KYMRIAH

Chimeric Antigen Receptor (CAR) T-Cell Therapy

NOTE: Employ universal precautions in handling leukapheresis material or tisagenlecleucel; follow local biosafety guidelines applicable for disposal of such products.
Emetic Risk
Low
Administer routine antiemetic prophylaxis prior to treatment.

Visually inspect the contents of the infusion bag(s) for any breaks or cracks and the thawed infusion bag for any visible cell clumps prior to administration. Do not infuse the contents if the bag is compromised or if clumps do not disperse after thawing and gentle mixing and call Novartis at 1-844-4KYMRIAH.

Tisagenlecleucel is for autologous and intravenous use.
Each dose of tisagenlecleucel is suspended in 1 to 3 patient-specific infusion bag(s); the total infusion bag volume ranges from 10 to 50 mL.
Each dose is patient specific; see the Certificate of Analysis for the actual number of chimeric antigen receptor (CAR)-positive T-cells in the product.
Verify the number of bags received for the dose; see the Certificate of Conformance.
Ensure tocilizumab and emergency equipment are available prior to the infusion and during the recovery period.
Coordinate the timing of the tisagenlecleucel thaw and infusion; confirm the infusion time in advance, and adjust the start time for thaw so that the recipient will be ready.
Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion; avoid the prophylactic use of corticosteroids.
 
Preparation
Match the patient's identity with the patient identifiers on the infusion bag(s).
Put the infusion bag inside a second, sterile bag to protect against leaks and port contamination.
Thaw each infusion bag one at a time at 37 degrees Celsius (C) using either a water bath or dry thaw method; once there is no visible ice in the infusion bag, remove it from the thawing device immediately.
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 has been safely administered.
Do not wash, spin down, and/or resuspend tisagenlecleucel in new media prior to infusion.
If visible cell clumps remain after thawing, gently mix the contents of the bag to allow the clumps of cellular material to disperse.
Storage of thawed infusion bag: once the product is at room temperature (20 to 25 degrees C), administer within 30 minutes.
 
Intravenous (IV) Infusion
Confirm the patient’s identity with the patient identifiers on the infusion bag(s).
Prime the tubing with normal saline prior to the infusion.
Administer as an IV infusion at a rate of 10 mL to 20 mL per minute until infusion bag is empty; adjust this rate as appropriate for smaller children and smaller volumes.
Do not use a leukocyte-depleting filter.
Rinse the infusion bag with 10 mL to 30 mL of normal saline; maintain a closed tubing system to assure as many cells as possible are infused into the patient.
Cells from all of the bag(s) must be infused to complete a single dose.

lymphopenia / Delayed / 0-95.0
neutropenia / Delayed / 0-82.0
leukopenia / Delayed / 0-78.0
anemia / Delayed / 0-59.0
thrombocytopenia / Delayed / 0-56.0
infection / Delayed / 21.0-48.0
cytokine release syndrome / Rapid / 0-48.0
elevated hepatic enzymes / Delayed / 0-29.0
hypokalemia / Delayed / 0-28.0
hypophosphatemia / Delayed / 12.0-24.0
neurotoxicity / Early / 6.0-22.0
hypotension / Rapid / 0-20.0
hypoxia / Early / 0-20.0
hyperbilirubinemia / Delayed / 0-19.0
anorexia / Delayed / 0-15.0
dyspnea / Early / 0-14.0
nephrotoxicity / Delayed / 0-14.0
fever / Early / 1.0-13.0
hypogammaglobulinemia / Delayed / 1.0-13.0
hyperglycemia / Delayed / 0-13.0
encephalopathy / Delayed / 0-11.0
hypofibrinogenemia / Delayed / 0-11.0
bleeding / Early / 0-10.0
heart failure / Delayed / 0-9.0
pulmonary edema / Early / 0-9.0
edema / Delayed / 0-8.0
seizures / Delayed / 0-6.0
tumor lysis syndrome (TLS) / Delayed / 2.0-6.0
fatigue / Early / 0-6.0
hypocalcemia / Delayed / 0-6.0
thrombosis / Delayed / 1.0-6.0
visual impairment / Early / 0-6.0
coagulopathy / Delayed / 0-6.0
hemophagocytic lymphohistiocytosis / Delayed / 1.0-6.0
macrophage activation syndrome / Delayed / 1.0-6.0
hypertension / Early / 0-5.0
tachypnea / Early / 0-5.0
delirium / Early / 0-4.0
sinus tachycardia / Rapid / 0-4.0
musculoskeletal pain / Early / 1.0-4.0
acute respiratory distress syndrome (ARDS) / Early / 0-4.0
pleural effusion / Delayed / 0-4.0
weight loss / Delayed / 0-4.0
headache / Early / 1.0-3.0
peripheral neuropathy / Delayed / 0-3.0
anxiety / Delayed / 0-3.0
capillary leak syndrome / Early / 0-3.0
abdominal pain / Early / 1.0-3.0
nausea / Early / 1.0-3.0
graft-versus-host disease (GVHD) / Delayed / 0-3.0
pancytopenia / Delayed / 3.0-3.0
dizziness / Early / 0-2.0
diarrhea / Early / 1.0-2.0
stroke / Early / 0-1.0
vomiting / Early / 0-1.0
constipation / Delayed / 0-1.0
arthralgia / Delayed / 0-1.0
intracranial bleeding / Delayed / 0-1.0
rash / Early / 0-1.0
hallucinations / Early / Incidence not known
cardiac arrest / Early / Incidence not known
AV block / Early / Incidence not known
atrial fibrillation / Early / Incidence not known
renal tubular necrosis / Delayed / Incidence not known
renal failure / Delayed / Incidence not known
anuria / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
hematemesis / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
ocular hemorrhage / Delayed / Incidence not known
retinal hemorrhage / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
hemorrhagic cystitis / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known

antibody formation / Delayed / 0-33.0
stomatitis / Delayed / 4.0-6.0
erythema / Early / 2.0-6.0
infusion-related reactions / Rapid / 3.0-6.0
ascites / Delayed / 0-4.0
hypercalcemia / Delayed / 0-4.0
ataxia / Delayed / 0-2.0
hemolysis / Early / 0-2.0
hyperesthesia / Delayed / Incidence not known
dyskinesia / Delayed / Incidence not known
dysarthria / Delayed / Incidence not known
myopathy / Delayed / Incidence not known
aphasia / Delayed / Incidence not known
supraventricular tachycardia (SVT) / Early / Incidence not known
QT prolongation / Rapid / Incidence not known
oral ulceration / Delayed / Incidence not known
bone pain / Delayed / Incidence not known
hypervolemia / Delayed / Incidence not known
fluid retention / Delayed / Incidence not known
melena / Delayed / Incidence not known
vaginal bleeding / Delayed / Incidence not known
hemoptysis / Delayed / Incidence not known
hematoma / Early / Incidence not known
hematuria / Delayed / Incidence not known
contact dermatitis / Delayed / Incidence not known
blurred vision / Early / Incidence not known
prolonged bleeding time / Delayed / Incidence not known

cough / Delayed / 17.0-27.0
chills / Rapid / 6.0-12.0
nasal congestion / Early / 2.0-11.0
influenza / Delayed / 0-9.0
pruritus / Rapid / 4.0-9.0
tremor / Early / 3.0-8.0
asthenia / Delayed / 0-7.0
xerostomia / Early / 1.0-5.0
myalgia / Early / 0-5.0
night sweats / Early / 1.0-5.0
hyperhidrosis / Delayed / 1.0-4.0
rhinorrhea / Early / 0-2.0
flushing / Rapid / 0-1.0
muscle cramps / Delayed / Incidence not known
dysesthesia / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
hypoesthesia / Delayed / Incidence not known
weakness / Early / Incidence not known
insomnia / Early / Incidence not known
nightmares / Early / Incidence not known
epistaxis / Delayed / Incidence not known
petechiae / Delayed / Incidence not known
purpura / Delayed / Incidence not known

Cytokine release syndrome (CRS) has been reported with tisagenlecleucel; some cases were fatal or life-threatening. Do not administer tisagenlecleucel in patients with active infection or inflammatory disorders. Delay the tisagenlecleucel infusion in patients who have unresolved serious adverse reactions from preceding chemotherapy (e.g., pulmonary or cardiac reactions or hypotension), active graft-versus-host disease (GVHD), or worsening leukemia burden following lymphocyte depleting chemotherapy. Confirm that 2 doses of tocilizumab are available at the facility site prior to the tisagenlecleucel infusion. Monitor patients for signs and symptoms of CRS 2 to 3 times during the first week following the tisagenlecleucel infusion at a certified healthcare facility, then monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment. CRS may be associated with hepatic, renal, and cardiac dysfunction and coagulopathy. Management of CRS may include hospitalization, supportive care (e.g., oxygen, fluids, high-dose vasopressors), medical management (e.g., tocilizumab and corticosteroids), and mechanical ventilation. Alternative CRS management strategies may be employed using institutional or academic guidelines. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Patients with B-cell acute lymphoblastic leukemia and a high tumor burden (i.e., greater than 50% blasts in the bone marrow), an active uncontrolled infection, or active GVHD may be at increased risk of developing severe CRS.

Severe and life-threatening neurotoxicity (e.g., encephalopathy, seizures) has been reported with tisagenlecleucel therapy; most cases occurred within 8 weeks of the tisagenlecleucel infusion. Consider non-sedating prophylaxis (e.g., levetiracetam) in patients who may be at high risk of having a seizure (e.g., history of seizures, central nervous system disease, abnormal EEG findings, or neoplastic brain tumor/lesions). Monitor patients for signs and symptoms of neurotoxicity 2 to 3 times during the first week at a certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion. Rule out other causes of neurologic symptoms; administer supportive care and/or corticosteroids as indicated. Advise patients to avoid driving or operating machinery or performing other hazardous activities for 8 weeks after the tisagenlecleucel infusion due to the risk of neurotoxicity (e.g., altered mental status or coordination).

KYMRIAH

Rx

CD19-directed chimeric antigen receptor (CAR) T-cell therapy
Used in patients aged up to 25 years with relapsed or refractory B-cell precursor acute lymphoblastic leukemia and in adult patients with relapsed or refractory large B-cell lymphoma or follicular lymphoma after 2 or more lines of systemic therapy
Cytokine release syndrome and severe neurotoxicity have been reported

For patients weighing greater than 50 kg, infuse a single dose of 0.1 to 2.5 X 108 CAR-positive viable T-cells (non-weight based). For patients weighing 50 kg or less, infuse a single dose of 0.2 to 5 X 106 CAR-positive viable T-cells per kg of body weight. Administer tisagenlecleucel at 2 to 14 days after the completion of lymphocyte depletion therapy. Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion. Ensure that tocilizumab and emergency equipment are available at the facility site prior to the infusion and during the recovery period. Additionally, confirm that tisagenlecleucel is available prior to starting the lymphocyte depletion regimen. Lymphocyte depletion therapy consists of fludarabine (30 mg/m2 IV daily for 4 days) plus cyclophosphamide (500 mg/m2 IV daily for 2 doses starting with the first fludarabine dose). The 3-month complete remission (CR) rate (CR + CR with incomplete hematologic recovery (CRi) rate) was 82% in 79 patients (median age, 12 years; range, 3 to 24 years) with relapsed or refractory B-cell ALL who received a single infusion of tisagenlecleucel in a phase 2 (ELIANA) trial. At a median follow-up time of 38.8, the median duration of response had not been reached, the median event-free survival (EFS) time was 24 months, and the median overall survival (OS) time had not been reached. At the time of analysis, the EFS and OS rates were 44% and 63%, respectively. Additionally, 22% of patients underwent a subsequent allogeneic stem-cell transplant. In this trial, leukapheresis was performed per institutional guidelines. Following leukapheresis and T-cell collection, most patients received bridging chemotherapy and all patients had lymphocyte depletion with fludarabine and cyclophosphamide. Prior to treatment with tisagenlecleucel, patients in this study had received a median of 3 (range, 1 to 8) prior therapies and 61% of patients had received a hematopoietic stem cell transplant.

0.6 to 6 X 108 chimeric antigen receptor (CAR)-positive viable T-cells infused as a single-dose which may be suspended in 1 or more patient-specific infusion bag(s). Administer tisagenlecleucel at 2 to 11 days after the completion of lymphocyte depletion therapy. Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion. Ensure that tocilizumab and emergency equipment are available at the facility site prior to the infusion and during the recovery period. Additionally, confirm that tisagenlecleucel is available prior to starting the lymphocyte depletion regimen. Lymphocyte depletion therapy consists of fludarabine (25 mg/m2 IV daily for 3 days) plus cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine); alternative therapy consists of bendamustine (90 mg/m2 IV daily for 2 days) for patients who experienced grade 4 hemorrhagic cystitis with prior cyclophosphamide administration or had resistance to a previous cyclophosphamide-containing regimen. Lymphocyte depletion therapy may be omitted in patients who have a white blood cell count of 1 X 109 cells/L or less within 1 week prior to the tisagenlecleucel infusion.[62282] The independent review committee-assessed overall response rate was 53% following a single infusion of tisagenlecleucel in 115 adult patients with relapsed or refractory DLBCL included in the efficacy analysis who received 2 or more lines of prior chemotherapy (including rituximab and an anthracycline) and had a relapse following autologous hematopoietic stem-cell transplantation (HSCT) or were ineligible for a HSCT in a nonrandomized, phase 2a trial (the JULIET trial). In these patients, the complete response rate was 39% and the partial response rate was 14%. At a median follow-up time of 40.3 months, the median progression-free survival time was 2.9 months and the median overall survival time was 11.1 months. Most patients (90%) received bridging therapy prior to the tisagenlecleucel infusion; additionally, 93% of patients received lymphocyte depletion therapy.

0.6 to 6 X 108 chimeric antigen receptor (CAR)-positive viable T-cells infused as a single-dose which may be suspended in 1 or more patient-specific infusion bag(s). Administer tisagenlecleucel at 2 to 6 days after the completion of lymphocyte depletion therapy. Premedicate patients with acetaminophen and a H1-antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes prior to the infusion. Ensure that tocilizumab and emergency equipment are available at the facility site prior to the infusion and during the recovery period. Additionally, confirm that tisagenlecleucel is available prior to starting the lymphocyte depletion regimen. Lymphocyte depletion therapy consists of fludarabine (25 mg/m2 IV daily for 3 days) plus cyclophosphamide (250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine); alternative therapy consists of bendamustine (90 mg/m2 IV daily for 2 days) for patients who experienced grade 4 hemorrhagic cystitis with prior cyclophosphamide administration or had resistance to a previous cyclophosphamide-containing regimen. Lymphocyte depletion therapy may be omitted in patients who have a white blood cell count of 1 X 109 cells/L or less within 1 week prior to the tisagenlecleucel infusion. The independent review committee-assessed complete response rate (primary endpoint) was 69.1% following a single dose of tisagenlecleucel in 94 adult patients with relapsed or refractory grade 1, 2, or 3A follicular lymphoma included in the efficacy analysis who received 2 or more lines of prior chemotherapy in a multinational, phase 2 trial (the ELARA trial). In these patients, the overall response rate was 86.2%. At a median follow-up time of 16.85 months, the median progression-free survival (PFS) time was not reached; the 12-month PFS rate was 67%. Patients in this study had received a median of 4 (range, 2 to 13) prior therapies; all patients had received an anti-CD20 monoclonal antibody plus an alkylating agent and 36.1% of patients had received an autologous hematopoietic stem-cell transplantation. Bridging therapy prior to the tisagenlecleucel infusion was administered in 45% of patients.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Live Vaccines: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel therapy, and prior to immune recovery following treatment with tisagenlecleucel. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

KYMRIAH/Tisagenlecleucel Intravenous Inj Susp

Diffuse Large B-cell Lymphoma or Follicular Lymphoma Adults 18 years and older: 6 X 108 CAR-positive viable T-cells.
Acute Lymphocytic Leukemia Older than 25 years: Safety and Efficacy not established. 25 years or younger: Greater than 50 kg: 2.5 X 108 CAR-positive viable T-cells. 50 kg or less: 5 X 106 CAR-positive viable T-cells per kg.

6 X 108 CAR-positive viable T-cells.

Greater than 50 kg: 2.5 X 108 CAR-positive viable T-cells.
50 kg or less: 5 X 106 CAR-positive viable T-cells per kg.

Greater than 50 kg: 2.5 X 108 CAR-positive viable T-cells.
50 kg or less: 5 X 106 CAR-positive viable T-cells per kg.

5 X 106 CAR-positive viable T-cells per kg.

5 X 106 CAR-positive viable T-cells per kg.

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that works by redirecting T-cells to target the CD19 antigen on B-cells in patients with hematologic malignancies. The extracellular domain of tisagenlecleucel is a murine monoclonal antibody that targets human CD19. The intracellular domain, CD3-zeta, initiates T-cell activation and mediates antitumor activity; the 4-1BB (CD137) costimulatory domain promotes antitumor activity and enhances proliferation of CAR T-cells. The binding of CAR to CD19 activates tisagenlecleucel and promotes cell expansion and differentiation and triggers the lysis of CD19-positive cells.
This immunotherapy involves removing, genetically modifying, and then re-infusing a patient’s own T-cells. During the manufacturing process, a lentiviral vector encodes the CAR molecule via transduction; the vector enters the cell and becomes integrated into the chromosomes of T cells and directs transcription of the tisagenlecleucel CAR.
To produce CAR T-cell therapy, T-cells are collected from the blood by leukapheresis; enriched by counterflow centrifugal elutriation; activated by using antibody-coated beads; incubated with a viral vector encoding the CD19 CAR; expanded to large numbers in a bioreactor culture system; and then washed, concentrated, and cryopreserved.

Tisagenlecleucel is administered intravenously. In patients with acute lymphoblastic leukemia (ALL), tisagenlecleucel distribution in bone marrow was 44% of that present in blood at day 28; at months 3 and 6, tisagenlecleucel distribution in the bone marrow was 67% and 69%, respectively. In ALL patients, the geometric mean half-life was 16.8 days (coefficient of variance, (CV), 155.9%) in responding patients (n = 54) and 2.52 days (CV, 171.9%) in nonresponding patients (n = 3). In diffuse large B-cell lymphoma (DLBCL) patients, the geometric mean half-life was 45.3 days (CV, 157.7%) in responding patients (n = 21) and 13.6 days (CV, 167%) in nonresponding patients (n = 22). In follicular lymphoma patients, the geometric mean half-life was 44 days (CV, 296%) in responding patients (n = 42) and 24.4 days (CV, 180%) in nonresponding patients (n = 6).

After IV administration, tisagenlecleucel exhibits an initial rapid expansion followed by a bi-exponential decline. The Cmax and AUC(0 to 28 days) values were similar in responding acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) patients compared with nonresponding ALL and DLBCL patients. In patients with follicular lymphoma, the geometric mean Cmax and AUC(0 to 28 days) values were 108% and 183% higher, respectively, in responders compared with nonresponders. In patients with ALL, the geometric mean Cmax in responding patients (n = 61) was 34,700 copies/microgram (mcg) (CV, 155.4%), reached at a median Tmax of 9.91 days; the geometric mean AUC(0 to 28 days) in responding patients was 318,000 copies/mcg X day (CV, 177.8%). Concentrations were lower in ALL patients who did not respond, with a geometric mean Cmax (n = 7) of 20,000 copies/mcg (CV, 71.6%), median Tmax of 20 days, and geometric mean AUC (n = 6) of 156,000 copies/mcg X day (CV, 99.4%). In patients with DLBCL, the geometric mean Cmax in responding patients (n = 33) was 5,210 copies/mcg (CV, 256.5%), reached at a median Tmax of 9.83 days; the geometric mean AUC(0 to 28 days) in responding patients was 582,000 copies/mcg X day (CV, 165.1%). Concentrations were higher in DLBCL patients who did not respond, with a geometric mean Cmax (n = 32) of 6,450 copies/mcg (CV, 408.2%), median Tmax of 8.39 days, and geometric mean AUC(0 to 28 days) (n = 25) of 75,800 copies/mcg X day (CV, 292.3%). The median Tmax for the expansion of transgene levels in peripheral blood occurred at 9 to 10 days in both responding and non-responding patients. In patients with follicular lymphoma, the geometric mean Cmax in responding patients (n = 64) was 6,250 copies/mcg (CV, 344%), reached at a median Tmax of 9.94 days; the geometric mean AUC(0 to 28 days) in responding patients was 56,900 copies/mcg X day (CV, 270%). Concentrations were lower in follicular lymphoma patients who did not respond, with a geometric mean Cmax (n = 8) of 3,000 copies/mcg (CV, 1,190%), median Tmax of 13 days, and geometric mean AUC(0 to 28 days) of 20,100 copies/mcg X day (CV, 18,100%).

Pregnancy should be avoided by females of reproductive potential during tisagenlecleucel treatment; pregnancy after tisagenlecleucel administration should be discussed with the treating physician. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. There are no available data with tisagenlecleucel use in pregnant women; animal reproductive and developmental toxicity studies have not been conducted. It is not known if tisagenlecleucel has the potential to be transferred to the fetus. However, based on its mechanism of action, fetal toxicity including B-cell lymphocytopenia may occur if the transduced cells cross the placenta.

Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for tisagenlecleucel and any potential adverse effects on the breast-fed infant from tisagenlecleucel or from the underlying maternal condition. It is not known whether tisagenlecleucel is present in human milk, although many drugs are excreted in human milk.