Lisocabtagene Maraleucel (Monograph)

Brand name: Breyanzi
Drug class: Gene Therapy

Medically reviewed by Drugs.com on Dec 17, 2023. Written by ASHP.

Introduction

Lisocabtagene maraleucel is a CD19-directed genetically modified autologous T cell immunotherapy.

Uses for Lisocabtagene Maraleucel

Lisocabtagene maraleucel has the following uses:

Lisocabtagene maraleucel is a chimeric antigen receptor (CAR) T-cell therapy indicated for the treatment of adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. The treatment is indicated for patients who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or relapsed or refractory disease after two or more lines of systemic therapy. Lisocabtagene maraleucel has been designated an orphan drug for the treatment of various types of B-cell lymphomas.

Lisocabtagene maraleucel is an individualized cellular product prepared from autologous T cells obtained by leukapheresis. The patient's T-cells are sent to a commercial laboratory where they are genetically modified to express chimeric antigen receptors (CAR), and then infused back into the patient.

Efficacy and safety of lisocabtagene maraleucel are based principally on 3 open label studies (TRANSFORM, PILOT, TRANSCEND). In all studies, lisocabtagene maraleucel was administered 2 to 7 days following completion of lymphodepleting chemotherapy (fludarabine and cyclophosphamide). Lisocabtagene maraleucel was given as a single IV infusion at a dose of 100 × 10⁶ CAR-positive viable T cells in TRANSFORM and PILOT, and at a dose of 50 to 110 × 10⁶ CAR-positive viable T cells in TRANSCEND. The TRANSFORM trial was conducted in adults with relapsed or refractory LBCL after first-line chemoimmunotherapy and who were potential candidates for autologous HSCT. A total of 184 patients were randomized to receive lisocabtagene maraleucel or standard therapy consisting of 3 cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who attained complete response (CR) or partial response (PR). The estimated 1-year event-free survival was 45% in the lisocabtagene maraleucel arm and 24% in the standard therapy arm. Of the 92 patients in the lisocabtagene maraleucel group, the estimated median duration of response was not reached in patients who achieved CR and was 2.3 months in patients who achieved a best response of PR. The PILOT trial was a single-arm study conducted in transplant-ineligible patients with relapsed or refractory LBCL after one line of chemoimmunotherapy. In the main efficacy population of 61 patients, the overall response rate was 80% and CR was 54%. The TRANSCEND trial was conducted in adults with relapsed or refractory LBCL who had received at least 2 prior lines of therapy. In the main efficacy population of 192 patients, the overall response rate was 73% and CR was 54%. Of the 104 patients who achieved CR, 65% maintained remission for at least 6 months and 62% maintained remission for at least 9 months.

Lisocabtagene maraleucel is not indicated for the treatment of patients with primary CNS lymphoma.

CAR T-cell therapies can be associated with severe toxicities; the American Society of Clinical Oncology (ASCO) has published a guideline to provide guidance on the diagnosis, evaluation and management of such toxicities.

Related/similar drugs

prednisone, rituximab, cyclophosphamide, doxorubicin, Rituxan, vincristine, Imbruvica

Lisocabtagene Maraleucel Dosage and Administration

General

Lisocabtagene maraleucel is available in the following dosage form(s) and strength(s):

• Lisocabtagene maraleucel is a cell suspension for infusion.

• A single dose of lisocabtagene maraleucel consists of 1:1 CAR-positive viable T cells of the CD8 and CD4 components, with each component supplied separately in one to four single-dose 5 mL vials. Each mL contains ≥ 1.5 × 10⁶ to 70 × 10⁶CAR-positive viable T cells. Each vial contains between 6.9 × 10⁶ and 322 x 10⁶ CAR-positive viable T cells in 4.6 mL cell suspension (between 1.5 × 10⁶ and 70 x 10⁶ CAR-positive viable T cells/mL).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

For autologous use only. For IV use only.

• Administer lisocabtagene maraleucel in a REMS-certified healthcare facility.

• Do NOT use a leukodepleting filter.

• Administer a lymphodepleting regimen of fludarabine and cyclophosphamide before infusion of lisocabtagene maraleucel. Confirm the availability of lisocabtagene maraleucel before starting lymphodepleting chemotherapy. Infuse lisocabtagene maraleucel 2 to 7 days after completion of lymphodepleting chemotherapy.

• Verify the patient’s identity prior to infusion. Check that the patient’s identity matches the patient identifiers on the cartons, vials, and syringe labels. Do not administer the therapy if the information on the patient-specific labels does not match the intended patient.

• Premedicate with acetaminophen and an H₁ antihistamine.

• Confirm availability of tocilizumab prior to infusion.

• Dosing of lisocabtagene maraleucel is based on the number of chimeric antigen receptor (CAR)-positive viable T cells.

• For relapsed or refractory large B-cell lymphoma (LBCL) after one line of therapy, the dose is 90 to 110 × 10⁶ CAR-positive viable T cells.

• For relapsed or refractory LBCL after two or more lines of therapy, the dose is 50 to 110 × 10⁶ CAR-positive viable T cells.

• See Full Prescribing Information for detailed instructions on preparation and administration.

Cautions for Lisocabtagene Maraleucel

Contraindications

None.

Warnings/Precautions

Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with lisocabtagene maraleucel. Among patients receiving lisocabtagene maraleucel for LBCL (N=418), CRS occur in 46% (190/418), including ≥ Grade 3 CRS (Lee grading system¹) in 3.1% of patients.

In patients receiving lisocabtagene maraleucel after two or more lines of therapy for LBCL, CRS occurred in 46% (122/268), including ≥ Grade 3 CRS in 4.1% of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 98% with a median duration of 5 days (range: 1 to 17 days).

In patients receiving lisocabtagene maraleucel after one line of therapy for LBCL, CRS occurred in 45% (68/150), including Grade 3 CRS in 1.3% of patients. The median time to onset was 4 days (range: 1 to 63 days). CRS resolved in all patients with a median duration of 4 days (range: 1 to 16 days).

The most common manifestations of CRS (≥ 10%) included fever (94%), hypotension (42%), tachycardia (28%), chills (23%), hypoxia (16%), and headache (12%).

Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of lisocabtagene maraleucel. Of the 418 patients who received lisocabtagene maraleucel for LBCL, 23% received tocilizumab and/or a corticosteroid for CRS, including 10% who received tocilizumab only and 2.2% who received corticosteroids only.

Monitor patients daily for at least 7 days following lisocabtagene maraleucel infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with lisocabtagene maraleucel. Serious events including cerebral edema and seizures occurred with lisocabtagene maraleucel. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.

In patients receiving lisocabtagene maraleucel after two or more lines of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 35% (95/268), including ≥ Grade 3 cases in 12% of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of neurotoxicity was 8 days (range: 1 to 46 days). Neurologic toxicities resolved in 85% with a median duration of 12 days (range: 1 to 87 days).

In patients receiving lisocabtagene maraleucel after one line of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 27% (41/150) of patients, including Grade 3 cases in 7% of patients. The median time to onset of neurologic toxicity was 8 days (range: 1 to 63 days). The median duration of neurologic toxicity was 6 days (range: 1 to 119 days).

In all patients combined receiving lisocabtagene maraleucel for LBCL, neurologic toxicities occurred in 33% (136/418), including ≥ Grade 3 cases in 10% of patients. The median time to onset was 8 days (range: 1 to 63), with 87% of cases developing by 16 days. Neurologic toxicities resolved in 85% of patients with a median duration of 11 days (range: 1 to 119 days). Of patients developing neurotoxicity, 77% (105/136) also developed CRS.

The most common neurologic toxicities (≥ 5%) included encephalopathy (20%), tremor (13%), aphasia (8%), headache (6%), dizziness (6%), and delirium (5%).

Monitor patients daily at least for at least 7 days following lisocabtagene maraleucel infusion at a REMS-certified healthcare facility for signs and symptoms of neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Manage neurologic toxicity with supportive care and/or corticosteroid as needed.

Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time.

REMS

Because of the risk of CRS and neurologic toxicities, lisocabtagene maraleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Breyanzi REMS. Healthcare facilities that dispense and administer lisocabtagene maraleucel must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after lisocabtagene maraleucel infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer lisocabtagene maraleucel are trained on the management of CRS and neurologic toxicities. Further information is available at www.BreyanziREMS.com, or contact Bristol-Myers Squibb at 1-888-423-5436.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of lisocabtagene maraleucel. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after lisocabtagene maraleucel infusion.

In patients receiving lisocabtagene maraleucel for LBCL, infections of any grade occurred in 36%, with Grade 3 or higher infections occurring in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections in 4.3%, viral infections in 1.9%, and fungal infections in 0.5% of patients.

Febrile neutropenia developed after lisocabtagene maraleucel infusion in 8% of patients with LBCL. Febrile neutropenia 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.

Monitor patients for signs and symptoms of infection before and after lisocabtagene maraleucel administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines.

Avoid administration of lisocabtagene maraleucel in patients with clinically significant, active systemic infections.

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. In patients who received lisocabtagene maraleucel for LBCL, 15 of the 16 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and lisocabtagene maraleucel infusion.

Grade 3 or higher cytopenias persisted at Day 29 following lisocabtagene maraleucel infusion in 36% of patients with LBCL and included thrombocytopenia in 28%, neutropenia in 21%, and anemia in 6% of the patients.

Monitor complete blood counts prior to and after lisocabtagene maraleucel administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving lisocabtagene maraleucel.

In patients receiving lisocabtagene maraleucel for LBCL, hypogammaglobulinemia was reported as an adverse reaction in 11% of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 28% of patients.

Monitor immunoglobulin levels after treatment with lisocabtagene maraleucel and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live Vaccines

The safety of immunization with live viral vaccines during or following lisocabtagene maraleucel treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during lisocabtagene maraleucel treatment, and until immune recovery following treatment with lisocabtagene maraleucel.

Secondary Malignancies

Patients treated with lisocabtagene maraleucel may develop secondary malignancies. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving lisocabtagene maraleucel are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following lisocabtagene maraleucel administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks.

Specific Populations

Pregnancy

There are no available data with lisocabtagene maraleucel use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with lisocabtagene maraleucel to assess whether it can cause fetal harm when administered to a pregnant woman.

It is not known if lisocabtagene maraleucel 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 and hypogammaglobulinemia. Therefore, lisocabtagene maraleucel is not recommended for women who are pregnant, and pregnancy after lisocabtagene maraleucel infusion should be discussed with the treating physician.

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.

Lactation

There is no information regarding the presence of lisocabtagene maraleucel in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lisocabtagene maraleucel and any potential adverse effects on the breastfed infant from lisocabtagene maraleucel or from the underlying maternal condition.

Females and Males of Reproductive Potential

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 lisocabtagene maraleucel.

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

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

There are no data on the effects of lisocabtagene maraleucel on fertility.

Pediatric Use

The safety and efficacy of lisocabtagene maraleucel have not been established in pediatric patients.

Geriatric Use

In clinical trials of lisocabtagene maraleucel, 111 (41%) of 268 patients with two or more prior lines of therapy for LBCL, and 89 (59%) of 150 patients with one prior line of therapy for LBCL, were 65 years of age or older; 27 (10%) and 28 (19%) were 75 years of age or older, respectively. No clinically important differences in safety or effectiveness of lisocabtagene maraleucel were observed between patients aged ≥ 65 and younger patients.

Common Adverse Effects

The most common nonlaboratory adverse reactions (incidence ≥ 30%) are fever, cytokine release syndrome, fatigue, musculoskeletal pain, and nausea. The most common Grade 3-4 laboratory abnormalities (≥ 30%) include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Lisocabtagene maraleucel is a chimeric antigen receptor (CAR)-positive T cell therapy consisting of genetically modified autologous T cells that bind to CD19 proteins on the surface of B cells. The CAR-positive viable T cells contain CD8 and CD4 components. CAR binding to CD19 expressed on the cell surface of tumor and normal B cells induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells. The CAR is comprised of an FMC63 monoclonal antibody-derived single chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. CD3 zeta signaling is critical for initiating activation and antitumor activity, while 4-1BB (CD137) signaling enhances the expansion and persistence of lisocabtagene maraleucel.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Ensure that patients understand the risk (11%) of manufacturing failure. In case of a manufacturing failure, a second manufacturing of lisocabtagene maraleucel may be attempted. While the patient awaits the product, additional bridging therapy (not the lymphodepletion) may be necessary. This bridging therapy may be associated with adverse events during the pre-infusion period, which could delay or prevent the administration of lisocabtagene maraleucel.

• Advise patients that they will be monitored daily for at least 7 days following the lisocabtagene maraleucel infusion at a REMS-certified healthcare facility and instruct patients to remain within 2 hours of a REMS-certified healthcare facility for at least 4 weeks following the infusion.

• Advise patients to seek immediate attention if Cytokine Release Syndrome (CRS) occurs. Signs or symptoms associated with CRS include fever, hypotension, tachycardia, chills, hypoxia, headache, and fatigue.

• Advise patients to seek immediate attention if neurologic toxicities occur. Signs or symptoms associated with neurologic events include encephalopathy, confusion, seizures, tremor, aphasia, delirium, and somnolence.

• Advise patients of the risk of serious infections.

• Advise patients of the risk of prolonged cytopenias. Signs or symptoms associated with bone marrow suppression include neutropenia, anemia, thrombocytopenia, and febrile neutropenia.

• Advise patients to contact Bristol-Myers Squibb at 1-888-805-4555 if they are diagnosed with a secondary malignancy.

• Advise patients to refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after lisocabtagene maraleucel administration.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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