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 disor-
ders. 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 treat-
ment 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 lym-
phoma 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 cortico -
steroids 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 resolu-
tion of CRS.
Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and pro-
gressive leukemia, and one patient had resolving CRS with abdominal compartment syndrome, coagulopa-
thy, 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 indi-
cated [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 follow-
ing lymphodepleting chemotherapy, active infections, and/or inflammatory processes. Risk factors for devel-
oping 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 neuropa-
thy (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 sup-
portive 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 pro-
gram under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS [see Boxed Warn-
ing, 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 ana-
phylaxis, 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 infu-
sion, 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 med-
ically 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 fol-
lowing 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, particu-
larly 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 informa-
tion]. The most common adverse reactions (> 20%) were cytokine release syndrome (79%), hypogamma-
globulinemia (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
Blood and lymphatic system disorders
Febrile Neutropenia
Cardiac disorders
a
Tachycardia
Gastrointestinal disorders
Nausea
Diarrhea
Vomiting
Constipation
b
Abdominal pain
General disorders and administration site conditions
Pyrexia
c
Fatigue
d
Edema
Chills
e
Pain
Immune system disorders
Cytokine release syndrome
f
Hypogammaglobulinemia
All Grades
(%) Grades 3 or Higher
(%)
37 37
26 4
26
26
26
18
16 3
1
1
0
3
40
25
21
10
18 15
0
1
0
3
79
43 49
7
(continued)