Axicabtagene Ciloleucel Intravenous

Axicabtagene ciloleucel is an individualized cellular product prepared from autologous T cells obtained by leukapheresis; the 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.^[3] Axicabtagene ciloleucel is a CAR T-cell therapy with indications for large-B-cell lymphoma and follicular lymphoma.^[1]

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.^[10]

Large B-cell Lymphoma

Axicabtagene ciloleucel is a CAR T-cell therapy indicated for the treatment of adults with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. ^[1]

Axicabtagene ciloleucel is also used for the treatment of adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.^[1] Axicabtagene ciloleucel is designated an orphan drug by FDA for treatment of DLBCL and primary mediastinal B-cell lymphoma.^[2]

Axicabtagene ciloleucel is not indicated for the treatment of patients with primary CNS lymphoma.^[1]

Efficacy of axicabtagene ciloleucel in the treatment of relapsed or refractory large B-cell lymphoma has been established in a randomized, open-label multicenter study (ZUMA-7).^[1] Following lymphodepleting chemotherapy, patients received axicabtagene ciloleucel (administered as a single IV infusion) or standard second-line treatment.^[1] Event-free survival (EFS) was longer in patients who received axicabtagene ciloleucel versus standard therapy (median of 8.3 versus 2 months).^[1] The estimated EFS rate at 18 months was 41.5% in the axicabtagene ciloleucel group and 17% in the standard therapy group.^[1]

A single-arm, open-label, multicenter trial (ZUMA-1) evaluated the efficacy of a single infusion of axicabtagene ciloleucel in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma.^[1] Following lymphodepleting chemotherapy, axicabtagene ciloleucel was administered as a single IV infusion.^[1] Among 101 patients who received axicabtagene ciloleucel, 73 (72%) had an objective response and 52 (51%) had a complete response; the median duration of response was 9.2 months.^[1]

Follicular Lymphoma

Axicabtagene ciloleucel is a CAR T-cell therapy indicated for the treatment of adults with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.^[1] This indication is approved under accelerated approval based on response rate.^[1] Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).^[1]

Axicabtagene ciloleucel is designated an orphan drug by FDA for treatment of follicular lymphoma.^[2]

Efficacy of axicabtagene ciloleucel in the treatment of relapsed or refractory follicular lymphoma has been established in a single-arm, open-label, multicenter study (ZUMA-5).^[1] Following lymphodepleting chemotherapy, axicabtagene ciloleucel was administered as a single IV infusion.^[1] In the primary efficacy analysis which included 81 patients, 74 (91%) achieved an objective response and 49 (60%) achieved a complete response.^[1] The median duration of response was not estimable at a median follow-up of 14.5 months.^[1]

General

Axicabtagene ciloleucel is available in the following dosage form(s) and strength(s):

Axicabtagene ciloleucel is a cell suspension for IV infusion.^[1]A single dose of axicabtagene ciloleucel contains 2 x 10⁶ CAR-positive viable T cells per kg of body weight, with a maximum of 2 x 10⁸ CAR-positive viable T cells in approximately 68 mL suspension in an infusion bag.^[1]

Dosage

It isessential 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.^[1]

Administer axicabtagene ciloleucel at a certified healthcare facility.^[1]Do NOT use a leukodepleting filter.^[1]Administer a lymphodepleting regimen of cyclophosphamide and fludarabine on the fifth, fourth, and third day before infusion of axicabtagene ciloleucel.^[1] Confirm availability of axicabtagene ciloleucel prior to starting the lymphodepleting regimen.^[1]Verify the patient's identity prior to infusion.^[1] The patient's identity must match the patient identifiers on the axicabtagene ciloleucel cassette and infusion bag.^[1] Do not infuse axicabtagene ciloleucel if the information on the patient-specific label does not match the intended patient.^[1]Premedicate with acetaminophen and an H₁-antihistamine approximately 1 hour before infusion.^[1] Consider the use of prophylactic corticosteroid after weighing the potential benefits and risks.^[1]Confirm availability of tocilizumab prior to infusion.^[1]Dosing of axicabtagene ciloleucel is based on the number of chimeric antigen receptor (CAR)-positive viable T cells.^[1]The target axicabtagene ciloleucel dose is 2 x 10⁶ CAR-positive viable T cells per kg body weight, with a maximum of 2 x 10⁸ CAR-positive viable T cells.^[1]See Full Prescribing Information for detailed instructions on preparation and administration.^[1]

Contraindications

None.^[1]

Warnings/Precautions

Cytokine Release Syndrome

CRS, including fatal or life-threatening reactions, occurred following treatment with axicabtagene ciloleucel.^[1] CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL) receiving axicabtagene ciloleucel, including >= Grade 3 (Lee grading system¹) CRS in 9%.^[1] CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including >= Grade 3 CRS in 9%.^[1] Among patients with LBCL who died after receiving axicabtagene ciloleucel, four had ongoing CRS events at the time of death.^[1] For patients with LBCL in the ZUMA-1 study, the median time to onset of CRS was 2 days following infusion (range: 1 to12 days) and the median duration of CRS was 7 days (range: 2 to 58 days).^[1] For patients with LBCL in the ZUMA-7 study, the median time to onset of CRS was 3 days following infusion (range: 1 to 10 days) and the median duration was 7 days (range: 2 to 43 days).^[1]

CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in the ZUMA-5 study, including >= Grade 3 CRS in 8%.^[1] Among patients with iNHL who died after receiving axicabtagene ciloleucel, one patient had an ongoing CRS event at the time of death.^[1] The median time to onset of CRS was 4 days (range: 1 to 20 days) and the median duration was 6 days (range: 1 to 27 days) for patients with iNHL.^[1]

Key manifestations of CRS (>= 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%).^[1] Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).^[1]

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in two subsequent cohorts of LBCL patients in ZUMA-1.^[1] Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event.^[1] The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days).^[1]

Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of axicabtagene ciloleucel.^[1] Thirty-one of the 39 patients (79%) developed CRS at which point the patients were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing Grade 3 or higher CRS.^[1] The median time to onset of CRS was 5 days (range: 1 to 15 days) and the median duration of CRS was 4 days (range: 1 to 10 days).^[1] Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.^[1]

Ensure that 2 doses of tocilizumab are available prior to infusion of axicabtagene ciloleucel.^[1] Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS.^[1] Monitor patients for signs or symptoms of CRS for 4 weeks after infusion.^[1] Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.^[1] At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.^[1]

Neurologic Toxicities

Neurologic toxicities (including ICANS) that were fatal or life-threatening occurred following treatment with axicabtagene ciloleucel.^[1] Neurologic toxicities occurred in 78% (330/422) of patients with NHL receiving axicabtagene ciloleucel, including >= Grade 3 cases in 25%.^[1]

Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including >= Grade 3 cases in 31% and in 74% (124/168) of patients in ZUMA-7 including >= Grade 3 cases in 25%.^[1] The median time to onset was 4 days (range: 1 to 43 days) and the median duration was 17 days in patients with LBCL in ZUMA-1.^[1] The median time to onset for neurologic toxicity was 5 days (range:1 to 133 days) and median duration was 15 days in patients with LBCL in ZUMA-7.^[1] Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including >= Grade 3 in 21%.^[1] The median time to onset was 6 days (range: 1 to 79 days) and the median duration was 16 days.^[1] Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of axicabtagene ciloleucel infusion.^[1] Neurologic toxicities occurred within the first 7 days of axicabtagene ciloleucel infusion in 87% of affected patients with LBCL and 74% of affected patients with iNHL.^[1]

The most common neurologic toxicities (>= 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%).^[1] Prolonged encephalopathy lasting up to 173 days was noted.^[1] Serious events including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred with axicabtagene ciloleucel.^[1] Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred in patients treated with axicabtagene ciloleucel.^[1]

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in two subsequent cohorts of LBCL patients in ZUMA-1.^[1] Among patients who received corticosteroids at the onset of Grade 1 toxicities neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event.^[1] The median time to onset of neurologic toxicities was 6 days (range: 1 to 93 days) with a median duration of 8 days (range: 1 to 144 days).^[1] Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of axicabtagene ciloleucel.^[1] Of these 39 patients, 85% (33/39) developed neurologic toxicities; 8% (3/39) developed Grade 3 and 5% (2/39) developed Grade 4 neurologic toxicities.^[1] The median time to onset of neurological toxicities was 6 days (range: 1 to 274 days) with a median duration of 12 days (range: 1 to 107 days).^[1] Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.^[1]

Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities.^[1] Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.^[1]

REMS Program

Because of the risk of CRS and neurologic toxicities, axicabtagene ciloleucel is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.^[1] The required components of the REMS Program are: ^[1]

Healthcare facilities that dispense and administer axicabtagene ciloleucel must be enrolled and comply with the REMS requirements.^[1] Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after axicabtagene ciloleucel infusion, if needed for treatment of CRS.^[1]Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer axicabtagene ciloleucel are trained about the management of CRS and neurologic toxicities.^[1]Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).^[1]

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of axicabtagene ciloleucel.^[1] Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in axicabtagene ciloleucel.^[1]

Serious Infections

Severe or life-threatening infections occurred in patients after axicabtagene ciloleucel infusion.^[1] Infections (all grades) occurred in 45% of patients with NHL.^[1] Grade 3 or higher infections occurred in 17% of patients, including Grade 3 or higher infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%.^[1] Axicabtagene ciloleucel should not be administered to patients with clinically significant active systemic infections.^[1] Monitor patients for signs and symptoms of infection before and after axicabtagene ciloleucel infusion and treat appropriately.^[1] Administer prophylactic antimicrobials according to local guidelines.^[1]

Febrile neutropenia was observed in 36% of patients with NHL after axicabtagene ciloleucel infusion and may be concurrent with CRS.^[1] In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.^[1]

In immunosuppressed patients, including those who have received axicabtagene ciloleucel, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported.^[1] The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.^[1]

Hepatitis B Virus Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with drugs directed against B cells, including axicabtagene ciloleucel.^[1] Perform screening for HBV, HCV, and HIV, and manage in accordance with clinical guidelines before collection of cells for manufacturing.^[1]

Prolonged Cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and axicabtagene ciloleucel infusion.^[1] Grade 3 or higher cytopenias not resolved by Day 30 following axicabtagene ciloleucel infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%).^[1] Monitor blood counts after axicabtagene ciloleucel infusion.^[1]

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with axicabtagene ciloleucel.^[1] Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL.^[1] Monitor immunoglobulin levels after treatment with axicabtagene ciloleucel and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.^[1]

The safety of immunization with live viral vaccines during or following axicabtagene ciloleucel treatment has not been studied.^[1] Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during axicabtagene ciloleucel treatment, and until immune recovery following treatment with axicabtagene ciloleucel.^[1]

Secondary Malignancies

Patients treated with axicabtagene ciloleucel may develop secondary malignancies.^[1] Monitor life-long for secondary malignancies.^[1] In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.^[1]

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving axicabtagene ciloleucel are at risk for altered or decreased consciousness or coordination in the 8 weeks following axicabtagene ciloleucel infusion.^[1] 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.^[1]

Specific Populations

Pregnancy

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

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively.^[1]

Lactation

There is no information regarding the presence of axicabtagene ciloleucel in human milk, the effect on the breastfed infant, and the effects on milk production.^[1] The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for axicabtagene ciloleucel and any potential adverse effects on the breastfed infant from axicabtagene ciloleucel or from the underlying maternal condition.^[1]

Females and Males of Reproductive Potential

Pregnancy status of females with reproductive potential should be verified.^[1] Sexually active females of reproductive potential should have a pregnancy test prior to starting treatment with axicabtagene ciloleucel.^[1]

See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.^[1]

There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with axicabtagene ciloleucel.^[1]

There are no data on the effect of axicabtagene ciloleucel on fertility.^[1]

Pediatric Use

The safety and efficacy of axicabtagene ciloleucel have not been established in pediatric patients.^[1]

Geriatric Use

Of the 422 patients with NHL who received axicabtagene ciloleucel in clinical trials, 127 patients (30%) were 65 years of age and older.^[1] No clinically important differences in safety or effectiveness were observed between patients 65 years of age and older and younger patients.^[1]

Common Adverse Effects

The most common adverse reactions (incidence >= 30%), excluding laboratory abnormalities, in patients with non-Hodgkin lymphoma are CRS, fever, hypotension, encephalopathy, fatigue, tachycardia, headache, nausea, febrile neutropenia, diarrhea, musculoskeletal pain, infections with pathogen unspecified, chills, and decreased appetite.^[1]

The most common Grade 3-4 laboratory abnormalities (>= 30%) are leukopenia, lymphopenia, neutropenia, anemia, thrombocytopenia, and hypophosphatemia.^[1]

Specific Drugs

It isessential 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.

Mechanism of Action

Axicabtagene ciloleucel, a CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells.^[1] Studies demonstrated that following anti-CD19 CAR T cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines.^[1] This sequence of events leads to killing of CD19-expressing cells.^[1]

Advise the patient to read the FDA-approved patient labeling (Medication Guide).^[1]Ensure that patients understand the risk of manufacturing failure (< 1% in clinical trials).^[1] In case of a manufacturing failure, a second manufacturing of axicabtagene ciloleucel may be attempted.^[1] In addition, while the patient awaits the product, additional chemotherapy (not the lymphodepletion) may be necessary and may increase the risk of adverse events during the pre-infusion period.^[1]Advise patients to seek immediate attention if Cytokine Release Syndrome (CRS) occurs.^[1] Signs or symptoms associated with CRS include fever, chills, fatigue, tachycardia, nausea, hypoxia, and hypotension.^[1]Advise patients to seek immediate attention if neurologic toxicities occur.^[1] Signs or symptoms include encephalopathy, seizures, changes in level of consciousness, speech disorders, tremors, and confusion.^[1] Advise patients to seek immediate attention if signs or symptoms of serious infection occur.^[1] Advise patients to seek immediate attention if prolonged cytopenia occurs; signs or symptoms include bone marrow suppression, including neutropenia, anemia, thrombocytopenia, and febrile neutropenia.^[1]Advise patients to refrain from driving or operating heavy or potentially dangerous machinery after axicabtagene ciloleucel infusion for at least 8 weeks after infusion.^[1]Advise patients to have periodic monitoring of blood counts.^[1]Advise patients to contact Kite at 1-844-454-KITE (5483) if they are diagnosed with a secondary malignancy.^[1]

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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