Lisocabtagene maraleucel is a chimeric antigen receptor (CAR) T-cell gene therapy. It is CD19-directed immunotherapy that works by using a patient's own genetically altered immune cells to kill B-cell cancer cells in the blood. Lisocabtagene maraleucel is indicated for use in adult patients with relapsed or refractory large B-cell lymphoma and chronic lymphocytic leukemia or small lymphocytic lymphoma. It is not indicated for the treatment of patients with primary central nervous system lymphoma. Lisocabtagene maraleucel has black box warning for cytokine release syndrome, severe neurotoxicity, and new T-cell malignancies. Lisocabtagene maraleucel is available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. Information for this program enrollment is available at www.BreyanziREMS.com or 1-866-340-7332.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Lisocabtagene maraleucel may carry the risk of transmitting infectious diseases to health care professionals handling the product. Employ universal precautions in handling lisocabtagene maraleucel; follow local biosafety guidelines applicable for disposal.
Route-Specific Administration
Injectable Administration
Visually inspect the vials for damage before thawing. After thawing, visually inspect the vials for damage or leaks; do not use if the clumps in the vial do not disperse. The vial liquid should be slightly opaque to opaque, colorless to yellow, or brownish-yellow. Call Bristol-Myers-Squibb at 1-888-805-4555 to report vial issues.
Intravenous Administration
-Lisocabtagene maraleucel is for autologous and intravenous use.
-Each dose of lisocabtagene maraleucel contains a maximum of 110 X 106 CAR-positive viable T-cells consisting of 1:1 CD8 and CD4 components; each component is supplied separately in 1 to 4 single-dose 5 mL vials containing a maximum of 70 X 106 CAR-positive viable T cells.
-Ensure tocilizumab and emergency equipment are available prior to the infusion and during the recovery period.
-Coordinate the timing of the lisocabtagene maraleucel 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 an H1-antihistamine 30 to 60 minutes prior to the infusion; avoid corticosteroids use except in the case of a life-threatening emergency.
Preparation
-Match the patient's identity with the patient identifiers on the cartons, vials, and syringe labels.
-Remove the CD8 and CD4 CAR-positive viable T-cells vials from frozen storage; place vials on a protective barrier pad and thaw at room temperature until there is no visible ice in the vials.
-Thaw all the vials at the same time; keep the CD8 and CD4 components separate.
-Refer to the manufacturer's prescribing information regarding dose preparation; prepare the CD8 component syringe(s) first.
-Storage: CD8 and CD4 CAR-positive viable T-cells must be administered within 2 hours of being completely thawed; place labeled CD8 and CD4 syringes on a protective barrier pad inside an insulated room temperature container and transport to the patient bedside.
Intravenous Infusion
-Confirm the patient's identity with the patient identifiers on the syringe label.
-Administer CD8 component syringe(s) doses first and the CD4 component syringe(s) doses second; do not use a leukocyte-depleting filter.
-Infuse the entire volume of each component at approximately 0.5 mL/minute using the closest port or Y-arm; typically, each component will be infused in less than 15 minutes.
-Administer syringes consecutively without any time in between infusions.
-Flush the infusion tubing prior to and after each CD8 or CD4 component syringe is administered.
Infection (36%; grade 3 or higher, 12%) and hypogammaglobulinemia (11%; or 28% when defined as an adverse reaction or immunoglobulin G level less than 500 mg/dL after therapy) were reported in patients with large B-cell lymphoma who received a single dose of lisocabtagene maraleucel in pooled safety data from clinical trials (n = 418). Infection (35%; grade 3 or higher, 16%) and hypogammaglobulinemia (14%; or 37% when defined as an adverse reaction or immunoglobulin G level less than 500 mg/dL after therapy) were reported in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who received a single dose of lisocabtagene maraleucel in a clinical study (n = 89). Monitor patients for signs and symptoms of infection prior to and after the lisocabtagene maraleucel infusion. Additionally, monitor immunoglobulin levels after lisocabtagene maraleucel therapy; manage immunoglobulin deficiency with infection precautions, prophylactic antibiotic therapy, and immunoglobulin replacement per standard guidelines. In clinical trials, infectious events included infection (pathogen unspecified) (12% to 29%; grade 3 or higher, 7% to 16%), viral infection (3.3% to 10%; grade 3 or higher, 1.1% to 1.9%), bacterial infection (4.5% to 13%; grade 3 or higher, 2.2% to 5%), upper respiratory tract infection (13% to 19%; grade 3 or higher, 1.1% or less), fungal infection (4.5% to 9%; grade 3 or higher, 0.5% to 2.2%), pneumonia (2.2% to 8%), sepsis including septic shock (2.2% to 10%; grade 3 or higher, 7% or less), and urinary tract infection (7% or less). The term bacterial infection included appendicitis, diverticulitis, peritonitis, skin infection, and tooth infection. The term upper respiratory tract infection included nasal congestion, nasopharyngitis, pharyngitis, rhinitis, rhinovirus infection, rhinorrhea, paranasal sinus hypersecretion, and sinusitis.
Grade 3 or higher cytopenias that persisted at day 29 (36%) and febrile neutropenia (8%) were reported in patients with large B-cell lymphoma who received a single dose of lisocabtagene maraleucel in pooled safety data from clinical trials (n = 418); prolonged cytopenias included thrombocytopenia (28%), neutropenia (21%), and anemia (6%). Grade 3 or higher cytopenias that persisted at day 29 (45%) and febrile neutropenia (12%) were reported in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who received a single dose of lisocabtagene maraleucel in clinical trial (n = 89); prolonged cytopenias included thrombocytopenia (23%), neutropenia (35%), and anemia (12%). Monitor complete blood counts prior to and after lisocabtagene maraleucel therapy. Febrile neutropenia sometimes occurred concurrently with cytokine release syndrome. If a patient develops febrile neutropenia, evaluate for signs of infection and manage with broad spectrum antibiotics and supportive care therapy (e.g., fluids) as medically indicated. Grade 3 or 4 decreased neutrophil count/neutropenia (80% to 94%), decreased hemoglobin level/anemia (30% to 49%), decreased platelet count/thrombocytopenia (26% to 53%), and decreased lymphocyte count/lymphopenia (87% to 98%) were reported in patients who received lisocabtagene maraleucel in clinical trials. Decreased white blood cell count/leukopenia occurred in 85% of patients with CLL/SLL who received a single dose of lisocabtagene maraleucel in clinical trial (n = 89).
Allergic reactions including anaphylactoid reactions may occur with lisocabtagene maraleucel therapy. Premedicate patients with acetaminophen and diphenhydramine prior to the lisocabtagene maraleucel infusion. Reactions may be due to dimethyl sulfoxide (DMSO) in the product.
Tachycardia/sinus tachycardia (10% to 25%; grade 3 or higher, 1.1% or less), hypotension/orthostatic hypotension (15% to 26%; grade 3 or higher, 3.4% or less), hypertension (7% to 14%; grade 3 or higher, 4.9% or less), and arrhythmia (6% or less) were reported in patients who received a single dose of lisocabtagene maraleucel in clinical trials. The term tachycardia includes increased heart rate, atrial flutter, atrial fibrillation, ventricular tachycardia, and supraventricular tachycardia (SVT). Cardiomyopathy occurred in 1.5% of patients with relapsed or refractory large B-cell lymphoma after 2 or more prior lines of therapy who received lisocabtagene maraleucel in a clinical trial (n = 268). Chest discomfort occurred in 4.5% of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who received a single dose of lisocabtagene maraleucel in clinical trial (n = 89).
Nausea (24% to 35%; grade 3 or higher, 1.6% or less), anorexia (13% to 28%; grade 3 or higher, 4.5% or less), diarrhea (15% to 30%; grade 3 or higher, 1.1% or less), constipation (11% to 24%; grade 3 or higher, 2.2% or less), abdominal pain (7% to 21%; grade 3 or higher, 3% or less), and vomiting (8% to 21%; grade 3 or higher, 0.4% or less) were reported in patients who received a single dose of lisocabtagene maraleucel in clinical trials. Dyspepsia (9%) and abdominal distension (7%) occurred in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who received a single dose of lisocabtagene maraleucel in clinical trial (n = 89).
Fever (16% to 55%; grade 3 or higher, 3.4% or less) and chills (17% or less; grade 3 or higher, 1.1% or less) were reported in patients who received a single dose of lisocabtagene maraleucel in clinical trials.
Fatigue was reported in 28% to 48% (grade 3 or higher, 1.1% to 4.5%) of patients who received a single dose of lisocabtagene maraleucel in clinical trials. The term fatigue included asthenia and malaise.
Edema was reported in 13% to 30% (grade 3 or higher, 4.5% or less) of patients who received a single dose of lisocabtagene maraleucel in clinical trials. The term edema included peripheral edema, fluid overload, fluid retention, hypervolemia, peripheral swelling, pulmonary congestion, pulmonary edema, and swelling.
Musculoskeletal pain (23% to 42%; grade 3 or higher, 1.1% to 4.9%) and motor dysfunction (7% to 14%; grade 3 or higher, 3.4% or less) were reported in patients who received a single dose of lisocabtagene maraleucel in clinical trials. The term musculoskeletal pain included arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort/stiffness, myalgia, arthritis/osteoarthritis, and pain in extremity. The term motor dysfunction included asterixis, eyelid ptosis, muscle rigidity, muscle cramps/spasms, muscle spasticity, muscle tightness, muscle twitching, muscular weakness, myoclonus, and myopathy.
Insomnia including somnambulism and sleep disorder (11% to 16%; grade 3 or higher, 1.1% or less) and anxiety including panic attacks (12% or less; grade 3 or higher, 1.1% or less) occurred in patients who received a single dose of lisocabtagene maraleucel in clinical trials. Affective disorder occurred in 7% of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who received a single dose of lisocabtagene maraleucel in clinical trial (n = 89).
Renal failure was reported in 3.4% to 15% (grade 3 or higher, 3.4% or less) of patients who received a single dose of lisocabtagene maraleucel in clinical trials The term renal failure included acute kidney injury, increased blood creatinine level, and chronic kidney disease.
Cough including upper-airway cough syndrome (11% to 23%), dyspnea (8% to 27%; grade 3 or higher, 8% or less), and hypoxia (8% or less) were reported in patients who received a single dose of lisocabtagene maraleucel in clinical trials. The term dyspnea included acute respiratory distress syndrome (ARDS), tachypnea, wheezing, and respiratory failure. Additionally, pleural effusion occurred in 7% of patients with relapsed or refractory large B-cell lymphoma after 2 or more prior lines of therapy who received lisocabtagene maraleucel in a clinical trial (n = 268) Oral pain occurred in 8% of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who received a single dose of lisocabtagene maraleucel in clinical trial (n = 89).
Thrombosis was reported in 6% to 8% of patients who received a single dose of lisocabtagene maraleucel in clinical trials. Pulmonary embolism was also reported in 2% or greater of patients with relapsed or refractory large B-cell lymphoma (LBCL) following 1 prior chemoimmunotherapy. Additionally, cerebrovascular events/stroke occurred in 1.9% of patients with relapsed or refractory LBCL after 2 or more prior lines of therapy who received lisocabtagene maraleucel in a clinical trial (n = 268).
Rash was reported in 7% to 23% (grade 3 or higher, 2.2% or less) of patients who received a single dose of lisocabtagene maraleucel in clinical trials. The term rash included contact dermatitis, dermatitis acneiform/acneiform rash, erythematous rash/erythema, maculopapular rash, morbilliform rash, pruritic rash, erythema multiforme, petechiae, seborrheic keratosis, urticaria, catheter-site rash, exfoliative dermatitis/rash, perineal rash, and pustular rash. Ecchymosis (8%), xerosis (7%), and pruritus (6%) occurred in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who received a single dose of lisocabtagene maraleucel in clinical trial (n = 89).
Bleeding (12% or less; grade 3 or higher, 1.5% or less) including GI bleeding (4.9% or less) were reported in patients who received a single dose of lisocabtagene maraleucel in clinical trials. The term bleeding included catheter site hemorrhage, conjunctival/ocular hemorrhage, hemorrhagic cystitis, epistaxis, hematoma, hematuria, intracranial bleeding, pulmonary hemorrhage, lower GI bleeding, retinal hemorrhage, and vaginal bleeding.
Infusion-related reactions occurred in 1.9% or less of patients with who received lisocabtagene maraleucel in clinical trials.
Tumor lysis syndrome (TLS) occurred in 0.7% of patients with relapsed or refractory large B-cell lymphoma after 2 or more prior lines of therapy (n = 268) and 11% of patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (n = 89) who received lisocabtagene maraleucel in clinical trials.
Blurred vision was reported in 3.3% of patients with relapsed or refractory large B-cell lymphoma (LBCL) after 1 prior lines of chemoimmunotherapy (n = 61) and 4.5% of patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (n = 89) who received a single dose of lisocabtagene maraleucel in clinical trials. Additionally, visual impairment/disturbance occurred in 5% of patients with relapsed or refractory LBCL after 2 or more prior lines of therapy who received lisocabtagene maraleucel in a clinical trial (n = 268).
Cytokine release syndrome (CRS) was reported in 46% (grade 3 or higher, 3.1%) of patients with large B-cell lymphoma who received a single dose of lisocabtagene maraleucel in pooled safety data from clinical trials (n = 418). One patient had fatal CRS and 2 patients had CRS at time of death. CRS symptoms included fever (94%), hypotension (42%), sinus tachycardia (28%), hypoxia (16%), chills (23%), and headache (12%). CRS was reported in 83% (grade 3, 9%) of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who received a single dose of lisocabtagene maraleucel in a clinical study (n = 89). CRS symptoms included fever (97%), hypotension (46%), sinus tachycardia (8%), hypoxia (35%), chills (43%), and headache (18%). Serious events that may be associated with CRS include cardiac arrhythmias (e.g., atrial fibrillation and ventricular tachycardia), cardiac arrest, heart failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Observe patients for signs or symptoms of CRS daily for at least 7 days in a REMS-certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion. Begin treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated at the first sign or symptom of CRS. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Monitor patients with grade 2 or higher CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) with continuous cardiac telemetry and pulse oximetry. Consider performing an echocardiogram to assess cardiac function in patients who develop severe CRS. Intensive care supportive therapy may be required in patients who have severe or life-threatening CRS. The median CRS times to onset were 4 and 5 days (range, 1 to 63 days) and the median duration of CRS ranged from 1 to 37 days.
Neurotoxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), was reported 33% (grade 3 or higher, 10%) of patients with large B-cell lymphoma (LBCL) who received a single dose of lisocabtagene maraleucel in pooled safety data from clinical trials (n = 418). Three patients had fatal neurologic toxicity and 7 patients had neurologic toxicity at time of death. Neurotoxicity occurred within 8 weeks in all patients. The most common neurologic symptoms included encephalopathy (20%), tremor (13%), aphasia (8%), headache (6%), dizziness (6%), and delirium (5%). Neurotoxicity occurred in 46% (grade 3 or higher, 21%) of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who received a single dose of lisocabtagene maraleucel in a clinical trial (n = 89). The most common neurologic symptoms included encephalopathy (36%), tremor (14%), aphasia (8%), headache (9%), dizziness (6%), and delirium (12%). Of note, 77% of patients with LBCL and 95% of patients with CLL/SLL who developed neurologic toxicity also experienced cytokine release syndrome. Observe patients for signs or symptoms of neurotoxicity daily for at least 7 days in a REMS-certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion. Exclude other causes of neurologic symptoms. Administer supportive care and/or corticosteroids as indicated. Begin nonsedating antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis in patients who develop any grade neurotoxicity. Provide intensive care supportive therapy in patients who develop severe or life-threatening neurologic toxicities. Headache including migraine (11% to 34%; grade 3 or higher, 1.1% to 6%), dizziness including syncope and vertigo (16% to 24%; grade 3 or higher, 1.1% to 2.6%), tremor (10% to 24%; grade 3 or higher, 2.2% or less), encephalopathy (8% to 44%; grade 3 or higher, 18% or less), aphasia (4.5% to 10%; grade 3 or higher, 2.2% or less), peripheral neuropathy (4.5% to 12%), ataxia or gait disturbance (3.4% to 7%), delirium (2.2% to 20%; grade 3 or higher, 3.4% or less), paresis (3.4% or less), taste disorder including dysgeusia (10% or less), and seizures (1.1% or less) were reported in patients who received a single dose of lisocabtagene maraleucel in clinical trials. Additionally, cerebral edema (0.4%) and cases of fatal leukoencephalopathy (some possibly due to fludarabine) occurred in patients with relapsed or refractory LBCL after 2 or more prior lines of therapy who received lisocabtagene maraleucel in a clinical trial (n = 268). ICANS was reported in postmarketing surveillance of lisocabtagene maraleucel. The term encephalopathy included amnesia, apraxia, bradyphrenia, cognitive disorder/impaired cognition, confusion/confusional state, depersonalization/derealization disorder, depressed level of consciousness/loss of consciousness, disturbance in attention, dyscalculia, flat affect, hypersomnia, incoherent, lethargy, leukoencephalopathy, memory impairment, mental status changes, and somnolence/drowsiness. The term peripheral neuropathy included hyperesthesia, hypoesthesia, meralgia paresthetica, neuralgia, paresthesias, sciatica, and sensory loss. The term aphasia included disorganized speech, dysarthria, dysphemia, dysphonia, slow speech, and speech disorder. The term delirium included agitation, delusion, disorientation, hallucinations, irritability, and restlessness. In patients who received lisocabtagene maraleucel, the median times to onset of neurotoxicity were 7 and 8 days (range, 1 to 63 days) and the median duration of neurotoxicity ranged from 1 to 119 days.
Grade 3 or 4 decreased fibrinogen level/hypofibrinogenemia was reported in 14% of patients with relapsed or refractory large B-cell lymphoma after 2 or more prior lines of therapy who received a single dose of lisocabtagene maraleucel in a clinical trial (n = 268).
Grade 3 or 4 decreased phosphate level/hypophosphatemia was reported in 16% of patients with relapsed or refractory large B-cell lymphoma after 2 or more prior lines of therapy who received a single dose of lisocabtagene maraleucel in a clinical trial (n = 268). Grade 3 or 4 hypophosphatemia (24%), hyponatremia (18%), and hypocalcemia (11%) occurred in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who received a single dose of lisocabtagene maraleucel in clinical trial (n = 89).
Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IECHS) was reported with lisocabtagene maraleucel. Manage patients who develop IECHS per current practice guidelines. Hemophagocytic lymphohistiocytosis was reported in 1.1% of patients with primary refractory large B-cell lymphoma or relapse within 1 year of first-line chemoimmunotherapy (n = 89) and 3.4% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; n = 89) who received a single dose of lisocabtagene maraleucel in clinical trials. Of the 3 patients with CLL/SLL who developed IEC-HS, 2 patients had ongoing CRS and 1 patient have ongoing neurotoxicity; fatal IEC-HS occurred in 2 patients. The time to IEC-HS onset ranged from 7 to 18 days.
Treatment-induced antibody formation was reported in 1% to 11% of patients who received a single dose of lisocabtagene maraleucel in clinical trials. The relationship between anti-product antibody status and efficacy, safety, or pharmacokinetic parameters is inconclusive.
T-cell malignancies, including chimeric antigen receptor (CAR)-positive lymphoma, have been reported in patients who received treatment with CD19-directed autologous CAR T-cell immunotherapy, including lisocabtagene maraleucel, in clinical trials or postmarketing surveillance. Mature T-cell malignancies may present in the weeks following the lisocabtagene maraleucel infusion. If a patient develops a new primary malignancy following treatment with lisocabtagene maraleucel, contact Bristol-Myers Squibb at 1-888-805-4555 for instructions on how to collect patient samples for testing for the presence of the CAR transgene. Report suspected adverse events, including T-cell malignancies, to the FDA.
Cytokine release syndrome (CRS) has been reported with lisocabtagene maraleucel; some cases were fatal or life-threatening. Do not administer lisocabtagene maraleucel in patients with active infection or inflammatory disorders. Confirm that 2 tocilizumab doses are available at the facility site prior to the lisocabtagene maraleucel infusion. Observe patients for signs or symptoms of CRS daily for at least 7 days in a REMS-certified healthcare facility following the infusion and continue monitoring for at least 4 weeks after the infusion. Begin treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated at the first sign or symptom of CRS. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. Patients with mild symptoms (e.g., fever, nausea, fatigue, headache, myalgia, and malaise) may require symptomatic treatment only. Monitor patients with grade 2 or higher CRS (e.g., hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) with continuous cardiac telemetry and pulse oximetry. Consider performing an echocardiogram to assess cardiac function in patients who develop severe CRS. Intensive care supportive therapy may be required in patients who have severe or life-threatening CRS.
Severe neurotoxicity (e.g., encephalopathy, seizures, and cerebral edema) has been reported with lisocabtagene maraleucel therapy; some cases were fatal or life-threatening. Neurologic toxicity may occur concurrently with cytokine release syndrome (CRS) or after CRS resolves. Most cases of neurotoxicity occurred within 8 weeks of the lisocabtagene maraleucel infusion. Advise patients to avoid driving or operating machinery or performing other dangerous duties for at least 8 weeks after the lisocabtagene maraleucel infusion due to the risk of neurologic events (e.g., mental status changes, seizures) and altered or decreased consciousness or coordination. Observe patients for signs or symptoms of neurotoxicity daily for at least 7 days in a REMS-certified healthcare facility following the infusion and assess patients for other causes of neurological symptoms. Continue monitoring for neurotoxicity for at least 4 weeks after the infusion; treat neurologic adverse events promptly. Exclude other causes of neurologic symptoms. Administer supportive care and/or corticosteroids as indicated. Begin nonsedating antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis in patients who develop any grade neurotoxicity. Provide intensive care supportive therapy in patients who develop severe or life-threatening neurologic toxicities.
Because of the risk of cytokine release syndrome and neurological toxicities, use requires an experienced clinician with training in the management of these toxicities. Lisocabtagene maraleucel administration also requires a specialized care setting that is enrolled in the BREYANZI REMS program and can comply with all program requirements (e.g., 2 doses of tocilizumab are available for each patient within 2 hours of the lisocabtagene maraleucel infusion).
Vaccination with live viral vaccines during or following treatment with lisocabtagene maraleucel has not been studied. Live virus vaccination is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and until immune recovery after lisocabtagene maraleucel therapy.
Prolonged cytopenias (e.g., anemia, neutropenia, and thrombocytopenia) have been reported following lymphodepleting chemotherapy and the lisocabtagene maraleucel infusion. Monitor complete blood counts prior to and after lisocabtagene maraleucel therapy.
Due to the risk of a new primary malignancy, including T-cell malignancies, life-long monitoring is recommended following lisocabtagene maraleucel therapy.
Hypogammaglobulinemia and B-cell aplasia may occur with lisocabtagene maraleucel therapy. Monitor immunoglobulin levels after lisocabtagene maraleucel therapy; manage immunoglobulin deficiency with infection precautions, prophylactic antibiotic therapy, and immunoglobulin replacement as indicated.
Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, fulminant hepatitis, hepatic failure, and death may occur with drugs directed against B cells, such as lisocabtagene maraleucel. Screen all patients for HBV, hepatitis C infection, and human immunodeficiency virus (HIV) infection prior to cell collection (leukapheresis). Consider antiviral prophylaxis per standard institutional guidelines in patients with a prior history of HBV.
Serious infections including bacterial infection, fungal infection, and viral infection have been reported with lisocabtagene maraleucel therapy; some cases were life-threatening or fatal. Monitor patients for signs and symptoms of infection prior to and after the lisocabtagene maraleucel infusion; administer prophylactic antimicrobial therapy and other anti-infective therapy as medically indicated. Febrile neutropenia has also been reported following lisocabtagene maraleucel therapy; it may occur concurrently with cytokine release syndrome. If a patient develops febrile neutropenia, evaluate for signs of infection and manage with broad spectrum antibiotics and supportive care therapy (e.g., fluids) as medically indicated.
Patients who receive lisocabtagene maraleucel should avoid cell, organ, tissue, and blood donation.
False-positive HIV tests have been reported in patients who received treatment with chimeric antigen receptor (CAR) T-cell immunotherapy, such as lisocabtagene maraleucel. The use of gammaretroviral or lentiviral vectors to reprogram T-cells as part of CAR T-cell therapy has resulted in laboratory test interference with HIV-1 nucleic acid amplification testing (NAAT). False test results may occur due to vector interference with long terminal repeat (LTR) genomes in HIV NAAT. Alternative testing methods for HIV (e.g., assays that target p24 antigen and anti-HIV-1 antibodies or the integrase gene) should be performed in patients who have received CAR T-cell therapy.
Use of lisocabtagene maraleucel is not recommended during pregnancy; pregnancy after lisocabtagene maraleucel administration should be discussed with the treating physician. There are no available data with lisocabtagene maraleucel use in pregnant women; animal reproductive and developmental toxicity studies have not been conducted. It is not known if lisocabtagene maraleucel has the potential to be transferred to the fetus. However, based on its mechanism of action, fetal toxicity including B-cell lymphocytopenia and hypogammaglobulinemia may occur if the transduced cells cross the placenta.
Counsel patients about the reproductive risk and contraception requirements during lisocabtagene maraleucel treatment. Sexually active females of reproductive potential should undergo pregnancy testing prior to lisocabtagene maraleucel therapy. See prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive lymphodepleting chemotherapy. There are insufficient data to recommend a duration of contraception following treatment with lisocabtagene maraleucel. There are no data on the effect of lisocabtagene maraleucel on fertility.
It is not known if lisocabtagene maraleucel is present in human milk or if it has effects on the breast-fed infant or on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for lisocabtagene maraleucel and any potential adverse effects on the breast-fed infant from lisocabtagene maraleucel or from the underlying maternal condition.
For the treatment of non-Hodgkin's lymphoma (NHL):
NOTE: Lisocabtagene maraleucel has been designated an orphan drug by the FDA for the treatment of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and primary mediastinal large B-cell lymphoma.
-for the treatment of relapsed or refractory large B-cell lymphoma (LBCL) following 2 or more lines of systemic therapy:
NOTE: For this indication, LBCL includes DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and grade 3B FL.
Intravenous dosage:
Adults: 50 X 106 CAR-positive viable T-cells to 110 X 106 CAR-positive viable T-cells as a single IV dose; administer at 2 to 7 days after the completion of lymphodepleting chemotherapy. Premedicate patients with acetaminophen 650 mg PO and diphenhydramine 25 to 50 mg (or another H1-antihistamine) IV or PO 30 to 60 minutes prior to the lisocabtagene maraleucel infusion. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion. The overall response rate was 73% in patients with relapsed or refractory large B-cell NHL who received a single infusion of lisocabtagene maraleucel (n = 256) in a multicohort trial (the TRANSCEND trial). The complete response rate was 53%. The median time to response was 1 month (range, 0.7 to 8.9 months) and the median duration of response was not reached at a median follow-up time of 12 months. The median progression-free survival time was 6.8 months and the median overall survival time was 21.1 months. Following leukapheresis and T-cell collection, all patients had lymphodepleting chemotherapy with fludarabine (30 mg/m2 IV daily for 3 doses) and cyclophosphamide (300 mg/m2 IV daily for 3 doses); 59% of patients received bridging therapy with systemic therapy and/or radiation therapy. Patients (median age, 63 years; range, 18 to 86 years) in this trial had DLBCL transformed from indolent lymphoma (25%), high-grade B-cell lymphoma (14%), primary mediastinal large B-cell lymphoma (7%), follicular lymphoma, grade 3B (1%) and had received a median of 3 prior therapies (range, 1 to 8 therapies).
-for the treatment of large B-cell lymphoma (LBCL) in patients who have refractory disease to or relapse within 12 months of first-line chemoimmunotherapy:
NOTE: LBCL includes DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and grade 3B FL.
Intervenous dosage:
Adults: 90 X 106 CAR-positive viable T-cells to 110 X 106 CAR-positive viable T-cells as a single IV dose; administer at 2 to 7 days after the completion of lymphodepleting chemotherapy. Premedicate patients with acetaminophen 650 mg PO and diphenhydramine 25 to 50 mg (or another H1-antihistamine) IV or PO 30 to 60 minutes prior to the lisocabtagene maraleucel infusion. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion. At a median follow-up time of 17.5 (range, 0.9 to 37) months, the independent review committee-assessed median event-free survival (primary endpoint; not reached vs. 2.4 months; hazard ratio (HR) = 0.36; 95% CI, 0.24 to 0.52) and progression-free survival (not reached vs. 6.2 months; HR = 0.4; 95% CI, 0.26 to 0.62) times were significantly improved in patients with LBCL primary refractory to or relapsed within 12 months of first-line therapy who received lisocabtagene maraleucel compared with standard of care therapy in a randomized (1:1), phase 3 (TRANSFORM) trial (n = 184). The median overall survival time was not significantly improved in patients who received lisocabtagene maraleucel compared with standard of care therapy (not reached vs. 29.9 months; HR = 0.72; 95% CI, 0.44 to 1.18); however, 63% of patients in the standard of care arm crossed over to the lisocabtagene maraleucel arm in this trial. Standard of care therapy consisted of 3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) in responders. In the lisocabtagene maraleucel arm, all patients had lymphodepleting chemotherapy with fludarabine (30 mg/m2 IV daily for 3 doses) and cyclophosphamide (300 mg/m2 IV daily for 3 doses) following leukapheresis and T-cell collection; 63% of patients received bridging therapy. In this trial, all patients (median age, 59 years; range, 20 to 75 years) were considered eligible for HSCT and had relapsed or refractory disease to first-line therapy that contained an anthracycline and an anti-CD20 monoclonal antibody.
-for the treatment of large B-cell lymphoma (LBCL) in patients who have refractory disease to or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem-cell transplantation (HSCT) due to comorbidities or age:
NOTE: LBCL includes DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and grade 3B FL.
Intravenous dosage:
Adults: 90 X 106 CAR-positive viable T-cells to 110 X 106 CAR-positive viable T-cells as a single IV dose; administer at 2 to 7 days after the completion of lymphodepleting chemotherapy. Premedicate patients with acetaminophen 650 mg PO and diphenhydramine 25 to 50 mg (or another H1-antihistamine) IV or PO 30 to 60 minutes prior to the lisocabtagene maraleucel infusion. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion. The complete response (CR) rate was 54% in transplant-ineligible patients with relapsed or refractory LBCL after 1 line of chemoimmunotherapy (median age, 74 years; range, 53 to 84 years) who received lisocabtagene maraleucel (n = 61) in a single-arm, phase 2 trial (the PILOT trial). The partial response (PR) rate was 26%. The median time to CR was 1 month (range, 0.8 to 6.9 months) and the median duration of response (CR or PR) was 11.2 months (range, 0 to 22.8+ months). Following leukapheresis and T-cell collection, all patients had lymphodepleting chemotherapy with fludarabine (30 mg/m2 IV daily for 3 doses) and cyclophosphamide (300 mg/m2 IV daily for 3 doses); 53% of patients received bridging therapy.
For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL):
NOTE: Lisocabtegene maraleucel is designated as an orphan drug by the FDA for the treatment of CLL.
-for the treatment of relapsed or refractory CLL or SLL who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor:
Intravenous dosage:
Adults: 90 X 106 CAR-positive viable T-cells to 110 X 106 CAR-positive viable T-cells as a single IV dose; administer at 2 to 7 days after the completion of lymphodepleting chemotherapy (consisting of fludarabine 30 mg/m2 IV daily for 3 days and cyclophosphamide 300 mg/m2 daily for 3 days). Premedicate patients with acetaminophen 650 mg PO and diphenhydramine 25 to 50 mg (or another H1-antihistamine) IV or PO 30 to 60 minutes prior to the lisocabtagene maraleucel infusion. Additionally, confirm that 2 doses of tocilizumab are available for each patient prior to the infusion. The overall response rate (assessed by an independent review committee) was 45% (complete response [CR] rate, 20%) in 65 evaluable patients with relapsed or refractory CLL/SLL who received lisocabtagene maraleucel in a multicenter, phase 1/2 (TRANSCEND-CLL) trial. The median duration of response was 35.3 (range, 2 to 35.3) months. Additionally, the minimal residual disease negativity rate was 100% in peripheral blood and 92.3% in the bone marrow in patients who achieved a CR. Patients (66 years; range, 49 to 82 years) in this trial had received a median of 5 (range, 2 to 12) prior therapies including a BTK inhibitor and a BCL-2 inhibitor.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Cytokine Release Syndrome (CRS)
NOTE: CRS treatment consists of tocilizumab and corticosteroids. Each dose of tocilizumab is 8 mg/kg (Max of 800 mg) IV given over 1 hour; do not exceed 3 doses per 24 hours or a maximum of 4 doses total. If initiated, continue corticosteroids for at least 3 doses or until complete resolution of symptoms; consider a corticosteroid taper.
Grade 1 toxicity (i.e., fever): If toxicity occurs less than 72 hours after the infusion, consider administering a tocilizumab dose and consider giving dexamethasone 10 mg IV every 24 hours. If toxicity occurs at 72 hours or more after the infusion, treat symptomatically.
Grade 2 toxicity (i.e., oxygen requirement less than 40% FiO2, hypotension responsive to fluids or a low-dose of 1 vasopressor agent, or grade 2 organ toxicity): Administer a tocilizumab dose; repeat every 8 hours as needed if the patient is not responding to IV fluids or increasing supplemental oxygen. If toxicity occurs less than 72 hours after the infusion, start dexamethasone 10 mg IV every 12 to 24 hours. If toxicity occurs at 72 hours or more after the infusion, consider starting dexamethasone 10 mg IV every 12 to 24 hours. If there is no improvement within 24 hours or rapid progression, repeat tocilizumab and increase the dosage of dexamethasone to 10 to 20 mg IV every 6 to 12 hours. If there is still no improvement or continued rapid progression, maximize the dexamethasone dosage or switch to high-dose IV methylprednisolone (2 mg/kg). Consider an alternative immunosuppressant after 2 doses of tocilizumab are given.
Grade 3 toxicity (i.e., oxygen requirement of 40% FiO2 or greater, hypotension requiring high-dose or multiple vasopressor agents, grade 3 organ toxicity, or grade 4 transaminitis): Administer a tocilizumab dose; repeat every 8 hours as needed if the patient is not responding to IV fluids or increasing supplemental oxygen. Start dexamethasone 10 mg IV every 12 hours. If there is no improvement within 24 hours or rapid progression, repeat tocilizumab and increase the dosage of dexamethasone to 10 to 20 mg IV every 6 to 12 hours. If there is still no improvement or continued rapid progression, maximize the dexamethasone dosage or switch to high-dose IV methylprednisolone (2 mg/kg). Consider an alternative immunosuppressant after 2 doses of tocilizumab are given.
Grade 4 toxicity (i.e., requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD), or grade 4 organ toxicity (excluding transaminitis): Administer a tocilizumab dose; repeat every 8 hours as needed if the patient is not responding to IV fluids or increasing supplemental oxygen. Start dexamethasone 20 mg IV every 6 hours. If there is no improvement within 24 hours or rapid progression, maximize tocilizumab and corticosteroid use. If there is still no improvement or continued rapid progression, maximize the dexamethasone dosage or switch to high-dose IV methylprednisolone (2 mg/kg). Consider an alternative immunosuppressant after 2 doses of tocilizumab are given.
Neurologic Toxicity
NOTE: Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. Begin nonsedating antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis in patients who develop any grade neurotoxicity. If concurrent CRS is suspected during neurologic toxicity, start tocilizumab per guidance on management of CRS; start corticosteroid therapy according to the more aggressive intervention based on the severity of CRS or neurotoxicity. Consider a corticosteroid taper if steroid treatment lasts longer than 3 days.
Grade 1 toxicity: If toxicity occurs at 72 hours or more after the infusion, observe the patient closely. If toxicity occurs less than 72 hours after the infusion, consider starting dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days.
Grade 2 toxicity: Start dexamethasone 10 mg IV every 12 hours for 2 to 3 days or longer for persistent symptoms. If there is no improvement within 24 hours or worsening of neurologic toxicity, increase the dosage of dexamethasone (Max of 20 mg IV every 6 hours). If there is still no improvement after another 24 hours, rapidly progressing symptoms, or life-threatening complications, begin IV methylprednisolone (2 mg/kg loading dose, followed by 0.5 mg/kg IV every 6 hours; taper within 7 days).
Grade 3 toxicity: Start dexamethasone 10 to 20 mg IV every 8 to 12 hours; steroids are not recommended for isolated grade 3 headache. If there is no improvement within 24 hours or worsening of neurologic toxicity, begin IV methylprednisolone (2 mg/kg loading dose, followed by 0.5 mg/kg IV every 6 hours; taper within 7 days).
Grade 4 toxicity: Start dexamethasone 20 mg IV every 6 hours. If there is no improvement within 24 hours or worsening of neurologic toxicity, begin IV methylprednisolone (2 mg/kg loading dose, followed by 0.5 mg/kg IV every 6 hours; taper within 7 days).
Suspected cerebral edema: Consider hyperventilation and hyperosmolar therapy; start high-dose methylprednisolone (1 to 2 grams IV repeated 24 hours if needed; taper as clinically indicated) and cyclophosphamide (1.5 grams/m2).
Maximum Dosage Limits:
-Adults
110 X 106 CAR-positive viable T-cells as a single IV dose.
-Geriatric
110 X 106 CAR-positive viable T-cells as a single IV dose.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Chikungunya Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
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.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Intranasal Influenza Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Live Vaccines: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Rotavirus Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (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.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (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.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Typhoid Vaccine: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Yellow Fever Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in the six weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel therapy, and prior to immune recovery following treatment with lisocabtagene maraleucel. 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.
Lisocabtagene maraleucel 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 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 lisocabtagene maraleucel 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 lisocabtagene maraleucel CAR. Lisocabtagene maraleucel manufacturing transduces and expands CD4+ and CD8+ T-cells and these are administered in a fixed 1:1 ratio.
To produce CAR T-cell therapy, T-cells are collected from the blood by leukapheresis, enriched, activated, incubated with a viral vector encoding the CD19 CAR, expanded, and then washed, concentrated, and cryopreserved.
Lisocabtagene maraleucel is administered intravenously. Post infusion, it exhibits an initial expansion followed by a bi-exponential decline.
Pharmacodynamics: Peak levels of soluble biomarkers were observed within 14 days of the lisocabtagene maraleucel infusion; these levels typically returned to baseline within 28 days.
-Route-Specific Pharmacokinetics
Intravenous Route
In patients with relapsed or refractory large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy who received lisocabtagene maraleucel in a clinical trial, the median Cmax level was 2.3-fold higher (35,335 vs. 15,527 copies/mcg) and the AUC(0-28 days) value was 1.8-fold higher (273,552 vs. 155,240 day x copies/mcg) in responding patients (n = 135) compared with non-responding patients (n = 37). In patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who received lisocabtagene maraleucel, the median Cmax level was 2-fold higher (99,559 vs. 48,948 copies/mcg) and the AUC(0-28 days) value was 1.9-fold higher (793,893 vs. 408,307 day x copies/mcg) in responding patients (n = 27) compared with non-responding patients (n = 25). The median times to maximal expansion in peripheral blood of lisocabtagene maraleucel occurred at 10 to 12 days and 14 days following the lisocabtagene maraleucel infusion in patients with LBCL and CLL/SLL, respectively. Additionally, it was present in peripheral blood for a median of approximately 12 (range, 0.1 to more than 30.1) months.
-Special Populations
Geriatric
Younger patients (less than 65 years) had lisocabtagene maraleucel Cmax and AUC(0-28 days) values that were 3.1-fold and 2.3-fold higher, respectively, compared with older patients (aged 65 years and older).
Gender Differences
Sex did not have a significant impact on lisocabtagene maraleucel Cmax or AUC(0-28 days) values.
Ethnic Differences
Race or ethnicity did not have a significant impact on lisocabtagene maraleucel Cmax or AUC(0-28 days) values.
Obesity
Body weight did not have a significant impact on lisocabtagene maraleucel Cmax or AUC(0-28 days) values.
Other
Immunosuppressive therapy
The lisocabtagene maraleucel Cmax and AUC(0-28 days) values were 3.6-fold and 3.7-fold higher, respectively, in patients who received tocilizumab to treat cytokine release syndrome or neurologic toxicity (n = 49) compared with patients who did not receive tocilizumab (n = 189). Additionally, the lisocabtagene maraleucel Cmax and AUC(0-28 days) values were 3.8-fold and 3.7-fold higher, respectively, in patients who received corticosteroids (n = 50) compared with patients who did not receive corticosteroids (n = 188).