Version May 2024
Hematologic malignancy has occurred in patients treated with lovotibeglogene autotemcel. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at months 6, 12, and as warranted.
Dosage guidance:
Safety: For autologous use only; confirm patient identity matches unique patient identifiers on the vial(s). Lovotibeglogene autotemcel is provided as a single dose for infusion containing a suspension of CD34+ cells provided in 1 to 4 infusion bags; confirm correct number of infusion bags to be administered are present (see lot information sheet provided with product shipment).
Dosage form information: Each infusion bag contains ∼20 mL with 1.7 to 20 × 106 CD34+ cells/mL.
Clinical considerations: A treatment course consists of multiple phases: 1) Plerixafor hematopoietic cell mobilization and apheresis to collect CD34+ cells for manufacturing, 2) busulfan myeloablative conditioning, 3) lovotibeglogene autotemcel infusion administered after a washout period of a minimum of 48 hours after completion of myeloablative conditioning.
Preparation for mobilization and apheresis: Prepare patients for mobilization with at least 2 cycles of scheduled transfusions (one each month), preferably with erythrocytapheresis. Patients should undergo a transfusion regimen to reach a target hemoglobin of 8 to 10 g/dL (not to exceed 12 g/dL) and hemoglobin S (HbS) level of <30% for at least 60 days prior to mobilization and through myeloablative conditioning to reduce the risk of sickle cell disease–related complications; scheduled transfusions may be continued between apheresis and conditioning. Discontinue hydroxyurea at least 2 months prior to mobilization; do not resume hydroxyurea until all cycles of apheresis are completed. Discontinue disease modifying agents (eg, L-glutamine, voxelotor, crizanlizumab) and erythropoietin at least 2 months prior to mobilization. Discontinue iron chelation at least 7 days prior to mobilization. Discontinue prophylactic HIV antiretroviral medications at least one month prior to mobilization (some long-acting antiretroviral medications may require a longer duration of discontinuation for elimination); do not resume antiretrovirals until all apheresis cycles are completed.
Mobilization: Mobilization is conducted using plerixafor; granulocyte-colony stimulating factor (G-CSF) should not be used in patients with sickle cell disease. Administer daily plerixafor 4 to 6 hours prior to each apheresis collection (if more than one apheresis day is required within a cycle, prior to plerixafor administration that day, confirm platelets ≥75,000/mm3 within 24 hours of subsequent apheresis sessions; if platelet goal is not met, defer mobilization and apheresis until platelets recover to ≥75,000/mm3). For patient undergoing more than one mobilization, separate each cycle by at least 14 days. If a sufficient number of cells are collected after the first mobilization, no further mobilization/apheresis is required. In clinical studies, the minimum number of cells to manufacture lovotibeglogene autotemcel was collected in most patients with 1 or 2 cycles of mobilization and apheresis, which typically required 2 consecutive collections days per cycle. A target CD34+ cell dose of ≥16.5 × 106 CD34+ cells/kg is recommended for product manufacturing and back-up. If the minimum dose (3 × 106 CD34+ cells/kg) is not met after manufacturing, the patient may undergo additional cycles of mobilization and apheresis, separated by ≥14 days to obtain more cells. Multiple product lots may be combined to administer the final dose. A collection of ≥1.5 × 106 CD34+ cells/kg for back-up unmodified rescue cells should also be collected and cryopreserved prior to myeloablative conditioning.
Myeloablative conditioning preparation: Scheduled transfusion support may be continued between apheresis and conditioning; a scheduled transfusion should be performed within 2 days prior to myeloablative conditioning. If hydroxyurea is administered after apheresis, discontinue at least 2 days prior to myeloablative conditioning. Discontinue disease modifying agents (eg, L-glutamine, voxelotor, crizanlizumab) at least 2 months prior to conditioning. If administered after apheresis, discontinue iron chelation therapy at least 7 days prior to myeloablative conditioning. Administer busulfan conditioning regimen (with busulfan pharmacokinetic monitoring). Administer antiseizure prophylaxis (using agents other than phenytoin) beginning at least 12 hours prior to busulfan initiation. Consider prophylaxis for hepatic sinusoidal obstruction syndrome (veno-occlusive disease) with ursodiol or defibrotide. Confirm availability of autologous lovotibeglogene autotemcel vials at the infusion center (and availability of back-up collection) prior to initiating myeloablative therapy. Refer to product labeling for further information.
Sickle cell disease: IV: Minimum recommended dose: 3 × 106 CD34+ cells/kg; administer after a washout period of a minimum of 48 hours after completion of myeloablative conditioning.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl <70 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); evaluate kidney function to ensure appropriateness of lovotibeglogene autotemcel treatment.
Advanced hepatic disease prior to treatment initiation: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); evaluate hepatic function to ensure appropriateness of lovotibeglogene autotemcel treatment.
Refer to adult dosing.
(For additional information see "Lovotibeglogene autotemcel: Pediatric drug information")
Dosage guidance:
Safety: For autologous use only; confirm patient identity matches unique patient identifiers on the infusion bag(s). Lovotibeglogene autotemcel is provided as a single dose for infusion containing a suspension of CD34+ cells in 1 to 4 infusion bag(s); confirm correct number of infusion bags to be administered are present (see lot information sheet provided with product shipment).
Dosage form information: Each infusion bag contains ~20 mL of lovotibeglogene autotemcel with 1.7 to 20 × 106 cells/mL.
Clinical considerations: A treatment course consists of multiple phases: 1) plerixafor hematopoietic cell mobilization and apheresis to collect CD34+ cells for manufacturing, 2) busulfan myeloablative conditioning, 3) lovotibeglogene autotemcel infusion administered after a minimum 48-hour washout period following completion of myeloablative conditioning.
Preparation for mobilization: Prepare patients for mobilization with at least 2 cycles of scheduled transfusions (one each month), preferably with erythrocytapheresis. Through transfusions, patient should be maintained at hemoglobin S (HbS) concentrations <30% of total hemoglobin while maintaining total hemoglobin 8 to 10 g/dL (not to exceed 12 g/dL) for ≥60 days prior to mobilization and through myeloablative conditioning. Discontinue hydroxyurea, disease-modifying agents (eg, L-glutamine, voxelotor, crizanlizumab), and erythropoietin ≥2 months prior to mobilization; do not resume hydroxyurea until all apheresis cycles are completed. Discontinue iron chelation ≥7 days prior to mobilization. Discontinue prophylactic HIV antiretroviral medications ≥1 month prior to mobilization (some long-acting antiretroviral medications may require a longer duration of discontinuation for elimination); do not resume antiretrovirals until all apheresis cycles are completed.
Mobilization: Use plerixafor for mobilization; granulocyte colony-stimulating factor (G-CSF) should not be used in patients with sickle cell disease. Administer daily plerixafor ~4 to 6 hours prior to each apheresis collection (if >1 apheresis day is required within a cycle, prior to plerixafor administration that day, confirm platelets ≥75,000/mm3 within 24 hours of subsequent apheresis sessions; if platelet goal is not met, defer mobilization and apheresis until platelets recover to ≥75,000/mm3). For patients undergoing >1 mobilization, separate each cycle by at least 14 days. A target CD34+ cell dose of ≥16.5 × 106 CD34+ cells/kg is recommended for manufacturing and back-up. If the minimum dose (3 × 106 CD34+ cells/kg) is not met, the patient may undergo additional cycles of mobilization and apheresis, separated by ≥14 days, to obtain more cells. Multiple product lots may be combined to administer the final dose. A collection of ≥1.5 × 106 CD34+ cells/kg for back-up unmodified rescue cells should be cryopreserved prior to myeloablative conditioning.
Myeloablative conditioning preparation: If hydroxyurea is administered after apheresis, discontinue ≥2 days prior to myeloablative conditioning. If iron chelation therapy is administered after apheresis, discontinue ≥7 days prior to conditioning. Administer antiseizure prophylaxis (using agents other than phenytoin) starting at least 12 hours prior to busulfan initiation. Consider prophylaxis for hepatic sinusoidal obstruction syndrome (veno-occlusive disease) with ursodiol or defibrotide. Confirm availability of autologous lovotibeglogene autotemcel and back-up cell collection at the infusion center prior to initiating myeloablative therapy. Refer to manufacturer's labeling for details.
Sickle cell disease: Children ≥12 years and Adolescents: IV: Minimum recommended dose: 3 × 106 CD34+ cells/kg; administer after a washout period of at least 48 hours after completion of myeloablative conditioning.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; has not been studied in patients with eGFR ≤70 mL/minute/1.73 m2; evaluate patient to ensure appropriateness of therapy.
There are no dosage adjustments provided in the manufacturer's labeling; has not been studied in patients with advanced hepatic disease; evaluate patient to ensure appropriateness of therapy.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are grade ≥3 in adolescents and adults unless otherwise indicated.
>10%:
Gastrointestinal: Decreased appetite, stomatitis
Hematologic & oncologic: Anemia, febrile neutropenia, leukopenia, neutropenia, thrombocytopenia
Hepatic: Increased gamma-glutamyl transferase, increased serum alanine aminotransferase, increased serum aspartate aminotransferase
Respiratory: Pharyngitis
1% to 10%:
Gastrointestinal: Nausea
Hepatic: Increased serum bilirubin
Infection: Bacteremia
Miscellaneous: Fever
Frequency not defined (any grade):
Hematologic & oncologic: Hematologic malignancy
Hypersensitivity: Infusion-related reaction
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Hematologic malignancy: Hematologic malignancy has occurred in lovotibeglogene autotemcel–treated patients. Two patients treated with an earlier version of lovotibeglogene autotemcel (which used a different manufacturing process and transplant procedure) developed acute myeloid leukemia (AML) and one patient with alpha-thalassemia trait developed myelodysplastic syndrome (MDS) (Ref). The additional hematopoietic stress associated with mobilization, conditioning, and infusion of lovotibeglogene autotemcel, including the need to regenerate the hematopoietic system, may increase the risk of hematologic malignancy. Patients with sickle cell disease have an increased risk of hematologic malignancy (compared to the general population). Lovotibeglogene autotemcel–treated patients may develop hematologic malignancies and should have lifelong monitoring. If a malignancy occurs, report to the manufacturer to obtain instructions on collection of samples for testing. Patients who intend to receive treatment with lovotibeglogene autotemcel are encouraged to enroll in the postmarketing long-term follow-up study (which includes monitoring at prespecified intervals for clonal expansion) to assess the long-term safety of lovotibeglogene autotemcel and the risk of malignancies following lovotibeglogene autotemcel treatment.
• Hypersensitivity: Allergic reactions may occur with lovotibeglogene autotemcel. Lovotibeglogene autotemcel contains dimethyl sulfoxide (DMSO) and dextran 40, which are associated with hypersensitivity reactions, including anaphylaxis.
• Insertional oncogenesis: There is a potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with lovotibeglogene autotemcel.
• Neutrophil engraftment failure: There is a potential risk of neutrophil engraftment failure after lovotibeglogene autotemcel treatment. Neutrophil engraftment failure is defined as not achieving neutrophil engraftment (3 consecutive ANC ≥500/mm3 obtained on different days) by day 43 after lovotibeglogene autotemcel infusion. In the study, the median time to neutrophil engraftment was 20 days (range: 12 to 35 days). If neutrophil engraftment failure occurs, provide rescue treatment with the back-up collection of CD34+ cells.
• Platelet engraftment delay: Delayed platelet engraftment has been observed with lovotibeglogene autotemcel. Platelet engraftment is defined as 3 consecutive measurements of platelets ≥50,000/mm3 on different days after the post-treatment nadir without administration of platelet transfusion for 7 days. In the study, median time to platelet engraftment was 37 days (range: 19 to 235 days). Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients achieved platelet engraftment >100 days post lovotibeglogene autotemcel treatment. Inform patients of the risk of bleeding until platelet recovery has been achieved.
Disease-related concerns:
• Patients with HIV: Lovotibeglogene autotemcel has not been studied in HIV-positive (HIV-1 and HIV-2) patients. A negative HIV serology test is necessary prior to apheresis. Patients with a positive HIV test cannot receive lovotibeglogene autotemcel.
Concurrent drug therapy issues:
• Immunizations: The safety of immunization with live viral vaccines during or following lovotibeglogene autotemcel has not been studied. Follow recommendations for vaccination schedules as per post-autologous hematopoietic cell transplant and functional asplenia guidelines as well as institutional guidelines for vaccine administration.
Special populations:
• Older adults: Lovotibeglogene autotemcel has not been studied in patients ≥65 years of age. Patients must be appropriate for autologous hematopoietic cell transplantation to receive lovotibeglogene autotemcel treatment.
Dosage form specific issues:
• Cryopreservative solution: Lovotibeglogene autotemcel contains dimethyl sulfoxide (DMSO) and dextran 40, which are associated with serious hypersensitivity reactions, including anaphylaxis.
• Universal precautions: Lovotibeglogene autotemcel contains genetically modified human cells; follow universal precautions and facility biosafety level 2 guidelines (BSL2) for handling and disposal to avoid potential transmission of infectious diseases.
Other warnings/precautions:
• Appropriate use: Confirm that autologous hematopoietic cell transplant is appropriate for the patient prior to initiation of mobilization and apheresis and myeloablation conditioning. After lovotibeglogene autotemcel administration, follow the standard procedures for patient management after hematopoietic cell transplantation. Irradiate any blood products required for at least the first 3 months after lovotibeglogene autotemcel infusion. There is no experience regarding the use of hydroxyurea, antiretrovirals, erythropoietin, or disease-modifying agents (eg, voxelotor, crizanlizumab) following lovotibeglogene autotemcel infusion. Avoid the use of myelosuppressive iron chelators for 6 months after lovotibeglogene autotemcel infusion; if iron chelation is necessary, consider nonmyelosuppressive iron chelators, or phlebotomy may be used in lieu of iron chelation. Granulocyte colony-stimulating factor use is not recommended for 21 days after lovotibeglogene autotemcel infusion. Patients should not donate blood, organs, tissues, or cells at any time in the future.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intravenous:
Lyfgenia: (1 ea)
No
Lovotibeglogene autotemcel can only be administered at qualified treatment centers; information is available from the manufacturer at https://www.lyfgenia.com/find-a-qualified-treatment-center.
IV: Before infusion, confirm patient identity matches unique identifiers on the lovotibeglogene autotemcel metal cassette(s) and infusion bag(s) (do not infuse if patient-specific label does not match).
Coordinate the timing of administration with thawing. If more than one infusion bag is required, administer the contents of each infusion bag completely before proceeding to thaw and infusing the contents of the next bag. Infuse as soon as possible after thawing; must be administered within 4 hours after thawing.
Administer the contents of each lovotibeglogene autotemcel infusion bag over a period of <30 minutes. After infusing the contents of each infusion bag, flush the infusion bag and tubing with at least 50 mL of NS to ensure the patient receives as many cells as possible. Ensure all infusion bags are administered. Do not use an inline blood filter or an infusion pump.
Follow universal precautions and facility biosafety guidelines for handling and disposal.
Note: For autologous use only; confirm patient identity matches unique identifiers on the cassette(s) and infusion bag(s). Lovotibeglogene 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 bags are present (see lot information sheet).
IV: Administer each infusion bag via IV infusion over a period of <30 minutes; do not administer via infusion pump or in-line blood filter. After infusing the contents of each infusion bag, flush the infusion bag and tubing with at least 50 mL NS to ensure the patient receives as many cells as possible.
If more than 1 infusion bag is required, administer the contents of each infusion bag completely before thawing and administering the next bag. Ensure all infusion bags are administered; each bag must be administered within 4 hours of thawing.
Follow universal precautions and facility biosafety guidelines for handling and disposal.
Sickle cell disease: Treatment of sickle cell disease in adults and pediatric patients ≥12 years of age with a history of vaso-occlusive events.
Limitations of use: Following treatment with lovotibeglogene autotemcel, patients with alpha-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia, which may require chronic RBC transfusions. Lovotibeglogene autotemcel has not been studied in patients with >2 alpha-globin gene deletions.
Lovotibeglogene autotemcel may be confused with axicabtagene ciloleucel, betibeglogene autotemcel, brexucabtagene autoleucel, ciltacabtagene autoleucel, elivaldogene autotemcel, exagamglogene autotemcel, 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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Antiretroviral Agents: May diminish the therapeutic effect of Lovotibeglogene Autotemcel. Risk X: Avoid combination
Crizanlizumab: May diminish the therapeutic effect of Lovotibeglogene Autotemcel. Risk X: Avoid combination
Erythropoiesis-Stimulating Agents: May diminish the therapeutic effect of Lovotibeglogene Autotemcel. Risk X: Avoid combination
Glutamine: May diminish the therapeutic effect of Lovotibeglogene Autotemcel. Risk X: Avoid combination
Granulocyte Colony-Stimulating Factors: May enhance the adverse/toxic effect of Lovotibeglogene Autotemcel. Risk X: Avoid combination
Hydroxyurea: May diminish the therapeutic effect of Lovotibeglogene Autotemcel. Risk X: Avoid combination
Iron Chelators: May enhance the myelosuppressive effect of Lovotibeglogene Autotemcel. Iron Chelators may diminish the therapeutic effect of Lovotibeglogene Autotemcel. Risk X: Avoid combination
Voxelotor: May diminish the therapeutic effect of Lovotibeglogene Autotemcel. Risk X: Avoid combination
A negative serum pregnancy test is required prior to initiating each mobilization cycle and reconfirmed prior to myeloablative conditioning and lovotibeglogene autotemcel administration.
Patients who could become pregnant and patients with a partner who could become pregnant should use effective contraception (eg, IUD or combination of hormonal and barrier contraceptives) prior to beginning mobilization through at least 6 months after administration of lovotibeglogene autotemcel.
Also consider precautions associated with myeloablative conditioning agents, including effects on fertility. Potential pregnancies (following treatment) should be discussed with the prescriber.
Animal reproduction studies have not been conducted.
The risks of myeloablative conditioning agents on pregnancy should be considered. Potential pregnancies (following treatment) should be discussed with the prescriber.
It is not known if lovotibeglogene autotemcel is present in breast milk.
Due to the potential for adverse events in a breastfed child, breastfeeding is not recommended by the manufacturer. Breastfeeding following treatment should be discussed with the prescriber.
Screen for infectious diseases, specifically HIV (1 and 2), in accordance with local guidelines prior to collection of cells for manufacturing. Assess kidney and hepatic function prior to treatment (to ensure appropriateness for therapy). Monitor neutrophil counts until engraftment has been achieved. Assess platelet counts frequently until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. Monitor for hematologic malignancies with a CBC with differential at least every 6 months for at least 15 years following receipt of lovotibeglogene autotemcel, and integration site analysis at months 6, 12, and as warranted. Evaluate pregnancy status prior to therapy; patients who could become pregnant are required to have a negative serum pregnancy test prior to initiating each mobilization cycle and reconfirmed prior to myeloablative conditioning and lovotibeglogene autotemcel administration. Monitor signs/symptoms of thrombocytopenia, bleeding, and hypersensitivity.
Lovotibeglogene autotemcel is a cellular gene therapy consisting of autologous CD34+ cells containing hematopoietic cells (HCs) transduced ex-vivo with a BB305 lentiviral vector encoding a modified β-globin gene. Following lovotibeglogene autotemcel infusion, the transduced CD34+ hematopoietic cells engraft in the bone marrow and differentiate to produce RBCs that combine with α-globin to produce HbAT87Q (a modified adult hemoglobin with an amino acid substitution [threonine to glutamine at position 87]), which then reduces intracellular and total hemoglobin S (HbS) levels, and sterically inhibits HbS polymerization, thereby limiting the sickling of RBCs. HbAT87Q maintains 99.9% identity to adult hemoglobin, has a similar oxygen-binding affinity and oxygen-hemoglobin dissociation curve (to wild type hemoglobin A), and can be differentiated from transfused adult hemoglobin (Ref).
Onset: HbAT87Q generally increased steadily following lovotibeglogene autotemcel infusion and stabilized by ∼6 months after lovotibeglogene autotemcel.
Duration: HbAT87Q remained durable with a median of 5.5 g/dL (range: 2.4 to 9.4 g/dL) at 24 months. HbAT87Q expression remained continuously durable through at least 48 months, demonstrating long-term gene integration into hematopoietic cells.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
