KYMRIAH™ ( tisagenlecleucel ) suspension for intravenous infusion Initial U . S . Approval : 2017
BRIEF SUMMARY : Please see package insert for full prescribing 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 administer KYMRIAH to patients with active infection or inflammatory disorders . Treat severe or life-threatening CRS with tocilizumab [ see Dosage and Administration ( 2.2 , 2.3 ) in the full prescribing information , Warnings and Precautions ( 5.1 )].
• 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 [ see Warnings and Precautions ( 5.2 )].
• KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ) called the KYMRIAH REMS [ see Warnings and Precautions ( 5.3 )].
1 INDICATIONS AND USAGE 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 .
4 CONTRAINDICATIONS None .
5 WARNINGS AND PRECAUTIONS 5.1 Cytokine Release Syndrome Cytokine release syndrome ( CRS ), including fatal or life-threatening reactions , occurred following treatment with KYMRIAH . In Study 1 , CRS occurred in 79 % ( 54 / 68 ) of patients receiving KYMRIAH , including Grade 3 or 4 ( Penn grading system 1 ) CRS in 49 % ( 33 / 68 ) of patients . The median time to onset of CRS was 3 days ( range : 1-22 days ). Of the 54 patients with CRS , 27 ( 50 %) received tocilizumab ; 7 ( 13 %) patients received two doses of tocilizumab , 3 ( 6 %) patients received three doses of tocilizumab , and 14 ( 26 %) patients received addition of corticosteroids ( e . g ., methylprednisolone ). The median time to resolution of CRS was 8 days ( range : 1-36 days ).
Key manifestations of CRS include high fever , lower than normal blood pressure , difficulty breathing , and may be associated with hepatic , renal , and cardiac dysfunction , and coagulopathy .
Risk factors for severe CRS are high pre-infusion tumor burden ( greater than 50 % blasts in bone marrow ), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy , active infections , and / or inflammatory processes .
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 , active graft versus host disease ( GVHD ), or worsening of leukemia burden [ see Dosage and Administration ( 2.2 ) in the full prescribing information ].
Ensure that tocilizumab is 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 [ see Patient Counseling Information ( 17 ) in the full prescribing information ]. At the first sign of CRS , immediately evaluate patient for hospitalization and institute treatment with supportive care , tocilizumab and / or cortico - steroids as indicated [ see Dosage and Administration ( 2.3 ) in the full prescribing information ].
5.2 Neurological Toxicities Neurological toxicities , which may be severe or life-threatening can occur following treatment with KYMRIAH . The majority of neurological toxicities occurred within 8 weeks following KYMRIAH infusion . In Study 1 , neurological toxicities within 8 weeks after KYMRIAH infusion occurred in 65 % of patients , including Grade 3 or 4 neurological toxicities in 18 % of patients , and 75 % of events resolved within 12 days . The most common neurological toxicities were headache ( 37 %), encephalopathy ( 34 %), delirium ( 21 %), anxiety ( 13 %), and tremor ( 9 %). Other manifestations of neurological toxicities included disturbances in consciousness , disorientation , confusion , agitation , seizures , mutism and aphasia . Onset of neurological toxicity can be concurrent with CRS , following resolution of CRS or in the absence of CRS .
Monitor patients for neurological events and exclude other causes for neurological symptoms . Provide supportive care as needed for KYMRIAH-associated neurological events .
5.3 KYMRIAH REMS to Mitigate Cytokine Release Syndrome 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 [ see Boxed Warning , Warnings and Precautions ( 5.1 , 5.2 )]. The required components of the KYMRIAH REMS are :
• Healthcare facilities that dispense and administer KYMRIAH must be enrolled and comply with the REMS requirements . Certified healthcare facilities must have on-site , immediate access to tocilizumab , and ensure that a minimum of two doses of tocilizumab are available for each patient for administration within 2 hours after KYMRIAH infusion , if needed for treatment of CRS .
• Certified healthcare facilities must ensure that healthcare providers who prescribe , dispense or administer KYMRIAH are trained about the management of CRS and neurological toxicities .
Further information is available at www . kymriah-rems . com or 1-844-4KYMRIAH .
5.4 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 .
5.5 Serious Infections Serious infections , including life-threatening or fatal infections , occurred in patients after KYMRIAH infusion . In Study 1 , infections ( all Grades ) after KYMRIAH infusion occurred in 40 patients ( 59 %), including 24 patients ( 35 %) with Grade 3-4 infections and 2 patients ( 3 %) with fatal infections . Infections with an unknown pathogen occurred in 41 % of patients , viral infections in 26 %, bacterial infections in 19 %, and fungal infections in 13 %. Prior to KYMRIAH infusion , infection prophylaxis should follow local guidelines . Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately [ see Dosage and Administration ( 2.3 ) in the full prescribing information ].
Febrile neutropenia ( Grade 3 or 4 ) was also observed in 37 % of patients 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 . Hepatitis cases have been reported in patients who are hepatitis B surface antigen ( HBsAg ) positive , and also in patients who are HBsAg-negative but hepatitis B core antibody ( anti-HBc ) positive . HBV reactivation has occurred in patients who appear to have resolved hepatitis B infection ( i . e ., HBsAg-negative , anti-HBc-positive and hepatitis B surface antibody [ anti-HBs ] positive ).
HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg-negative and anti-HBc-positive . Reactivation of HBV replication is often followed by hepatitis , i . e ., increase in trans - aminase levels . In severe cases , increase in bilirubin levels , liver failure , and death can occur .
Perform screening for HBV , HCV , and HIV in accordance with clinical guidelines before collection of cells for manufacturing .
5.6 Prolonged Cytopenias Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion Grade 3 and 4 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 and 4 neutropenia or thrombocytopenia respectively . 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 .
5.7 Hypogammaglobulinemia Hypogammaglobulinemia and agammaglobulinemia ( IgG ) can occur in patients with a complete remission ( CR ) after KYMRIAH infusion . In Study 1 , 43 % of patients had hypogammaglobulinemia . B-cell aplasia is an on-target effect of KYMRIAH and therefore a patient may experience hypogammaglobulinemia for as long as KYMRIAH persists [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ].
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 2 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 immuno - globulin levels in newborns of mothers treated with KYMRIAH .
5.8 Secondary Malignancies Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their leukemia . 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 .
5.9 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 .
6 ADVERSE REACTIONS Most common adverse reactions ( incidence greater than 20 %) are hypogammaglobulinemia , infectionspathogen unspecified , pyrexia , decreased appetite , headache , encephalopathy , bleeding , hypotension , tachycardia , nausea , diarrhea , vomiting , viral infectious disorders , hypoxia , fatigue , acute kidney injury , and delirium .
The following serious adverse reactions are discussed in greater detail in another section of the label :
• Cytokine Release Syndrome [ see Warnings and Precautions ( 5.1 )]
• Neurological Toxicities [ see Warnings and Precautions ( 5.2 )]
• Infections and Febrile Neutropenia [ see Warnings and Precautions ( 5.5 )]
• Prolonged Cytopenias [ see Warnings and Precautions ( 5.6 )]
• Hypogammaglobulinemia [ see Warnings and Precautions ( 5.7 )]
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .
The safety data described in this section reflect exposure to KYMRIAH in the clinical trial ( Study 1 ) in which 68 patients with pediatric and young adult relapsed / refractory ( R / R ) B-cell ALL received CAR-positive viable T cells .
Based on a recommended dose which was weight-based , all patients received a single intravenous dose of KYMRIAH [ see Clinical Studies ( 14 )]. The most common adverse reactions were cytokine release syndrome ( 79 %), hypogammaglobulinemia ( 43 %), infections-pathogen unspecified ( 41 %), pyrexia ( 40 %), decreased appetite ( 37 %), headache ( 37 %), encephalopathy ( 34 %), hypotension ( 31 %), bleeding episodes ( 31 %), tachycardia ( 26 %), nausea ( 26 %), diarrhea ( 26 %), vomiting ( 26 %), viral infectious disorders ( 26 %), hypoxia ( 24 %), fatigue ( 22 %), acute kidney injury ( 22 %), and delirium ( 21 %).
Eleven deaths were reported for patients who received KYMRIAH , of which 2 deaths occurred within 30 days of infusion . Seven were disease-related , three were attributed to infections , and one to intra - cerebral hemorrhage . Of the two deaths before Day 30 , one patient died with CRS and progressive leukemia and the second patient had resolving CRS with abdominal compartment syndrome , coagulopathy , and renal failure when an intracranial hemorrhage occurred .
The adverse reactions with greater or equal to 10 % incidence for any Grade are summarized in Table 2 . Table 2 . Selected Adverse Reactions ( ≥ 10 %) Following Treatment with KYMRIAH ( N = 68 )
Adverse Reaction
All Grades Grades 3 or Higher (%) (%)
Cardiac disorders a Tachycardia 26 4
Gastrointestinal disorders Nausea 26 3 Diarrhea 26 1 Vomiting 26 1 Constipation 18 0 b Abdominal pain 16 3
General disorders and administration site conditions Pyrexia 40 15 Fatigue 22 0 Face edema 10 1 Edema peripheral 10 1 Chills 10 0
Immune system disorders Cytokine release syndrome 79 49 c
Hypogammaglobulinemia 43 7
Infections and infestations Infections-pathogen unspecified 41 16 Viral infectious disorders 26 18 Bacterial infectious disorders 19 13 Fungal infectious disorders 13 7
Investigations International normalized ratio increased 13 0
( continued )