Brand name: Aucatzyl
Drug class: Gene Therapy

Introduction

Obecabtagene autoleucel is a CD19-directed genetically modified autologous T cell immunotherapy.

Uses for Obecabtagene Autoleucel

Obecabtagene autoleucel has the following uses:

Obecabtagene autoleucel is a chimeric antigen receptor (CAR) T-cell therapy indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL); obecabtagene autoleucel has been designated an orphan drug by FDA for the treatment of ALL.

Efficacy of obecabtagene autoleucel for this use was evaluated in an open-label, single-arm, multicenter trial (FELIX) in adults with relapsed or refractory B-cell ALL. Treatment consisted of lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by obecabtagene autoleucel as a split-dose infusion at a total recommended dose of 410 x 10⁶ CD19 CAR-positive viable T cells. Among 65 patients in the efficacy population, the overall complete remission rate was 63%; 42% of patients achieved complete remission within 3 months. The median duration of remission was 14.1 months.

Obecabtagene autoleucel is an individualized cellular product prepared from autologous T cells obtained by leukapheresis.

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.

Obecabtagene Autoleucel Dosage and Administration

General

Obecabtagene autoleucel is available in the following dosage form(s) and strength(s):

• Cell suspension for IV infusion.

• Obecabtagene autoleucel contains a total recommended dose of 410 × 10⁶ CD19 CAR-positive viable T cells supplied in 3 to 5 infusion bags.

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. Strictly follow the manufacturer's administration instructions to minimize dosing errors.

• Do NOT use a leukodepleting filter.

• Prior to obecabtagene autoleucel infusion, administer a lymphodepleting chemotherapy regimen of fludarabine/cyclophosphamide.

• Ensure availability of bone marrow assessment results from a sample obtained within 7 days prior to start of lymphodepleting chemotherapy.

• Infuse obecabtagene autoleucel 3 days (± 1 days) after completion of lymphodepleting chemotherapy treatment.

• To minimize the risk of an infusion reaction, premedicate with acetaminophen approximately 30 minutes prior to obecabtagene autoleucel infusion.

• Avoid prophylactic use of systemic corticosteroids.

• Confirm availability of tocilizumab prior to infusion.

• Verify patient's identity prior to infusion.

• The total recommended dose of obecabtagene autoleucel is 410 × 10⁶ CD19 chimeric antigen receptor (CAR)-positive viable T cells.

• The treatment regimen consists of a split dose infusion to be administered on Day 1 and Day 10 (± 2 days). Dose to be administered on the given dosing day is determined by the patient bone marrow blast assessment.

• Dosing is guided by the Dose Schedule Planner (provided to the infusion site) which indicates the actual cell counts and volumes to be infused.

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

Cautions for Obecabtagene Autoleucel

Contraindications

None.

Warnings/Precautions

Cytokine Release Syndrome

Cytokine Release Syndrome (CRS) occurred following treatment with obecabtagene autoleucel. CRS was reported in 75% (75/100) of patients including Grade 3 CRS in 3% of patients.

The median time to onset of CRS was 8 days (range: 1 to 23 days) with a median duration of 5 days (range: 1 to 21 days). Sixty-eight percent of patients (51/75) experienced CRS after the first infusion, but prior to the second infusion of obecabtagene autoleucel with a median time to onset of 6 days (range 1 to 10 days). Among patients with CRS, the most common manifestations of CRS included fever (100%), hypotension (35%), and hypoxia (19%)

The primary treatment for CRS was tocilizumab (73%; 55/75), with patients also receiving corticosteroids (21%; 16/75).

Prior to administering obecabtagene autoleucel, ensure that healthcare providers have immediate access to medications and resuscitative equipment to manage CRS. During and following treatment with obecabtagene autoleucel, closely monitor patients for signs and symptoms of CRS daily for at least 14 days at the healthcare facility following the first infusion. Continue to monitor patients for CRS for at least 4 weeks following each infusion with obecabtagene autoleucel.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care based on severity and consider further management per current practice guidelines.

Neurologic Toxicities

Neurologic toxicities including Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS), which were fatal or life-threatening, occurred following treatment with obecabtagene autoleucel. Neurologic toxicities were reported in 64% (64/100) of patients, including Grade ≥3 in 12% of patients.

The median time to onset of neurologic toxicities was 10 days (range: 1 to 246 days) with a median duration of 13 days (range: 1 to 904 days). Fifty-five percent of patients (35/64) experienced neurologic toxicities after the first infusion but prior to the second infusion of obecabtagene autoleucel with a median time to onset of 6 days (range: 1 to 11 days). Among patients with neurologic toxicities, the most common symptoms (>5%) included ICANS (38%), headache (34%), encephalopathy (33%), dizziness (22%), tremor (13%), anxiety (9%), insomnia (9%), and delirium (8%).

Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS)

ICANS events occurred in 24% (24/100) of patients, including Grade ≥3 in 7% (7/100) of patients. Of the 24 patients who experienced ICANS, 33% (8/24) experienced an onset after the first infusion, but prior to the second infusion of obecabtagene autoleucel.

The median time to onset for ICANS events after the first infusion was 8 days (range: 1 to 10 days) and 6.5 days (range: 2 to 22 days) after the second infusion, with a median duration of 8.5 days (range: 1 to 53 days).

Eighty-eight percent (21/24) of patients received treatment for ICANS. All treated patients received high-dose corticosteroids and 42% (10/24) of patients received anti-epileptics prophylactically. Prior to administering obecabtagene autoleucel, ensure that healthcare providers have immediate access to medications and resuscitative equipment to manage ICANS.

During and following obecabtagene autoleucel administration, closely monitor patients for signs and symptoms of neurologic toxicity/ICANS. Following treatment with obecabtagene autoleucel, monitor patients daily for at least 14 days at the healthcare facility. Continue to monitor patients for at least 4 weeks following treatment with obecabtagene autoleucel.

Counsel patients to seek medical attention should signs or symptoms of neurologic toxicity/ICANS occur. At the first sign of neurologic toxicity/ICANS, immediately evaluate patients for hospitalization and institute treatment with supportive care based on severity and consider further management per current practice guidelines.

Effect on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving obecabtagene autoleucel are at risk for altered or decreased consciousness or coordination in the 8 weeks following obecabtagene autoleucel infusion or until resolution of the neurological event by the treating physician. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Prolonged Cytopenias

Patients may exhibit cytopenias including anemia, neutropenia, and thrombocytopenia for several weeks after treatment with lymphodepleting chemotherapy and obecabtagene autoleucel. In patients who were responders to obecabtagene autoleucel, Grade ≥3 cytopenias that persisted beyond Day 30 following the infusion were observed in 71% (29/41) of patients and included neutropenia (66%, 27/41) and thrombocytopenia (54%, 22/41). Grade 3 or higher cytopenias that persisted beyond Day 60 following obecabtagene autoleucel infusion was observed in 27% (11/41) of patients and included neutropenia (17%, 7/41) and thrombocytopenia (15%, 6/41). Monitor blood counts after obecabtagene autoleucel infusion.

Infections

Severe, including life-threatening and fatal infections, occurred in patients after obecabtagene autoleucel infusion. Non-COVID-19 infections of all grades occurred in 67% (67/100) of patients. Grade 3 or higher non-COVID-19 infections occurred in 41% (41/100) of patients.

Obecabtagene autoleucel should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after obecabtagene autoleucel infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Grade 3 or higher febrile neutropenia was observed in 26% (26/100) of patients after obecabtagene autoleucel infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage according to treatment guidelines as medically indicated.

Viral reactivation, potentially severe or life-threatening, can occur in patients treated with drugs directed against B cells. There is no experience with manufacturing obecabtagene autoleucel for patients with a positive test for human immunodeficiency virus (HIV) or with active hepatitis B virus (HBV) or active hepatitis C virus (HCV). Perform screening for HBV, HCV and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Hypogammaglobulinemia

Hypogammaglobulinemia and B-cell aplasia can occur in patients after treatment with obecabtagene autoleucel. Hypogammaglobulinemia was reported in 10% (10/100) of patients treated with obecabtagene autoleucel including Grade 3 events in 2 patients (2%).

Immunoglobulin levels should be monitored after treatment with obecabtagene autoleucel and managed per institutional guidelines including infection precautions, antibiotic or antiviral prophylaxis and immunoglobulin replacement.

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

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS)

HLH/MAS, including fatal and life-threatening reactions, occurred after treatment with obecabtagene autoleucel. HLH/MAS was reported in 2% (2/100) of patients and included Grade 3 and Grade 4 events with a time of onset at Day 22 and Day 41, respectively. One patient experienced a concurrent ICANS events after obecabtagene autoleucel infusion and died due to sepsis with ongoing HLH/MAS that had not resolved.

Administer treatment for HLH/MAS according to institutional standards.

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO), an excipient used in obecabtagene autoleucel. Observe patients for hypersensitivity reactions during and after obecabtagene autoleucel infusion.

Secondary Malignancies

Patients treated with obecabtagene autoleucel may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes.

Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Autolus Inc at 1-855-288-5227 for reporting and to obtain instructions on the collection of patient samples for testing.

Specific Populations

Pregnancy

There is limited available data with obecabtagene autoleucel use in pregnant women. In the FELIX study, one patient became pregnant 6 months following treatment with obecabtagene autoleucel. The patient had a premature delivery at 30 weeks of pregnancy.

No animal reproductive and developmental toxicity studies have been conducted with obecabtagene autoleucel to assess whether obecabtagene autoleucel can cause fetal harm when administered to a pregnant woman.

It is not known if obecabtagene autoleucel has the potential to be transferred to the fetus and cause fetal toxicity. Based on the mechanism of action of obecabtagene autoleucel, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia and hypogammaglobinemia. Therefore, obecabtagene autoleucel is not recommended for women who are pregnant. Pregnancy after obecabtagene autoleucel infusion should be discussed with the treating physician.

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

Lactation

There is no information regarding the presence of obecabtagene autoleucel 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 obecabtagene autoleucel and any potential adverse effects on the breastfed infant from obecabtagene autoleucel 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 negative pregnancy test before starting treatment with obecabtagene autoleucel.

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

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

There are no data on the effect of obecabtagene autoleucel on fertility.

Pediatric Use

The safety and efficacy of obecabtagene autoleucel have not been established in pediatric patients.

Geriatric Use

Of the 100 patients treated with obecabtagene autoleucel, 20 (20%) were 65 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Common Adverse Effects

The most common (non-laboratory) adverse reactions (incidence ≥ 20%) are cytokine release syndrome (CRS), infections - pathogen unspecified, musculoskeletal pain, viral infections, fever, nausea, bacterial infectious disorders, diarrhea, febrile neutropenia, immune effector cell-associated neurotoxicity syndrome (ICANS), hypotension, pain, fatigue, headache, encephalopathy, and hemorrhage.

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

Obecabtagene autoleucel is a CD19-directed genetically modified autologous T cell immunotherapy consisting of the patient's own T cells expressing an anti-CD19 chimeric antigen receptor (CAR). Engagement of anti-CD19 CAR-positive T cells with CD19 expressed on target cells, such as cancer cells and normal B cells, leads to activation of the anti-CD19 CAR-positive T cells and downstream signaling through the CD3-zeta domain. Proliferation and persistence by the anti-CD19 CAR-positive T cells following activation are enhanced by the presence of the 4-1BB co-stimulatory domain. This binding to CD19 results in anti-tumor activity and killing of CD19-expressing target cells.

Advice to Patients

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

• Inform patients that there is a risk of manufacturing failure (4.5% [5/112 in clinical studies]). Therefore, a second manufacturing of obecabtagene autoleucel may be attempted, after a second leukapheresis collection.

• Inform patients that additional therapy (other than lymphodepletion) may be necessary before obecabtagene autoleucel manufacturing is completed. This may increase the risk of adverse events during the pre-infusion period, which could delay or prevent the administration of obecabtagene autoleucel.

• Advise patients to seek immediate attention if cytokine release syndrome occurs. Inform patients that symptoms may include fever, hypotension, and hypoxia.

• Advise patients to seek immediate attention if neurologic toxicity or ICANS occurs. Inform patients that symptoms may include ICANS, headache, dizziness, anxiety, insomnia, delirium, tremor, and encephalopathy.

• Advise patients to seek immediate attention if prolonged cytopenias occur. Inform patients that symptoms may include neutropenia, anemia, thrombocytopenia, or bleeding.

• Advise patients to seek immediate attention if severe infections occur. Inform patients that they may exhibit signs or symptoms associated with infection, and that past infections can be reactivated following treatment with obecabtagene autoleucel.

• Secondary malignancies, including T cell malignancies, have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies. Advise patients to seek immediate attention if secondary malignancies occur and to contact Autolus Inc at 1-855-288-5227 if they are diagnosed with a secondary malignancy.

• Advise patients of the need to refrain from driving or operating heavy or potentially dangerous machinery for at least 8 weeks after obecabtagene autoleucel infusion.

• Advise patients of the need to have periodic monitoring of blood counts.

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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