Important Safety Information


WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES

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Indications

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.

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 54 (79%) of the 68 patients with r/r ALL and 78 (74%) of the 106 patients with r/r DLBCL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 49% of patients with r/r ALL and in 23% of patients with r/r DLBCL. 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 54 patients with r/r ALL who had CRS, 27 (50%) received tocilizumab; 7 (13%) received 2 doses of tocilizumab, 3 (6%) received 3 doses of tocilizumab and 14 (26%) received addition of corticosteroids (eg, methylprednisolone). 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.

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 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 (92% r/r ALL and r/r DLBCL), hypotension (67% r/r ALL; 47% r/r DLBCL), hypoxia (20% r/r ALL; 35% r/r DLBCL), and tachycardia (30% r/r ALL; 14% r/r DLBCL). 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.

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 remain within proximity of the health care facility for at least 4 weeks following infusion and 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 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. Risk factors for developing severe CRS in r/r DLBCL are unknown.

Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 49 (72%) of the 68 patients with r/r ALL and 62 (58%) of the 106 patients with r/r DLBCL following treatment with KYMRIAH, including ≥ grade 3 in 21% of patients with r/r ALL and 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 6 days for patients with r/r ALL and 14 days for patients with r/r DLBCL. Resolution occurred within 3 weeks in 79% of patients with r/r ALL and 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 included headache (37% r/r ALL; 21% r/r DLBCL), encephalopathy (34% r/r ALL; 16% r/r DLBCL), delirium (21% r/r ALL; 6% r/r DLBCL), anxiety (13% r/r ALL; 9% r/r DLBCL), sleep disorders (10% r/r ALL; 9% r/r DLBCL), dizziness (6% r/r ALL; 11% r/r DLBCL), tremor (9% r/r ALL; 7% r/r DLBCL), and peripheral neuropathy (4% r/r ALL; 8% r/r DLBCL). 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 (1-844-459-6742).

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 patients with r/r ALL or with r/r DLBCL after KYMRIAH infusion. Fifty-eight patients (33%) experienced grade ≥3 infections, including fatal infections in 2 patients (3%) with r/r ALL and 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 37% of patients with r/r ALL and 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 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 (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 43% of patients with r/r ALL and 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 ALL were cytokine release syndrome, hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, edema, cough, and delirium.

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.