Elivaldogene Autotemcel (Monograph)

Brand name: Skysona
Drug class: Gene Therapy

Introduction

Elivaldogene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy.

Uses for Elivaldogene Autotemcel

Elivaldogene autotemcel has the following uses:

Elivaldogene autotemcel is indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD). Early, active CALD refers to asymptomatic or mildly symptomatic (neurologic function score [NFS] ≤1) boys who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes scores of 0.5-9. Elivaldogene autotemcel has been designated an orphan drug by FDA for the treatment of adrenoleukodystrophy.

This indication is approved under accelerated approval based on 24-month Major Functional Disability (MFD)-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

CALD is an X-linked neurodegenerative disease caused by a genetic mutation that leads to impaired expression of adrenoleukodystrophy protein (ALDP) and accumulation of very long chain fatty acids; this leads to an inflammatory cascade that ultimately results in inflammatory cerebral demyelination.

Elivaldogene autotemcel is an autologous HSC-based gene therapy prepared from the patient's HSCs, which are collected via apheresis procedure(s). The collected cells are shipped to the manufacturing site where CD34+ cells are selected and then transduced with Lenti-D lentiviral vector containing the ATP-binding cassette, sub-family D, member 1 (ABCD1) gene encoding ALDP.

Efficacy and safety of elivaldogene autotemcel have been established in two 24-month, open-label, single-arm studies in patients with early, active CALD and NFS 1. Patients underwent hematopoietic cell mobilization and apheresis followed by full myeloablative and lymphodepleting conditioning, and then were administered an IV infusion of elivaldogene autotemcel. A subpopulation of symptomatic elivaldogene autotemcel-treated patients was compared to an external untreated natural history control for the primary efficacy analysis. Compared to the natural history group, patients treated with elivaldogene autotemcel had slower progression to major functional disability (MSD) or death from time of symptom onset (first NFS 1). Kaplan-Meier MFD-free survival estimates at month 24 from time of first NFS 1 were 72% for the symptomatic elivaldogene autotemcel subpopulation and 43% for the natural history population. There are insufficient data to compare the relative efficacy of elivaldogene autotemcel to allogeneic HSCT in the treatment of CALD.

Elivaldogene autotemcel does not treat or prevent adrenal insufficiency.

An immune response to elivaldogene autotemcel may cause rapid loss of efficacy of elivaldogene autotemcel in patients with full deletions of the human ABCD1 gene.

Elivaldogene autotemcel has not been studied in CALD secondary to head trauma.

Given the risk of hematologic malignancy with elivaldogene autotemcel, and unclear long-term durability of elivaldogene autotemcel and ALDP expression, careful consideration should be given to the timing of treatment for each boy and treatment of boys with isolated pyramidal tract disease as clinical manifestations do not usually occur until adulthood.

Related/similar drugs

Skysona

Elivaldogene Autotemcel Dosage and Administration

General

Elivaldogene autotemcel is available in the following dosage form(s) and strength(s):

• Cell suspension for IV infusion.

• Supplied in 20 mL bags; each bag contains between 4 × 10⁶ and 30 × 10⁶ cells/mL (3.6 to 30 × 10⁶ CD34+ cells/mL), frozen in cryopreservation solution.

• A single dose of elivaldogene autotemcel contains a minimum of 5.0 × 10⁶ CD34+ cells/kg of body weight, suspended in a solution containing 5% dimethyl sulfoxide (DMSO).

Dosage

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

Pediatric Patients

Dosage and Administration in Boys 4–17 Years of Age

For autologous use only. For IV use only.

• Patients must undergo hematopoietic stem cell (HSC) mobilization and apheresis to obtain CD34+ cells for elivaldogene autotemcel manufacturing.

• Before mobilization, apheresis, and conditioning are initiated, confirm that hematopoietic stem cell (HSC) transplantation is appropriate for the patient.

• Dosing of elivaldogene autotemcel is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. The dose is calculated based on the patient's weight prior to first apheresis.

• The minimum recommended dose is 5.0 × 10⁶ CD34+ cells/kg.

• Full myeloablative and lymphodepleting conditioning must be administered before infusion of elivaldogene autotemcel. Do not begin conditioning until elivaldogene autotemcel has been received and stored at the treatment center and the availability of the back-up collection of CD34+ cells is confirmed. After completion of conditioning, allow a minimum of 48 hours of washout before elivaldogene autotemcel infusion.

• Verify the patient's identity matches the unique patient identification information on the elivaldogene autotemcel infusion bag(s) prior to infusion. Do not infuse elivaldogene autotemcel if the information on the patient-specific label does not match the intended patient.

• Do not sample, alter, or irradiate elivaldogene autotemcel.

• Do not use an in-line blood filter or an infusion pump.

• Standard procedures for patient management after HSC transplantation should be followed after elivaldogene autotemcel infusion.

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

Cautions for Elivaldogene Autotemcel

Contraindications

None.

Warnings/Precautions

Hematologic Malignancy

Myelodysplastic syndrome (MDS), a hematologic malignancy, has developed in patients treated with elivaldogene autotemcel in clinical studies. At the time of initial product approval, MDS had been diagnosed in three patients after administration of elivaldogene autotemcel. The clinical presentation for the three patients varied. Two patients who were diagnosed at 14 months and 2 years after treatment with elivaldogene autotemcel had preceding delayed platelet engraftment. The third patient had normal blood counts from 18 months to 5 years following treatment with elivaldogene autotemcel and presented 7.5 years after elivaldogene autotemcel administration with symptomatic anemia and thrombocytopenia and was subsequently diagnosed with MDS with increased blasts. All 3 patients underwent allogeneic hematopoietic stem cell transplant; 1 patient required pre-transplant chemotherapy and total body irradiation as treatment for excess blasts prior to transplant and 1 patient underwent total body irradiation as part of his conditioning regimen.

Elivaldogene autotemcel Lenti-D lentiviral vector integration into proto-oncogenes appears to have mediated the three cases of hematologic malignancy. The hematologic malignancies diagnosed at 14 months and 2 years involved integration into the MECOM proto-oncogene and increased expression of the oncoprotein EVI1. All patients treated with elivaldogene autotemcel in clinical studies have integrations into MECOM; it is unknown which integrations into MECOM or other proto-oncogenes are likely to lead to malignancy.

Because of the risk of hematologic malignancy, carefully consider alternative therapies prior to the decision to treat a child with elivaldogene autotemcel. Consider consultation with hematology experts prior to elivaldogene autotemcel treatment to inform benefit-risk treatment decision and to ensure adequate monitoring for hematologic malignancy. Consider performing the following baseline hematologic assessments: complete blood count with differential, hematopathology review of peripheral blood smear, and bone marrow biopsy (core and aspirate) with flow cytometry, conventional karyotyping, and next generation sequencing (NGS) with a molecular panel appropriate for age and including coverage for gene mutations expected in myeloid and lymphoid malignancies; and testing for germline mutations that are associated with hematologic malignancy.

Early diagnosis of hematologic malignancy can be critically important; therefore, monitor patients treated with elivaldogene autotemcel lifelong for hematologic malignancy. For the first fifteen years after treatment with elivaldogene autotemcel, monitor via complete blood count (with differential) at least twice per year and via integration site analysis or other testing for evidence of clonal expansion and predominance at least twice in the first year and then annually. Consider appropriate expert consultation and additional testing such as more frequent complete blood count (with differential) and integration site analysis, bone marrow studies, and gene expression studies in the following settings after treatment with elivaldogene autotemcel:

• Delayed or failed engraftment of platelets or other cell lines (patients who do not achieve unsupported platelet counts of ≥ 20 × 10⁹/L on or after Day 60 appear to be at particularly high risk for developing malignancy); or

• New or prolonged cytopenias; or,

• Presence of clonal expansion or predominance (e.g., increasing relative frequency of an integration site, especially if ≥10% and present in MECOM or another proto-oncogene known to be involved in hematologic malignancy).

If hematologic malignancy is detected in a patient who received elivaldogene autotemcel, contact bluebird bio at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for further testing.

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after elivaldogene autotemcel infusion. Important opportunistic infections that have been diagnosed within the first 3 months after treatment with elivaldogene autotemcel include BK cystitis, cytomegalovirus reactivation, human herpesvirus-6 viremia, candidiasis, and bacteremias. Opportunistic infections after the first 3 months include an atypical mycobacterium vascular device infection, pseudomonas bacteremia, and Epstein-Barr virus reactivations diagnosed as late as 18 months after treatment with elivaldogene autotemcel. Serious infections involving adenovirus include a case of transverse myelitis at 6 months that was attributed to adenovirus and entero/rhinovirus infection, and a fatal adenovirus infection at 21 months in a patient with CALD progression who developed multisystem organ failure.

Grade 3 or higher infections occurred in 21% of all patients (12% bacterial, 3% viral, and 6% unspecified). The most common Grade 3 or higher infections were vascular device infections (7% of patients) diagnosed as late as 6 months after treatment with elivaldogene autotemcel, and bacteremias (6% of patients) diagnosed as late as 8 months after treatment with elivaldogene autotemcel.

Febrile neutropenia developed within two weeks after elivaldogene autotemcel infusion in 72% of patients. 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 elivaldogene autotemcel administration and treat appropriately. Administer prophylactic antimicrobials according to best clinical practices and clinical guidelines.

Avoid administration of elivaldogene autotemcel in patients with active infections.

Prolonged Cytopenias

Patients may exhibit cytopenias, including pancytopenia, for >1 year following conditioning and elivaldogene autotemcel infusion.

Grade 3 or higher cytopenias on or after Day 60 following elivaldogene autotemcel infusion occurred in 47% of patients and included low platelet count (14%), low neutrophil count (22%), low lymphocyte count (27%), and low hemoglobin (2%). Grade 3 cytopenias persisted beyond Day 100 in 15% of patients and included low platelet count (7%), low neutrophil count (9%), and low lymphocyte count (6%).

Serious adverse reactions of pancytopenia occurred in two patients who required support with blood and platelet transfusions as well as growth factors (G-CSF for up to 6 months and eltrombopag for up to 14 months) after elivaldogene autotemcel administration. One patient had intercurrent parvovirus infection and his pancytopenia was ongoing at least two years after elivaldogene autotemcel administration. Pancytopenia in the other patient was ongoing until he was diagnosed with myelodysplastic syndrome approximately two years after elivaldogene autotemcel administration.

Monitor blood counts until normalization and assess patients for signs and symptoms of bleeding and/or infection prior to and after elivaldogene autotemcel administration.

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with elivaldogene autotemcel. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 14% of patients had a platelet count ≤ 50 × 10⁹/L beyond 60 days after treatment with elivaldogene autotemcel.

Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

Risk of Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with elivaldogene autotemcel. Neutrophil engraftment failure was defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 10⁹Cells/L obtained on different days by Day 43 after infusion of elivaldogene autotemcel. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with elivaldogene autotemcel, provide rescue treatment with the back-up collection of CD34+ cells.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of elivaldogene autotemcel. The dimethyl sulfoxide (DMSO) in elivaldogene autotemcel may cause hypersensitivity reactions, including anaphylaxis which is potentially life-threatening and requires immediate intervention.

Anti-retroviral Use

Patients should not take anti-retroviral medications for at least one month prior to mobilization or the expected duration for elimination of the medications, and until all cycles of apheresis are completed. Anti-retroviral medications may interfere with manufacturing of the apheresed cells.

If a patient requires anti-retrovirals for HIV prophylaxis, mobilization and apheresis of CD34+ cells should be delayed until HIV infection is adequately ruled out.

Laboratory Test Interference

Elivaldogene autotemcel affects polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion. A PCR-based assay should not be used to screen for HIV infection in patients treated with elivaldogene autotemcel as a false-positive test result is likely.

Specific Populations

Pregnancy

There are no available data with elivaldogene autotemcel administration in pregnant women. Consider the risks associated with mobilization and conditioning agents on pregnancy and fertility.

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

No nonclinical germline transmission studies have been conducted with elivaldogene autotemcel.

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 elivaldogene autotemcel in human milk, the effect on the breastfed infant, and the effects on milk production.

Females and Males of Reproductive Potential

Consult the Prescribing Information of the mobilization and conditioning agents for information on the need for effective contraception.

There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with elivaldogene autotemcel. Males capable of fathering a child and their female partners of childbearing potential should use an effective method of contraception (intra-uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of elivaldogene autotemcel.

There are no data on the effects of elivaldogene autotemcel on fertility.

Data are available on the risk of infertility with myeloablative conditioning. Advise patients of the option to cryopreserve semen before treatment if appropriate.

Pediatric Use

The safety and efficacy of elivaldogene autotemcel in children younger than 4 years of age have not been established. No data are available.

Patients with a Full ABCD1 Gene Deletion

In the only patient in the elivaldogene autotemcel clinical studies who had a full ABCD1 deletion, disease progression occurred. The patient experienced radiologic disease progression in the setting of declining peripheral blood vector copy number, suggesting loss of product efficacy which may have been immune mediated. The patient was subsequently treated with allogeneic hematopoietic stem cell transplant.

Renal Impairment

Elivaldogene autotemcel has not been studied in patients with renal impairment. Patients should be assessed for renal impairment to ensure hematopoietic stem cell (HSC) transplantation is appropriate.

Hepatic Impairment

Elivaldogene autotemcel has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate.

Patients Seropositive For Human Immunodeficiency Virus (HIV)

Elivaldogene autotemcel has not been studied in patients with HIV-1, HIV-2, HTLV-1, or HTLV-2. A negative serology test for HIV is necessary to ensure acceptance of apheresis material for elivaldogene autotemcel manufacturing. Apheresis material from patients with a positive test for HIV will not be accepted for elivaldogene autotemcel manufacturing.

Common Adverse Effects

• Most common non-laboratory adverse reactions (≥ 20%): mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, rash.

• Most common Grade 3 or 4 laboratory abnormalities (≥40%): leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia, hypokalemia.

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:

Anti-retrovirals: Do not take anti-retroviral medications for at least one month prior to initiating medications for stem cell mobilization and for the expected duration for elimination of the medications, and until all cycles of apheresis are complete.

Actions

Mechanism of Action

Elivaldogene autotemcel adds functional copies of the ABCD1 cDNA into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with Lenti-D lentiviral vector (LVV). After elivaldogene autotemcel infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate into various cell types, including monocytes (CD14⁺) capable of producing functional ALDP. Functional ALDP can then participate in the local degradation of very long chain fatty acids (VLCFAs), which is believed to slow or possibly prevent further inflammation and demyelination.

Advice to Patients

• Review the FDA-approved patient labeling (Medication Guide) with the patient and their caregiver(s).

• Ensure that the patient and/or caregiver understands the risk of manufacturing failure. In case of manufacturing failure or the need for additional cells, additional cell collection and manufacturing of elivaldogene autotemcel may be needed.

• Inform the patient and/or caregiver that there has been unexplained efficacy failure after treatment with elivaldogene autotemcel.

• Inform the patient and/or caregiver that insertional oncogenesis has been observed and resulted in myelodysplastic syndrome (MDS) in several children following treatment with elivaldogene autotemcel. Inform the patient that MDS is a life-threatening disease and that the only curative treatment is another bone marrow transplant, with or without the addition of chemotherapy and total body irradiation. Patients will need monitoring for hematologic malignancies via blood tests at least every 6 months for a minimum of 15 years. Advise patients that they may require more frequent blood tests and invasive bone marrow biopsies if routine blood test results are concerning for the development of malignancy. Advise the patient and/or caregiver to seek attention for any signs or symptoms of malignancy, such as fatigue or easy bleeding or bruising, and advise the patient to contact bluebird bio at 1-833-999-6378 if they are diagnosed with a hematologic malignancy.

• Some patients have required an allogeneic hematopoietic stem cell transplant after treatment with elivaldogene autotemcel, in order to treat efficacy failure or hematologic malignancy. Advise patients that they will be monitored for these complications.

• Inform the patient that severe infections, including life-threatening infections, have occurred following elivaldogene autotemcel treatment and may require prolonged hospitalization.

• Inform the patient and/or caregiver that prolonged cytopenias have been observed following elivaldogene autotemcel treatment and that they may require frequent blood draws until blood counts have returned to safe levels. Advise the patient and/or caregiver to seek attention for any signs or symptoms of thrombocytopenia, neutropenia, or anemia, such as easy bleeding, serious infections, or fatigue.

• Inform the patient that a risk of bleeding and a likely need for platelet transfusion exists after myeloablative conditioning and during the weeks to months before platelet engraftment occurs.

• Inform the patient and/or caregiver of the potential risk of neutrophil engraftment failure and the need for rescue treatment with their back-up collection of CD34+ cells, if engraftment failure occurs.

• Advise patients that they may test positive for HIV if tested using a PCR test after being treated with elivaldogene autotemcel. Advise the patient and/or caregiver that they should notify any healthcare provider about this possibility prior to being tested for HIV.

• Advise patients that they will be screened for HBV, HCV, HIV, and HTLV before collection of cells.

• Inform patients that they should not donate blood, organs, tissues, or cells at any time in the future.

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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