCL; 92% r/r FL), hypotension (69% r/r ALL; 45% r/r DLBCL; 40% r/r FL), hypoxia (57% r/r ALL; 35% r/r DLBCL; 19% r/r FL), and tachycardia (26% r/r ALL; 13% r/r DLBCL; 2% r/r FL). 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, active graft vs host disease, or worsening of leukemia burden.

Risk factors for severe CRS in the r/r ALL population are high pre-infusion tumor burden (>50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes. Ensure that a minimum of 2 doses of tocilizumab are available on-site prior to infusion of KYMRIAH. Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with KYMRIAH. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred following treatment with KYMRIAH. Neurological toxicities occurred in 56 (71%) of the 79 patients with r/r ALL, including ≥ grade 3 in 22%. The median times to the first event and duration were 6 days from infusion (range: 1-301) and 7 days, respectively.

Neurological toxicities occurred in 69 (60%) of the 115 patients with r/r DLBCL, including ≥ grade 3 in 19%. The median times to the first event and duration were 5 days (range: 1-368) and 17 days, respectively.

Neurological toxicities occurred in 42 (43%) of the 97 patients with r/r FL, including ≥ grade 3 in 6%. The median times to the first event and duration were 8 days (range: 1-345) and 5 days, respectively.

Among patients who had a neurological toxicity, 84% occurred within 8 weeks following KYMRIAH infusion. Resolution occurred within 3 weeks in 71% of patients with r/r ALL, 50% of patients with r/r DLBCL, and 74% of patients with r/r FL. Encephalopathy lasting up to 70 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 included headache (35% r/r ALL; 21% r/r DLBCL; 25% r/r FL), encephalopathy (30% r/r ALL; 16% r/r DLBCL; 3% r/r FL), delirium (19% r/r ALL; 5% r/r DLBCL; 1% r/r FL), anxiety (16% r/r ALL; 10% r/r DLBCL; 2% r/r FL), sleep disorders (11% r/r ALL; 10% r/r DLBCL; 6% r/r FL), dizziness (5% r/r ALL; 12% r/r DLBCL; 8% r/r FL), tremor (8% r/r ALL; 6% r/r DLBCL; 3% r/r FL), and peripheral neuropathy (4% r/r ALL; 12% r/r DLBCL; 7% r/r FL). Other manifestations included seizures and aphasia..

Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of neurological toxicities. Rule out other causes of neurological symptoms. Monitor patients for signs or symptoms of neurological toxicities for at least 4 weeks after infusion and treat promptly. Neurological toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms of neurological toxicity occur at any time.

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.

The required components of the KYMRIAH REMS are:

• Health care facilities that dispense and administer KYMRIAH must be enrolled in the program and comply with the REMS requirements
• Certified health care facilities must have on-site, immediate access to tocilizumab and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hours after KYMRIAH infusion, if needed for treatment of CRS

Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH (1-844-459-6742).

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS, which can be life-threatening or fatal, has occurred following treatment with KYMRIAH. HLH was reported in 6% (5/79) of patients with r/r ALL (time to onset ranged from 3 to 18 days) and 2% (2/115) of patients with r/r DLBCL (times to onset were Day 7 and Day 10); all HLH events occurred during ongoing CRS and resolved. One patient (1%) with r/r FL developed HLH with a fatal outcome >1 year after receiving KYMRIAH. The patient did not have CRS during or immediately preceding HLH. Treatment of HLH should be administered as per institutional standards.

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

Serious Infections: Infections, including life-threatening or fatal infections, occurred following treatment with KYMRIAH. Infections occurred in 57 (72%) of the 79 patients with r/r ALL; 38 patients (48%) experienced ≥ grade 3 infections, including fatal infections in 2 patients (3%); in 67 (58%) of the 115 patients with r/r DLBCL; 38 patients (33%) experienced ≥ grade 3 infections, including fatal infection in 1 patient (1%); and in 50 (52%) of the 97 patients with r/r FL; 20 patients (21%) experienced ≥ grade 3 infections, including fatal infection in 1 patient (1%). 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 34% of patients with r/r ALL, 17% of patients with r/r DLBCL, and 13% of patients with r/r FL 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. There is no experience with manufacturing KYMRIAH for patients with a positive test for HIV or with active HBV or active hepatitis C virus (HCV). 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 patients with r/r ALL, ≥ grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia (40%) and thrombocytopenia (27%) among 52 responding patients. At 56 days following KYMRIAH, 17% and 12% of responding patients had ≥ grade 3 neutropenia or thrombocytopenia, respectively. In patients with r/r DLBCL, ≥ grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included thrombocytopenia (39%) and neutropenia (25%) among 115 treated patients. In patients with r/r FL ≥ grade 3, cytopenias not resolved by Day 28 following KYMRIAH treatment included thrombocytopenia (17%) and neutropenia (16%) among 97 treated patients.

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

Hypogammaglobulinemia: Hypogammaglobulinemia and agammaglobulinemia related to B-cell aplasia can occur in patients after KYMRIAH infusion. Hypogammaglobulinemia was reported in 53% of patients with r/r ALL, 17% of patients with r/r DLBCL, and 18% of patients with r/r FL. 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 vaccines during or following KYMRIAH treatment has not been studied. Vaccination with live 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. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including KYMRIAH. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion and may include fatal outcomes.

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 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 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. A risk to the breastfed infant cannot be excluded. 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 ALL were CRS, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, hemorrhage, musculoskeletal pain, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, tachycardia, edema, fatigue, and acute kidney injury.

The most common adverse reactions (>20%) reported in patients with r/r DLBCL were CRS, infections-pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema, hemorrhage, dyspnea, and headache.

The most common adverse reactions (>20%) reported in patients with r/r FL were CRS, infections-pathogen unspecified, fatigue, musculoskeletal pain, headache, and diarrhea.

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

KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

• Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse
• 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.

• Adult patients with r/r follicular lymphoma (FL) after two or more lines of systemic therapy

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