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 or tocilizumab and corticosteroids [ see Dosage and Administration ( 2.3 , 2.4 ) 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 :
1.1 Pediatric and Young Adult Relapsed or Refractory ( r / r ) B-cell Acute Lymphoblastic Leukemia ( ALL ) Patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia ( ALL ) that is refractory or in second or later relapse .
1.2 Adult Relapsed or Refractory ( r / r ) Diffuse Large B-Cell Lymphoma ( DLBCL ) 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 .
4 CONTRAINDICATIONS None .
5 WARNINGS AND PRECAUTIONS 5.1 Cytokine Release Syndrome ( CRS ) CRS , including fatal or life-threatening reactions , occurred following treatment with KYMRIAH . CRS occurred in 54 ( 79 %) of the 68 pediatric and young adult patients with r / r ALL and 78 ( 74 %) of the 106 adult patients with r / r DLBCL receiving KYMRIAH , including ≥ Grade 3 ( Penn grading system 1 ) 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 two patients was onset after Day 10 . The median time to resolution of CRS was 8 days ( range : 1-36 ).
Of the 54 patients with r / r ALL who had CRS , 27 ( 50 %) received tocilizumab . Seven ( 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 ). 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 . One patient with r / r ALL died with CRS and progressive leukemia , and one patient had resolving CRS with abdominal compartment syndrome , coagulopathy , and renal failure when an intracranial hemorrhage occurred . 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 ALL and r / r DLBCL ), hypotension ( 67 % in r / r ALL ; 47 % in r / r DLBCL ), hypoxia ( 20 % in r / r ALL ; 35 % in r / r DLBCL ) and tachycardia ( 30 % in r / r ALL ; 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 , active graft versus host disease ( GVHD ), or worsening of leukemia burden [ see Dosage and Administration ( 2.3 ) in the full prescribing information ].
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 [ 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 corticosteroids as indicated [ see Dosage and Administration ( 2.3 , 2.4 ) in the full prescribing information ].
Risk factors for severe CRS in the pediatric and young adult r / r B-cell ALL population 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 . Risk factors for developing severe CRS in adult r / r DLBCL are not known .
5.2 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 include headache ( 37 % in r / r ALL ; 21 % in r / r DLBCL ), encephalopathy ( 34 % in r / r ALL ; 16 % in r / r DLBCL ), delirium ( 21 % in r / r ALL ; 6 % in r / r DLBCL ), anxiety ( 13 % in r / r ALL ; 9 % in r / r DLBCL ), sleep disorders ( 10 % in r / r ALL ; 9 % in r / r DLBCL ), dizziness ( 6 % in r / r ALL ; 11 % in r / r DLBCL ), tremor ( 9 % in r / r ALL ; 7 % r / r DLBCL ) and peripheral neuropathy ( 4 % in r / r ALL ; 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 .
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 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 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 [ see Dosage and Administration ( 2.3 ) in the full prescribing information ].
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 .
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 .
5.6 Prolonged Cytopenias Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion .
In the ELIANA study ( Study 1 ), ≥ 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 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 .
5.7 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 43 % of patients treated with KYMRIAH for r / r ALL and 14 % of patients with r / r DLBCL [ 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 .
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 .
5.8 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 .
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
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 the WARNINGS AND PRECAUTIONS and in this section reflect exposure to KYMRIAH in two non-randomized , single-arm studies in which 68 pediatric and young adult patients with relapsed / refractory ( r / r ) B-cell ALL ( ELIANA Study ) and 106 adults with r / r diffuse large B-cell lymphoma ( JULIET Study ) received a single dose of CAR-positive viable T cells .
Pediatric and Young Adult r / r B-cell Acute Lymphoblastic Leukemia ( ALL ) ( up to 25 years of age ) Based on a recommended dose which was weight-based , all 68 patients in the ELIANA study ( Study 1 ) received a single intravenous dose of KYMRIAH [ see Clinical Studies ( 14.1 ) in the full prescribing information ]. The most common adverse reactions (> 20 %) 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 ( 25 %), acute kidney injury ( 24 %), edema ( 21 %), cough ( 21 %), and delirium ( 21 %).
The adverse reactions with greater or equal to 10 % incidence for any Grade are summarized in Table 2 .
Table 2 . Selected Adverse Reactions Anytime After Infusion ( ≥ 10 %) Following Treatment with KYMRIAH in Pediatric and Young Adult r / r B-cell ALL ( N = 68 )
Adverse Reaction
All Grades Grades 3 or Higher (%) (%)
Blood and lymphatic system disorders Febrile Neutropenia 37 37
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 c
Fatigue 25 0 d
Edema 21 1 Chills 10 0 e
Pain 18 3
Immune system disorders Cytokine release syndrome 79 49 f
Hypogammaglobulinemia 43 7 ( continued )