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.

1.3     Adult Relapsed or Refractory (r/r) Follicular Lymphoma (FL)

Adult patients with relapsed or refractory (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 [see Clinical Studies (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

2.1     Dosage in Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)

KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells.

Based on the patient weight reported at the time of leukapheresis:

- Patients 50 kg or less: administer 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight.

- Patients above 50 kg: administer 0.1 to 2.5 x 108 CAR-positive viable T cells.

2.2     Dosage in Adult Relapsed or Refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL)

KYMRIAH is provided as a single-dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells.

 - For adult patients: administer 0.6 to 6.0 x 108 CAR-positive viable T cells.

2.3     Administration

Preparing Patient for KYMRIAH Administration with Lymphodepletion

 - Confirm availability of KYMRIAH prior to starting the lymphodepleting regimen.

Pediatric and Young Adult Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)

• Lymphodepleting chemotherapy: Fludarabine (30 mg/m2 intravenously daily for 4 days) and cyclophosphamide (500 mg/m2 intravenously daily for 2 days starting with the first dose of fludarabine).
• Infuse KYMRIAH 2 to 14 days after completion of the lymphodepleting chemotherapy.

Adult Relapsed or Refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL) and r/r Follicular Lymphoma (FL)

• Lymphodepleting chemotherapy: Fludarabine (25 mg/m2 intravenously daily for 3 days) and cyclophosphamide (250 mg/m2 intravenously daily for 3 days starting with the first dose of fludarabine).

• Alternate lymphodepleting chemotherapy: bendamustine 90 mg/m2 intravenously daily for 2 days if a patient experienced a previous Grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen.

• Infuse KYMRIAH 2 to 11 days (r/r DLBCL) or 2 to 6 days (r/r FL) after completion of the lymphodepleting chemotherapy.

• Lymphodepleting chemotherapy may be omitted if a patient is experiencing significant cytopenia, e.g., white blood cell (WBC) count is less than 1 x 109/L within 1 week prior to KYMRIAH infusion.

Preparation of KYMRIAH for Infusion and Administration

Delay the infusion of KYMRIAH if a patient has unresolved serious adverse reactions (including pulmonary reactions, cardiac reactions, or hypotension) from preceding chemotherapies, active uncontrolled infection, active graft versus host disease (GVHD), or worsening of leukemia burden following lymphodepleting chemotherapy [see Warnings and Precautions (5.1)].

A KYMRIAH dose may be contained in one to three cryopreserved patient specific infusion bag(s). Verify the number of bags received for the dose of KYMRIAH with the Certificate of Conformance (CoC) and Certificate of Analysis (CoA). Coordinate the timing of thaw of KYMRIAH and infusion in the following manner. Confirm the infusion time in advance, and adjust the start time for thaw so that KYMRIAH is available for infusion when the recipient is ready. If more than one bag has been received for the treatment dose, thaw 1 bag at a time. Wait to thaw/infuse the next bag until it is determined that the previous bag is safely administered.

Preparation of KYMRIAH for Infusion

1. Ensure tocilizumab and emergency equipment are available prior to infusion and during the recovery period.

2. Premedicate patient with acetaminophen and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to KYMRIAH infusion. Avoid prophylactic use of systemic corticosteroids, as it may interfere with the activity of KYMRIAH.

3. Confirm patient identity: Prior to KYMRIAH preparation, match the patient's identity with the patient identifiers on each KYMRIAH infusion bag(s). KYMRIAH is for autologous use only. Employ universal precautions to avoid potential transmission of infectious diseases when handling the product.

Note: The patient identifier number may be preceded by the letters DIN or Aph ID.

Figure 1. KYMRIAH Infusion Bag

4. Inspect the infusion bag(s) for any breaks or cracks prior to thawing. If a bag is compromised, do not infuse the contents. Call Novartis at 1-844-4KYMRIAH.

5. Place the infusion bag inside a second, sterile bag in case of a leak and to protect ports from contamination.

6. Thaw each infusion bag one at a time at 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Remove bag from thawing device immediately; do not store product bag at 37°C. Once the infusion bag has been thawed and is at room temperature (20°C to 25°C), it should be infused within 30 minutes. Do not wash, spin down, and/or resuspend KYMRIAH in new media prior to infusion.

7. Inspect the contents of the thawed infusion bag for any visible cell clumps. If visible cell clumps remain, gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not infuse KYMRIAH if clumps are not dispersed, the infusion bag is damaged or leaking, or otherwise appears to be compromised. Call Novartis at 1-844-4KYMRIAH.

Administration

8. Confirm the patient’s identity with the patient identifiers on the infusion bag.

9. Administer KYMRIAH as an intravenous infusion at 10 mL to 20 mL per minute, adjusted as appropriate for smaller children and smaller volumes. The volume in the infusion bag ranges from 10 mL to 50 mL. Do NOT use a leukocyte-depleting filter. If more than one bag is being infused for the treatment dose, wait to thaw/infuse the next bag until it is determined that the previous bag is safely administered.

 - Prime the tubing prior to infusion with sodium chloride 9 mg/mL (0.9%) solution for injection.

 - Infuse all contents of the infusion bag.

 - Rinse the infusion bag with 10 mL to 30 mL sodium chloride 9 mg/mL (0.9%) solution for injection while maintaining a closed tubing system to assure as many cells as possible are infused into the patient.

 - Cells from all the bag(s) must be infused to complete a single dose.

KYMRIAH contains human cells genetically modified with a lentivirus. Follow local biosafety guidelines applicable for handling and disposal of such products.

Monitoring

 - Administer KYMRIAH at a REMS-certified healthcare facility.

 - Monitor patients 2-3 times during the first week following KYMRIAH infusion at the certified healthcare facility for signs and symptoms of CRS and neurologic toxicities [see Warnings and Precautions (5.1, 5.2)].

 - Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following infusion.

 - Instruct patients to refrain from driving or hazardous activities for at least 8 weeks following infusion.

2.4     Management of Severe Adverse Reactions

Cytokine Release Syndrome

Identify cytokine release syndrome (CRS) based on clinical presentation [see Warnings and Precautions (5.1)]. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1 (Lee et al 2014). Alternative CRS management strategies may be implemented based on appropriate institutional or academic guidelines.

Neurologic Toxicities

Patients should be monitored for neurologic toxicities, including ICANS, following KYMRIAH infusion, particularly during and after resolution of CRS. Identify neurologic toxicities based on clinical presentation. Evaluate for and treat other causes of neurological symptoms. Consider non-sedating seizure prophylaxis (e.g., levetiracetam) for patients at higher risk of seizure, such as those with seizure history, CNS disease, concerning EEG findings, or neoplastic brain lesions. If neurologic toxicity is suspected, manage according to the recommendations in Table 2. Alternative neurologic toxicities management strategies may be implemented based on appropriate institutional, academic, or consensus guidelines.

5.1     Cytokine Release Syndrome (CRS)

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 receiving KYMRIAH, including ≥ Grade 3 CRS (Penn grading system1) occurring 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 two doses of tocilizumab and 3 (5%) patients received three doses of tocilizumab; 17 (28%) patients received addition of corticosteroids (e.g., methylprednisolone).

CRS occurred in 85 (74%) of the 115 adult patients with r/r DLBCL receiving KYMRIAH, including ≥ Grade 3 CRS (Penn grading system1) occurring 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 two doses of tocilizumab; 11 (13%) patients received corticosteroids in addition to tocilizumab. One patient received corticosteroids for CRS without concomitant tocilizumab, and two 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 system2). 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 dosages of tocilizumab, 4 (8%) patients required 2 dosages and 8 (16%) patients required 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 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 (93% in r/r ALL; 85% in r/r DLBCL; 92% in r/r FL), hypotension (69% in r/r ALL; 45% in r/r DLBCL; 40% in r/r FL), hypoxia (57% in r/r ALL; 35% in r/r DLBCL; 19% in r/r FL), and tachycardia (26% in r/r ALL; 13% in r/r DLBCL; 2% in r/r FL). 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)].

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.

Ensure that a minimum of two doses of tocilizumab are available on site prior to infusion of KYMRIAH.

Monitor patients 2-3 times during the first week following KYMRIAH infusion at the REMS-certified healthcare 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 [see Dosage and Administration (2.3, 2.4)].

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)].

5.2     Neurological Toxicities

Neurological toxicities, including severe or life-threatening reactions, occurred following treatment with KYMRIAH. Neurologic 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.

Neurologic 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.

Neurologic 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 include headache (35% in r/r ALL; 21% in r/r DLBCL; 25% in r/r FL), encephalopathy (30% in r/r ALL; 16% in r/r DLBCL; 3% in r/r FL), delirium (19% in r/r ALL; 5% in r/r DLBCL; 1% in r/r FL), anxiety (16% in r/r ALL; 10% in r/r DLBCL; 2% in r/r FL), sleep disorders (11% in r/r ALL; 10% in r/r DLBCL; 6% in r/r FL), dizziness (5% in r/r ALL; 12% in r/r DLBCL; 8% of r/r FL), tremor (8% in r/r ALL; 6% r/r DLBCL; 3% of r/r FL), and peripheral neuropathy (4% in r/r ALL; 12% in r/r DLBCL; 7% in r/r FL). Other manifestations included seizures and aphasia.

Monitor patients 2-3 times during the first week following KYMRIAH infusion at the REMS-certified healthcare facility for signs and symptoms of neurologic toxicities. Rule out other causes of neurological symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed [see Dosage and Administration (2.3)].

Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [see Patient Counseling Information (17)].

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     Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (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 > 1 year after receiving KYMRIAH with a fatal outcome. The patient did not have CRS during or immediately preceding HLH. Treatment of HLH should be administered as per institutional standards.

5.5     Hypersensitivity Reactions

Allergic reactions may occur with infusion of KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to the DMSO or dextran 40 in KYMRIAH. Observe patients for hypersensitivity reactions during the infusion.

5.6     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%).

Infections occurred 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%).

Infections occurred 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 [see Dosage and Administration (2.3)].

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.

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.

There is no experience with manufacturing KYMRIAH for patients with a positive test for HIV or with active HBV or active HCV. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

5.7     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 (39%) and neutropenia (25%) among 115 treated patients.

In the ELARA study (Study 3), ≥ 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 GM-CSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.

5.8     Hypogammaglobulinemia

Hypogammaglobulinemia and agammaglobulinemia related to B-cell aplasia can occur in patients after KYMRIAH infusion.

Hypogammaglobulinemia was reported in 53% of patients treated with KYMRIAH for r/r ALL, 17% of patients with r/r DLBCL, and 18% of patients with r/r FL [see Clinical Pharmacology (12.3)].

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 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.

5.9     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.

5.10     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.

6.1     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 three non-randomized, single-arm studies in which 79 pediatric and young adult patients with relapsed/refractory (r/r) B-cell ALL (ELIANA Study), 115 adults with r/r diffuse large B-cell lymphoma (JULIET Study), and 97 adults with r/r follicular lymphoma (ELARA 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 79 patients in the ELIANA study (Study 1) received a single intravenous dose of KYMRIAH [see Clinical Studies (14.1)]. The most common adverse reactions (> 20%) were cytokine release syndrome (77%), infections-pathogen unspecified (57%), hypogammaglobulinemia (53%), fever (42%), decreased appetite (38%), viral infectious disorders (38%), headache (35%), febrile neutropenia (34%), hemorrhage (32%), musculoskeletal pain (32%), vomiting (32%), encephalopathy (30%), bacterial infectious disorders (29%), diarrhea (29%), hypotension (29%), cough (27%), nausea (27%), pain (25%), hypoxia (25%), tachycardia (24%), edema (23%), fatigue (23%), and acute kidney injury (22%).

The adverse reactions with greater or equal to 10% incidence for any Grade are summarized in Table 3.

Laboratory Abnormalities

All patients experienced neutropenia, anemia and thrombocytopenia. See Table 5 for the incidences of ≥ Grade 3 prolonged thrombocytopenia and prolonged neutropenia in responding patients.

Adult r/r Diffuse Large B-cell Lymphoma (DLBCL)

In the JULIET study (Study 2) 115 adults with r/r DLBCL received a single intravenous dose of KYMRIAH [see Clinical Studies (14.2)]. The most common adverse reactions (incidence > 20%) were cytokine release syndrome, infections-pathogen unspecified, fever, diarrhea, nausea, fatigue, hypotension, edema, bleeding episodes, dyspnea, and headache.

The study population characteristics were: median age of 56 years (range: 22-76 years), 80% DLBCL; a median of 3 prior lines of therapy (range: 1-6), 49% had a prior autologous hematopoietic stem cell transplantation, and 32% had received prior radiation therapy. One hundred seven patients (93%) received lymphodepleting chemotherapy prior to KYMRIAH, that included fludarabine (n = 85) or bendamustine (n = 22).

The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 6 below.

Laboratory Abnormalities

Adult r/r Follicular Lymphoma (FL)

The safety of KYMRIAH was evaluated in the ELARA study (Study 3), a trial that included 97 patients with r/r FL who received a single intravenous dose of KYMRIAH [see Clinical Studies (14.3)]. Patients with a history of CNS disorders or autoimmune disease requiring systemic immunosuppression were ineligible. The median age was 57 years (range: 29 to 73 years), 34% were female, 75% were White, 13% were Asian, and 1% were Black or African American.

The most common adverse reactions (incidence > 20%) were cytokine release syndrome, infections-pathogen unspecified, fatigue, musculoskeletal pain, headache, and diarrhea.

The adverse reactions with greater than or equal to 10% incidence for any Grade are summarized in Table 8 below.

Laboratory Abnormalities

6.2     Postmarketing Experience

The following adverse reaction has been identified during postapproval use of KYMRIAH. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

• Anaphylactic reaction

6.3     Immunogenicity

In clinical studies, humoral immunogenicity of KYMRIAH was measured by determination of anti-murine CAR19 antibodies (anti-mCAR19) in serum pre- and post-administration. The majority of patients, 91% in ELIANA (Study 1), 94% in JULIET (Study 2), and 66% in ELARA (Study 3), tested positive for pre-dose anti-mCAR19 antibodies prior to KYMRIAH infusion. Treatment induced anti-mCAR19 antibodies were detected in 9% and 33% of the patients in JULIET and ELARA, respectively. However, the preexisting and treatment-induced antibodies were not associated with an impact on clinical response and did not have an impact on the initial expansion and persistence of KYMRIAH. Persistence of KYMRIAH was similar between patients with positive post-infusion anti-mCAR19 antibodies compared with patients with negative post-infusion anti-mCAR19 antibodies. There is no evidence that the presence of preexisting and treatment-induced anti-mCAR19 antibodies impact the safety or effectiveness of KYMRIAH.

T cell immunogenicity responses were not observed in r/r ALL, r/r DLBCL, or r/r FL patients.

8.1     Pregnancy

Risk Summary

There are no available data with KYMRIAH use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with KYMRIAH to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if KYMRIAH has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, KYMRIAH is not recommended for women who are pregnant, and pregnancy after KYMRIAH administration should be discussed with the treating physician. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. 

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2     Lactation

Risk Summary

There is no information regarding the presence of KYMRIAH in human milk, the effect on the breastfed infant, and the effects on milk production. A risk to the breastfed infant cannot be excluded. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KYMRIAH and any potential adverse effects on the breastfed infant from KYMRIAH or from the underlying maternal condition.

8.3     Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy status of females with reproductive potential should be verified. Sexually-active females of reproductive potential should have a pregnancy test prior to starting treatment with KYMRIAH.

Contraception

See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.

There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with KYMRIAH.

Infertility

There are no data on the effect of KYMRIAH on male and female fertility.

8.4     Pediatric Use

The safety and efficacy of KYMRIAH have been established in pediatric patients with r/r B-cell ALL. Use of KYMRIAH is supported by a single-arm trial [see Clinical Studies (14.1)] that included 61 pediatric patients with r/r B-cell precursor ALL in the following age groups: 40 children (ages 2 years to less than 12 years) and 21 adolescents (ages 12 years to less than 17 years). No differences in efficacy or safety were observed between the different age subgroups or in comparison to the young adults in the trial.

The safety and efficacy of KYMRIAH in pediatric patients with r/r DLBCL and r/r FL have not been established.

8.5     Geriatric Use

The safety and effectiveness of KYMRIAH have not been established in geriatric patients with r/r B-cell ALL. Clinical studies of KYMRIAH did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

12.1     Mechanism of Action

KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. The CAR is comprised of a murine single-chain antibody fragment which recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T cell activation and antitumor activity, while 4-1BB enhances the expansion and persistence of KYMRIAH. Upon binding to CD19-expressing cells, the CAR transmits a signal to promote T cell expansion, activation, target cell elimination, and persistence of the KYMRIAH cells.

12.2     Pharmacodynamics

Due to the on-target effect of KYMRIAH, a period of B-cell aplasia is expected.

Among evaluable pediatric and young adult r/r B-cell ALL patients with an ongoing response at Month 24, 33% had no detectable B cells at baseline prior to infusion. At Month 24, 88% had no detectable B cells.

Most adult r/r DLBCL patients had B-cell depletion at baseline prior to infusion due to previous treatment with rituximab. Recovery of B-cell levels were observed with longer follow-up in some of the responding DLBCL patients after KYMRIAH infusion. Among evaluable adult r/r DLBCL and FL patients with an ongoing response at Month 24, all patients had no detectable B cells at baseline prior to infusion or at Month 24.

12.3     Pharmacokinetics/Cellular Kinetics

Following infusion, KYMRIAH exhibited an initial rapid expansion followed by a bi-exponential decline in pediatric and young adult r/r B-cell acute lymphoblastic leukemia (ALL) patients, adult r/r diffuse large B-cell lymphoma patients, and adult r/r follicular lymphoma patients.

A summary of pharmacokinetic parameters of KYMRIAH is provided in Table 10 below.

Description of Pharmacokinetics in Pediatric and Young Adult r/r B-cell ALL (up to 25 years of age)

The Cmax and AUC0-28d were similar between CR/CRi patients compared with non-responding (NR) patients.

KYMRIAH was present in the blood as well as bone marrow and was measurable beyond 2 years. Blood to bone marrow partitioning suggested that KYMRIAH distribution in bone marrow was 44% of that present in blood at Day 28 while at Months 3 and 6 KYMRIAH distributed at 67% and 69%, respectively, indicating high distribution to bone marrow.

Children < 10 years and between 10-18 years of age had similar- to 1.7-fold higher Cmax and AUC0-28d than adults. Due to small sample size and high variability, it is difficult to assess the impact of age on the pharmacokinetics of KYMRIAH.

Description of Pharmacokinetics in Adult r/r DLBCL

The Cmax and AUC0-28d were similar between responding and non-responding (NR) patients.

KYMRIAH was present in adult r/r DLBCL patients up to 18 months in peripheral blood and up to 9 months in the bone marrow for patients having a complete response. The median time of maximal expansion of transgene levels (Tmax) in peripheral blood occurred at 9-10 days in both responding and non-responding patients.

Description of Pharmacokinetics in Adult r/r FL

KYMRIAH has been detected for up to 18 months in peripheral blood and up to 3 months in bone marrow for patients who achieved a response. The median time of maximal expansion of transgene levels (Tmax) in peripheral blood occurred at 10 days in responding and 13 days in non-responding patients.

The blood to bone marrow partitioning in bone marrow was nearly 50% at Month 3 in responding patients.

The geometric mean AUC0-28d value of responders was 183% higher compared to non-responders, while, the geometric mean Cmax value was 108% higher in responders compared to non-responders. Considering the high inter-individual variability, small number of non-responders, overlapping expansion ranges observed between responders and non-responders, the exposure differences should be interpreted with caution.

Tocilizumab and Corticosteroid used for CRS Management

Some patients required tocilizumab and corticosteroids for the management of CRS. KYMRIAH continues to expand and persist following treatment as per the CRS management algorithm (see Table 1). Patients who have higher expansion tended to have higher CRS Grades [see Warnings and Precautions (5.1)].

Pediatric and young adult r/r B-cell ALL patients (N = 28) treated with tocilizumab had 298% and 183% higher KYMRIAH AUC0-28d and Cmax, respectively, as compared to patients (N = 46) who did not receive tocilizumab. In addition, patients who received corticosteroids for CRS management (N = 17) had 280% higher AUC0-28d compared with patients who did not receive corticosteroids (N = 31).

Adult r/r DLBCL patients treated with tocilizumab (N = 18) had 238% (n = 14) and 311% (n = 16) higher KYMRIAH AUC0-28d and Cmax, respectively, as compared to patients (N = 97) who did not receive tocilizumab. In addition, patients who received corticosteroids for CRS management (N = 12) had 104% and 179% higher AUC0-28d and Cmax, respectively, as compared with patients who did not receive corticosteroids (N = 79).

Adult r/r FL patients treated with tocilizumab (N = 14) had 245% (n = 12) and 312% (n = 11) higher KYMRIAH AUC0-28d and Cmax, respectively, as compared to patients (N = 76) who did not receive tocilizumab. Three patients received corticosteroids for CRS management while all other patients received corticosteroids for other reasons, therefore a formal comparison for exposure differences by use of corticosteroids cannot be performed.

Hepatic and renal impairment studies of KYMRIAH were not conducted.

13.1     Carcinogenesis, Mutagenesis, Impairment of Fertility

Genotoxicity assays and carcinogenicity assessment in rodent models were not performed for KYMRIAH. In vitro expansion studies with transduced T cells (KYMRIAH) from healthy donors and patients showed no evidence for transformation and/or immortalization of T cells. In vivo studies in immunocompromised mice did not show signs of abnormal cell growth or signs of clonal cell expansion for up to 7 months after cell injection. A genomic insertion site analysis was performed on KYMRIAH products from 14 individual donors (12 patients and 2 healthy volunteers). There was no evidence for preferential integration near genes of concern, or preferential outgrowth of cells harboring integration sites of concern.

No studies on the effects of KYMRIAH on fertility have been conducted.

14.1     Relapsed or Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL)

The efficacy of KYMRIAH in pediatric and young adults with r/r B-cell precursor ALL was evaluated in an open-label, multicenter single-arm trial (ELIANA, NCT02435849). In total, 107 patients were screened, 88 were enrolled, 68 were treated, and 63 were evaluable for efficacy. Nine percent of the enrolled patients did not receive the product due to manufacturing failure. The 63 evaluable patients included 35 males and 28 females of median age 12 years (range: 3-23 years). Seventy-three percent of patients were White, 10% were Asian, and 17% were of other races. Six (10%) had primary refractory disease, 30 (48%) had one prior stem cell transplantation, 5 patients (8%) had two stem cell transplantations. Treatment consisted of lymphodepleting chemotherapy (fludarabine 30 mg/m2 daily for 4 days and cyclophosphamide 500 mg/m2 daily for 2 days) followed by a single dose of KYMRIAH. Of the 22 patients who had a WBC count < 1000/µL, 20 received lymphodepleting chemotherapy prior to KYMRIAH while 2 received KYMRIAH infusion without lymphodepleting chemotherapy. Fifty-three patients received bridging chemotherapy between time of enrollment and lymphodepleting chemotherapy.

The efficacy of KYMRIAH was established on the basis of complete remission (CR) within 3 months after infusion, the duration of CR, and proportion of patients with CR and minimal residual disease (MRD) < 0.01% by flow cytometry (MRD-negative) (Table 11). Among the 63 infused patients, 52 (83%) achieved CR/CRi, all of which were MRD-negative. With a median follow-up of 4.8 months from response, the median duration of CR/CRi was not reached (range: 1.2 to 14.1+ months). Median time to onset of CR/CRi was 29 days with onset of CR/CRi between 26 and 31 days for 50/52 (96%) responders. The stem cell transplantation rate among those who achieved CR/CRi was 12% (6/52). Table 11 shows the efficacy results from this study.

14.2     Adult Relapsed or Refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL)

The efficacy and safety of KYMRIAH was evaluated in an open-label, multicenter, single-arm trial (JULIET; NCT02445248). Eligible patients were ≥ 18 years of age with relapsed or refractory DLBCL, who received ≥ 2 lines of chemotherapy, including rituximab and anthracycline, or relapsed following autologous hematopoietic stem cell transplantation (HSCT). The study excluded patients with active central nervous system malignancy, prior allogenic HSCT, an ECOG performance status ≥ 2, a creatinine clearance < 60, alanine aminotransferase > 5 times normal, cardiac ejection fraction < 45%, or absolute lymphocyte concentration less than 300/µL.

Following 2 to 11 days after completion of lymphodepleting (LD) chemotherapy consisting of either fludarabine (25 mg/m2 intravenously daily for 3 days) and cyclophosphamide (250 mg/m2 intravenously daily for 3 days starting with the first dose of fludarabine) or bendamustine (90 mg/m2 intravenously daily for 2 days), KYMRIAH was administered as a single intravenous infusion. Bridging chemotherapy between leukapheresis and LD chemotherapy was permitted to control disease burden. LD chemotherapy could be omitted if the white blood cell count was < 1000 cells/µL. The major efficacy outcome measures were objective response rate per Lugano criteria [2014] as assessed by an independent review committee and duration of response.

Of the 160 patients enrolled, 106 patients received tisagenlecleucel, including 92 patients who received product manufactured in the U.S. and were followed for at least 3 months or discontinued earlier. Eleven out of 160 patients enrolled did not receive tisagenlecleucel due to manufacturing failure. Thirty-eight other patients did not receive tisagenlecleucel, primarily due to death (n = 16), physician decision (n = 16), and adverse events (n = 3).

Of the 92 patients receiving KYMRIAH, 90% received physician’s choice of bridging chemotherapy in the interval between start of screening and KYMRIAH infusion, among whom the median number of bridging chemotherapy regimens was 1 (range: 1 to 5) with 83% of patients receiving ≤ 2 regimens. A retrospectively identified sub-group of 68 patients was evaluable for the major efficacy outcome measures. Patients included in this sub-group had either had no bridging chemotherapy, or had imaging that showed measurable disease after completion of bridging chemotherapy, prior to KYMRIAH infusion. Of the 24 patients not included, 8 had no evidence of disease at baseline prior to KYMRIAH infusion, 15 did not have baseline imaging following bridging chemotherapy, and 1 was excluded because of initial misclassification of a neuroendocrine tumor as DLBCL.

Among the efficacy evaluable population of 68 patients, the baseline characteristics were: median age 56 years (range: 22 to 74 years); 71% male; 90% White, 4% Asian, and 3% Black or African American; 78% had primary DLBCL not otherwise specified (NOS) and 22% had DLBCL following transformation from follicular lymphoma, of whom 17% were identified as high grade; and 44% had undergone prior autologous HSCT. The median number of prior therapies was 3 (range: 1 to 6), 56% had refractory disease and 44% relapsed after their last therapy. Ninety percent of patients received lymphodepleting chemotherapy (66% of patients received fludarabine and 24% received bendamustine) and 10% did not receive any LD chemotherapy. The median time from leukapheresis and cryopreservation to KYMRIAH infusion was 113 days (range: 47 to 196 days). The median dose was 3.5 × 108 CAR-positive viable T cells (range: 1.0 to 5.2 × 108 cells). Seventy-three percent of patients received KYMRIAH in the inpatient setting.

Efficacy was established on the basis of complete response (CR) rate and duration of response (DOR), as determined by an independent review committee (Table 12 and Table 13). The median time to first response to KYMRIAH (CR or PR) was 0.9 months (range: 0.7 to 3.3 months). The median duration of response was not reached. Response durations were longer in patients who achieved CR, as compared to patients with a best response of partial response (PR) (Table 13). Of the 22 patients who experienced a CR, 9 achieved this status by 1 month, 12 more by month 3, and the last by month 6 after KYMRIAH infusion.

14.3     Adult Relapsed or Refractory (r/r) Follicular Lymphoma (FL)

The efficacy of KYMRIAH was evaluated in a multicenter, single-arm, open-label trial (ELARA, Study 3; NCT03568461) that included patients who were refractory to or relapsed within 6 months after completion of two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent), relapsed during or within six months after completion of an anti-CD20 antibody maintenance therapy following at least two lines of therapy, or relapsed after autologous hematopoietic stem cell transplant (HSCT). The trial excluded patients with active or serious infections, transformed lymphoma, or other aggressive lymphomas, prior allogeneic HSCT, or disease with active CNS involvement. Following lymphodepleting (LD) chemotherapy, KYMRIAH was administered as a single dose intravenous infusion with a target dose of 0.6 to 6.0 × 108 CAR-positive viable T cells. The median dose administered was 2.06 × 108 CAR-positive viable T-cells (range: 0.1 to 6.0 × 108 CAR-positive viable T cells). The LD chemotherapy regimen consisted of either fludarabine (25 mg/m2 intravenously daily for 3 days) and cyclophosphamide (250 mg/m2 intravenously daily for 3 days starting with the first dose of fludarabine) or bendamustine (90 mg/m2 IV daily for 2 days); bridging chemotherapy between leukapheresis and LD chemotherapy was permitted as needed. Of the 90 patients included in the primary efficacy analysis, 40 patients (45%) were treated with bridging therapies. The most commonly used agents (in ≥ 5% of patients) were rituximab (22%), dexamethasone (13%), gemcitabine (12%), prednisone (11%), oxaliplatin (8%), etoposide (8%), and vincristine (6%).

Of 98 patients who were enrolled and underwent leukapheresis, 97 patients received infusion with KYMRIAH and one patient without measurable disease did not receive KYMRIAH. There were no manufacturing failures for the 98 enrolled patients. Of the 97 patients infused with KYMRIAH, the efficacy evaluable population, as specified in the protocol, included the first 90 patients with measurable disease who received KYMRIAH consecutively and had at least 9 months follow-up from first objective response or discontinued earlier.

Among the 90 patients with FL included in the efficacy analysis, the median age was 58 years (range: 29 to 73 years), 31% were female, 78% were White, 10% were Asian, and 1% were Black or African American. The median number of prior therapies was 4 (range: 2 to 13), with 24% receiving 2 prior lines, 21% receiving 3 prior lines, and 54% receiving ≥4 prior lines. Eighty-seven percent had Stage III-IV disease at study entry, 64% had bulky disease, 36% had a prior autologous HSCT, 79% were refractory to the most recent regimen, and 66% had progression within 24 months of initiating their first anti-CD20 combination therapy (POD24).

Efficacy was established on the basis of objective response rate and duration of response (DOR) as determined by an independent review committee (Table 14 and Table 15). The first disease assessment was scheduled to be performed at Month 3 post-infusion; the median time to first response was 2.9 months (range: 0.6 to 6.0 months). All responders achieved their response (complete response [CR] or partial response [PR]) at the first performed post-infusion disease assessment.