Hematologic malignancies, including life-threatening cases of myelodysplastic syndrome and acute myeloid leukemia, have occurred in patients treated with elivaldogene autotemcel. Patients have been diagnosed between 14 months and 7.5 years after elivaldogene autotemcel administration, and the cancers appear to be the result of the elivaldogene autotemcel lentiviral vector, Lenti-D, integration in proto-oncogenes. Monitor patients closely for evidence of malignancy through complete blood counts at least every 3 months. Monitor patients through assessments for evidence for clonal expansion or predominance at least twice in the first year and annually thereafter; consider bone marrow evaluations as clinically indicated.
Note: A treatment course consists of multiple phases: 1) mobilization and apheresis to collect CD34+ cells for manufacturing, 2) myeloablative and lymphodepleting conditioning, and 3) elivaldogene autotemcel infusion, with a minimum of 48 hours washout between conditioning and elivaldogene autotemcel infusion.
For autologous use only; confirm patient identity matches unique patient identifiers on the cassette and infusion bag(s). Elivaldogene autotemcel is provided as a single dose for infusion containing a suspension of CD34+ cells in 1 or more infusion bags; confirm correct number of infusion bags are present (see lot information sheet).
Mobilization: Confirm a negative HIV test prior to beginning mobilization and apheresis of CD34+ cells if antiretrovirals are required for HIV prophylaxis. Patients should not take prophylactic HIV antiretroviral medications for at least 1 month prior to mobilization (or for the expected duration for elimination of the medications) and until all cycles of apheresis are completed.
Granulocyte colony-stimulating factor (G-CSF) and plerixafor were used for mobilization in clinical trials. The target collection is ≥12 × 106 CD34+ cells/kg. A back-up collection of CD34+ cells (either via apheresis or marrow harvest; refer to product labeling for details) is required for rescue treatment (if needed); collect and cryopreserve prior to myeloablative conditioning.
Myeloablative and lymphodepleting conditioning preparation: Full myeloablative and lymphodepleting conditioning must be administered before infusion; in clinical trials, busulfan and cyclophosphamide/fludarabine, respectively, were used. Confirm availability of autologous elivaldogene autotemcel at the infusion center (and availability of back-up collection) prior to initiating myeloablative therapy. Refer to manufacturer's labeling for conditioning agents and specific protocols.
Cerebral adrenoleukodystrophy: Males: Children ≥4 years and Adolescents <18 years: IV: Dose calculated based on patient weight prior to first apheresis and is specific to lot; see lot information sheet provided with product. Minimum recommended dose: 5 × 106 CD34+ cells/kg; administer after a washout period of at least 48 hours after completion of conditioning (refer to specific protocols).
There are no dosage adjustments provided in the manufacturer's labeling; has not been studied in patients with kidney impairment.
There are no dosage adjustments provided in the manufacturer's labeling; has not been studied in patients with hepatic impairment.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for children and adolescents; 48-hours post-administration of conditioning agents. Adverse reactions were more commonly reported in the first 60-days after elivaldogene autotemcel treatment and may be attributed to conditioning agents.
>10%:
Cardiovascular: Hypertension, tachycardia
Dermatologic: Alopecia, pruritus, skin hyperpigmentation, skin rash (including erythematous rash, maculopapular rash, urticaria)
Endocrine & metabolic: Hypokalemia
Gastrointestinal: Abdominal pain, constipation, decreased appetite, diarrhea, nausea, stomatitis (including colitis, gastrointestinal inflammation, proctitis), vomiting
Hematologic & oncologic: Anemia, febrile neutropenia, leukopenia, lymphocytopenia, neutropenia, thrombocytopenia
Hypersensitivity: Transfusion reaction (including anaphylaxis, hypersensitivity reactions)
Infection: Infection (including bacterial infection, opportunistic infection [including atypical mycobacterial infection, BK virus infection, candidiasis, cytomegalovirus disease, human herpes virus-6 viremia, pseudomonas infection, reactivation of latent Epstein-Barr virus], severe infection [including bacteremia, transverse myelitis], viral infection)
Nervous system: Anxiety (including agitation, akathisia), headache
Respiratory: Epistaxis, oropharyngeal pain
Miscellaneous: Fever
1% to 10%:
Hematologic & oncologic: Hematologic malignancy (including acute myeloid leukemia, myelodysplastic syndrome), pancytopenia
Nervous system: Seizure
Ophthalmic: Blurred vision
Respiratory: Cough
Frequency not defined: Hypersensitivity: Infusion-related reaction
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Cytopenias: Prolonged (>1 year) cytopenias including pancytopenia may occur following lymphodepleting chemotherapy and elivaldogene autotemcel infusion.
• Hematologic malignancy: May cause hematologic malignancies; consider hematologist consult and alternative therapies prior to initiating. Patients are encouraged to enroll in the study, as available, to assess the long-term safety of elivaldogene autotemcel and the risk of malignancies by calling the manufacturer at 1-833-999-6378.
• Hypersensitivity: Allergic reactions may occur with elivaldogene autotemcel. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) component.
• Infection: Serious infections (including life-threatening or fatal infections) occurred in patients after elivaldogene autotemcel infusion, including ≥ grade 3 infections. Neutropenic fever has been commonly observed and may be a sign of severe infection; manage infections with appropriate medical and supportive care. Avoid administration in patients with active infection.
• Neutrophil engraftment failure: There is a potential risk of neutrophil engraftment failure after treatment with elivaldogene autotemcel. Neutrophil engraftment failure is defined as failure to achieve 3 consecutive ANCs ≥500/mm3 obtained on different days by day 43 after elivaldogene autotemcel infusion. If neutrophil engraftment failure occurs in a patient treated with elivaldogene autotemcel, provide rescue treatment with the backup collection of CD34+ cells.
• Platelet engraftment delay: Delayed platelet engraftment (platelet count ≤50,000/mm3 beyond 60 days after treatment) has been observed with elivaldogene autotemcel treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved.
Concurrent drug therapy issues:
• Immunizations: Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during elivaldogene autotemcel treatment, and until immune recovery following treatment. The safety of immunization with live viral vaccines during or following elivaldogene autotemcel treatment has not been studied.
Special populations:
• Patients with HIV: Elivaldogene autotemcel has not been studied in patients with HIV-1, HIV-2, human T-lymphotropic virus 1 (HTLV-1), or HTLV-2. A negative serology test for HIV is necessary to ensure acceptance of apheresis material to manufacture elivaldogene autotemcel. Apheresis material from patients with a positive HIV test will not be accepted for elivaldogene autotemcel manufacturing. Antiretroviral medications are not recommended within 1 month prior to mobilization or the expected duration for elimination, and until all cycles of apheresis are completed; may interfere with manufacturing of the apheresed cells. Delay mobilization and apheresis of CD34+ cells in patients requiring antiretroviral prophylaxis until HIV infection is ruled out.
Dosage form specific issues:
• Dimethyl sulfoxide: Elivaldogene autotemcel contains DMSO, which is associated with serious hypersensitivity reactions, including anaphylaxis.
• Universal precautions: Elivaldogene autotemcel contains human blood cells that are genetically modified with replication-incompetent, self-inactivating Lenti-D lentiviral vector; follow universal precautions and facility biosafety guidelines for handling and disposal to avoid potential transmission of infectious diseases.
Other warnings/precautions:
• Appropriate use: After elivaldogene autotemcel administration, the standard procedures for patient management after hematopoietic cell transplantation should be followed. Irradiate any blood products required within the first 3 months after elivaldogene autotemcel infusion. Patients should not donate blood, organs, tissues, or cells at any time in the future.
Skysona is composed of one or two infusion bags which contain 4 to 30 × 106 cells/mL suspended in cryopreservation solution. Each infusion bag contains ~20 mL. A single dose of Skysona contains a minimum of 5 × 106 CD34+ cells/kg suspended in cryopreservation solution.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intravenous:
Skysona: (1 ea)
No
Note: For autologous use only; confirm patient identity matches unique patient identifiers on the cassette and infusion bag(s). Elivaldogene autotemcel is provided as a single dose for infusion containing a suspension of CD34+ cells in 1 or more infusion bags; confirm correct number of infusion bags are present (see lot information sheet).
IV: For IV use only. Prime tubing set with NS prior to infusion. Infuse each bag via gravity flow drip over <60 minutes. Do not use an inline blood filter or an infusion pump. After infusing each bag, flush all elivaldogene autotemcel remaining in infusion bag and any associated tubing with at least 50 mL NS to ensure that as many cells as possible are infused.
Coordinate the timing of administration with thawing. If more than 1 bag is required, administer each infusion bag completely before proceeding to thaw and infuse the next bag. Infuse as soon as possible after thawing; must be administered within 4 hours after thawing.
Keep the infusion bag(s) in the metal cassette(s) and store/transfer in the vapor phase of liquid nitrogen at ≤−140°C (≤−220°F) until ready for thaw and administration. Thaw prior to infusion. Do not refreeze after thawing. Do not irradiate, as this could lead to inactivation. Product must be administered within 4 hours after thawing. Contact manufacturer (1-833-999-6378) with any concerns about product or packaging upon receipt.
To slow the progression of neurologic dysfunction in males with early, active cerebral adrenoleukodystrophy (CALD) (FDA approved in ages 4 to 17 years). Note: Early, active CALD refers to asymptomatic or mildly symptomatic disease with neurologic function score ≤1, gadolinium enhancement on MRI, and Loes score of 0.5 to 9.
Limitations of use:
Has not been studied in patients with CALD secondary to head trauma and does not prevent the development of or treat adrenal insufficiency due to adrenoleukodystrophy.
An immune response to elivaldogene autotemcel may limit the persistence of descendent cells of elivaldogene autotemcel, causing rapid loss of efficacy of elivaldogene autotemcel in patients with full deletion of the human adenosine triphosphate binding cassette, sub family D, member 1 transgene.
Elivaldogene autotemcel may be confused with axicabtagene ciloleucel, betibeglogene autotemcel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, sipuleucel-T, tisagenlecleucel.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Antiretroviral Agents: May diminish the therapeutic effect of Elivaldogene Autotemcel. Management: Avoid use of antiretroviral medications for at least one month, or for the amount of time required for elimination of the retroviral medication, prior to stem cell mobilization and until the all apheresis cycles are finished Risk X: Avoid combination
Antithymocyte Globulin (Equine): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Antithyroid Agents: Myelosuppressive Agents may enhance the neutropenic effect of Antithyroid Agents. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Chikungunya Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Linezolid: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines: Elivaldogene Autotemcel may enhance the adverse/toxic effect of Vaccines. Specifically, there may be a greater risk for contracting an infection from any live vaccine. Elivaldogene Autotemcel may diminish the therapeutic effect of Vaccines. Management: Administration of vaccines is not recommended in the 6 weeks before myeloablative conditioning, and until hematologic recovery after elivaldogene autotemcel treatment. Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Patients who could become pregnant and patients who could father a child should use effective contraception prior to beginning mobilization through at least 6 months after administration of elivaldogene autotemcel. Effective methods of contraception include an IUD or a combination hormonal contraceptive plus barrier contraception.
Also consider risks associated with myeloablative conditioning agents, including effects on fertility and the option to cryopreserve semen prior to therapy if appropriate.
Reproduction studies have not been conducted. Consider risks associated with myeloablative conditioning agents.
Screen for hepatitis B virus, hepatitis C virus, human T-lymphotrophic virus 1 and 2, and HIV (1 and 2) prior to collection of cells for manufacturing. Confirm a negative HIV test prior to beginning mobilization and apheresis of CD34+ cells if antiretrovirals are required for HIV prophylaxis. Assess renal function (including CrCl) and hepatic function prior to treatment (to ensure appropriate for stem cell transplant therapy). Monitor neutrophil counts until engraftment has been achieved. Monitor platelet counts frequently until platelet engraftment and platelet recovery are achieved; perform CBC and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. Monitor for signs/symptoms of hypersensitivity, infection, and/or bleeding.
Monitor lifelong for hematologic malignancies, with a CBC (with differential) every 6 months for at least 15 years after elivaldogene autotemcel treatment; perform integration site analysis (or other testing) at months 6 and 12, and then annually. If a malignancy occurs, contact the manufacturer for instructions on sample collection for testing.
Elivaldogene autotemcel is a gene therapy consisting of autologous CD34+ hematopoietic cells transduced with the Lenti-D lentiviral vector to add functional copies of the ABCD1 cDNA into the hematopoietic stem cells. After elivaldogene autotemcel infusion, transduced CD34+ hematopoietic stem cells engraft in the bone marrow and differentiate to produce various cell types, including monocytes (CD14+) capable of producing functional ALDP. Functional ALDP participates in the local degradation of very long chain fatty acids, which slows or possibly prevents further demyelination and inflammation.
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