Betibeglogene autotemcel is an intravenous autologous hematopoietic stem cell-based gene therapy indicated for the treatment of beta thalassemia in persons requiring regular red blood cell transfusions. Betibeglogene autotemcel adds functional copies of a modified beta-globin gene into subjects' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 lentiviral vector (LVV). After betibeglogene autotemcel infusion, the transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce functional hemoglobin. Beta thalassemia is characterized by the absence or reduction in the rate of production of the beta-globin chain. Beta thalassemia major is the most severe type of beta thalassemia and results in severe anemia requiring blood transfusions. Regular treatment with blood transfusions can result in iron overload to various organs. Efficacy of betibeglogene autotemcel in persons with beta thalassemia requiring blood transfusions was evaluated in 2 clinical trials (n = 41) by achievement of transfusion independence, defined as a weighted average hemoglobin of 9 g/dL or more without any transfusions for 12 months or more; transfusion independence was achieved in 86% to 91% of subjects. Delayed platelet engraftment has been reported with betibeglogene autotemcel, and there is a potential risk for neutrophil engraftment failure and new hematologic malignancy after betibeglogene autotemcel treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Betibeglogene autotemcel may carry the risk of transmitting infectious diseases to health care professionals handling the product. Follow universal precautions and biosafety guidelines for handling and disposal of betibeglogene autotemcel.
-Allow a minimum of 48 hours after completion of myeloablative conditioning before betibeglogene autotemcel infusion.
Route-Specific Administration
Injectable Administration
-Visually inspect each infusion bag for any breaches of integrity before thawing and infusion. If an infusion bag is compromised, follow local guidelines..
Intravenous Administration
Preparation
-Coordinate the timing of betibeglogene autotemcel thaw and infusion; confirm the infusion time in advance and adjust the start time for thaw so that the recipient and care team are ready.
-Remove each metal cassette from liquid nitrogen storage and each infusion bag from the metal cassette. Confirm that betibeglogene autotemcel is printed on the infusion bag(s).
-Confirm that recipient identity matches the unique personal identification information located on the betibeglogene autotemcel infusion bag(s). Do not infuse if the information on the recipient-specific label on the infusion bag does not match the intended recipient.
-Ensure the correct number of infusion bags are present. Use the accompanying Lot Information Sheet to confirm that each infusion bag is within the expiration date.
-Thaw the infusion bag(s) at 37 degrees C (98.6 degrees F) in a water bath or dry bath. Thawing of each infusion bag takes approximately 2 to 4 minutes. Do not leave unattended and do not submerge the infusion ports in a water bath. If more than 1 infusion bag is provided, thaw and administer each infusion completely before proceeding to thaw the next infusion bag.
-After thawing, mix the contents gently by massaging the infusion bag to disperse clumps of cellular material until all the contents are uniform. If visible cell clumps remain, continue to gently mix the contents of the bag; most small clumps of cellular material should disperse with gentle manual mixing.
-Do not filter, wash, spin down, and/or resuspend betibeglogene autotemcel in new media before infusion.
-Do not sample, alter, irradiate or refreeze betibeglogene autotemcel.
-Storage: Infuse betibeglogene autotemcel as soon as possible after thawing and complete the infusion within 4 hours.
Intravenous (IV) Infusion
-Confirm the recipient's identity with the personal identifiers on the infusion bag. Confirm the total number of infusion bags with the Lot Information Sheet.
-If more than 1 infusion bag is provided, thaw and administer each infusion completely before proceeding to thaw the next infusion bag.
-Do not use an in-line blood filter or an infusion pump.
-Administer each bag by IV infusion over a period of less than 30 minutes.
-Flush all betibeglogene autotemcel remaining in the infusion bag(s) and the tubing with at least 50 mL of 0.9% Sodium Chloride Injection to ensure as many cells as possible are infused into the patient.
-Repeat steps for each infusion bag.
Allergic reactions may occur with betibeglogene autotemcel infusion. The dimethyl sulfoxide (DMSO) in betibeglogene autotemcel may cause hypersensitivity reactions, including anaphylaxis.
Gastrointestinal adverse reactions, including mucositis/oral ulceration (95%; grade 3 or more, 63%) which includes anal inflammation, mucosal inflammation, oral mucosal exfoliation, oral mucosal roughening, pharyngeal inflammation, and stomatitis, vomiting (49%), abdominal pain (39%; grade 3 or more, 2%) which includes abdominal discomfort and infusion-related abdominal pain (7%), diarrhea (27%), nausea (24%; grade 3 or more, 2%), constipation (24%), dyspepsia (10%; grade 3 or more, 5%), and gingival bleeding (10%; grade 3 or more, 2%) were reported with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
In clinical trials, grade 3 or 4 hematologic laboratory abnormalities that occurred between the start of conditioning and 24 months after betibeglogene autotemcel treatment included anemia (95%), leukopenia (100%), lymphopenia (61%), neutropenia (100%), and thrombocytopenia (100%). Grade 3 or higher febrile neutropenia was reported in 51% of subjects treated with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials. Delayed platelet engraftment, defined as 3 consecutive platelet values of 20,000 cells/mm3 or more on different days with no platelet transfusions for 7 days immediately preceding and during the evaluation period, has been reported with betibeglogene autotemcel. Monitor for thrombocytopenia and bleeding according to standard guidelines. Perform frequent platelet counts until platelet engraftment and platelet recovery are achieved. When clinical symptoms suggestive of bleeding are observed, perform blood cell count determination and other appropriate testing. Platelet engraftment occurred by a median of day 46 (range, 20 to 94) in 41 subjects treated with betibeglogene autotemcel. Subjects without a spleen achieved platelet engraftment earlier (median day 42; range, 21 to 53 days) compared to subjects with an intact spleen (median day 50; range, 20 to 94 days). Subjects achieving platelet engraftment at day 46 or later did not have an increased incidence of bleeding compared to subjects achieving platelet engraftment earlier than day 46. Neutrophil engraftment failure, defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) of 500 cells/mm3 or more obtained on different days by day 43 after betibeglogene autotemcel infusion, has also been reported. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a person treated with betibeglogene autotemcel, provide rescue treatment with the back-up collection of CD34+ cells. All subjects in clinical trials achieved neutrophil engraftment after treatment with betibeglogene autotemcel; however, 7% of subjects remained dependent on granulocyte colony stimulating factor (G-CSF) beyond day 43, including 1 subject who required G-CSF through day 77. Transient decreases in neutrophil counts to less than 500 cells/mm3 followed G-CSF discontinuation after day 43 in 6 subjects (15%).
Infection, including viral infection (17%; grade 3 or more, 2%) which includes BK virus infection, positive test for human rhinovirus, influenza, influenza-like illness, parainfluenza virus infection, rhinovirus infection, and positive test for SARS-CoV-2, upper respiratory tract infection (15%) which includes upper airway cough syndrome, viral upper respiratory tract infection, pharyngitis, and streptococcal pharyngitis, naso-pharyngitis (12%), sepsis (grade 3 or more, 10%) which includes bacterial sepsis, neutropenic sepsis, and fungal sepsis, and pneumonia (7%) was reported in subjects treated with betibeglogene autotemcel after busulfan myeloablative conditioning in clinical trials.
Headache (29%), including migraine, was reported with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
Respiratory adverse events, including cough (34%) which includes upper airway cough syndrome and productive cough, dyspnea (12%), hypoxia (12%; grade 3 or more, 7%), and rhinitis (12%) which includes rhinorrhea and allergic rhinitis, were reported with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials. Oropharyngeal pain (15%), which includes oral pain, oropharyngeal discomfort, and jaw pain, and epistaxis (42%; grade 3 or more, 20%) were also reported.
Grade 3 or 4 electrolyte abnormalities, including hypokalemia (12%), hyponatremia (10%), and hypophosphatemia (20%), as well as grade 3 or 4 hyperglycemia (14%) were reported with betibeglogene autotemcel after myeloablative conditioning therapy in clinical trials.
Hepatic veno-occlusive disease (VOD) was reported in 10% (grade 3 or more, 7%) of subjects treated with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials. Of the 3 subjects with serious VOD, 2 subjects did not receive prophylaxis for VOD. All subjects who experienced serious VOD received treatment with defibrotide and recovered. Prophylaxis for VOD is recommended during myeloablative conditioning. Grade 3 or more elevated hepatic enzymes (i.e., increased alanine aminotransferase [ALT]) (24%) and hyperbilirubinemia (10%) were also reported with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
Fever was reported in 49% (grade 3 or more, 12%) and fatigue was reported in 12% of subjects treated with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
Musculoskeletal pain (37%), which includes musculoskeletal chest pain, bone pain, musculoskeletal discomfort, chest pain (unspecified), myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain, tendon pain, and back pain, and procedural pain (15%) were reported with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
Anorexia was reported in 24% (grade 3 or more, 15%) of subjects treated with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
Alopecia (44%), rash (27%) which includes acne, acneiform rash, atopic dermatitis, macule, petechiae, follicular rash, macular rash, maculopapular rash, pruritic rash, pustular rash, and vesicular rash, pigmentation disorder (24%) which includes oral pigmentation, skin hyperpigmentation, and skin hypopigmentation, and pruritus (22%) were reported with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials.
Infusion-related reactions, including abdominal pain (7%) and sinus tachycardia (2%), and transfusion reactions (15%) were reported with betibeglogene autotemcel after busulfan myeloablative conditioning in clinical trials.
Cardiovascular adverse events such as heart failure (2%) and hypertension (10%) were reported with betibeglogene autotemcel after busulfan myeloablative conditioning therapy in clinical trials. Infusion-related tachycardia (2%) was also reported.
Betibeglogene autotemcel has not been studied in persons with human immunodeficiency virus (HIV) infection (i.e., HIV-1, HIV-2) or human T-lymphotrophic virus infection (i.e., HTLV-1, HTLV-2). A negative serology test for HIV is necessary to assure acceptance of apheresis material for betibeglogene autotemcel manufacturing. Apheresis material from persons with a positive test for HIV will not be accepted for betibeglogene autotemcel manufacturing. Do not screen persons treated with betibeglogene autotemcel for HIV infection using a polymerase chain reaction (PCR)-based assay due to laboratory test interference. Persons who have received betibeglogene autotemcel are likely to test positive by PCR assays for HIV due to integrated BB305 lentiviral vector (LVV) proviral DNA, resulting in a false-positive test for HIV.
The safety of immunization with live virus vaccines during or after betibeglogene autotemcel treatment has not been studied. Follow institutional guidelines for vaccination.
Lentiviral vector (LVV)-mediated insertional ongogenesis is a potential risk after treatment with betibeglogene autotemcel. New primary malignancy, such as hematologic malignancy, may develop after treatment with betibeglogene autotemcel. Monitor for hematologic malignancies with a complete blood count with differential at months 6 and 12 and then at least annually for at least 15 years after betibeglogene autotemcel treatment, and integration site analysis at months 6 and 12, and as indicated. If a malignancy occurs, contact the manufacturer at 1-833-999-6378 to report and obtain instructions on collection of samples for testing.
Delayed platelet engraftment, defined as 3 consecutive platelet values of 20,000 cells/mm3 or more on different days with no platelet transfusions for 7 days immediately preceding and during the evaluation period, has been reported with betibeglogene autotemcel. Bleeding risk is increased before platelet engraftment and may continue after engraftment in persons with prolonged thrombocytopenia. Monitor for thrombocytopenia and bleeding according to standard guidelines. Perform frequent platelet counts until platelet engraftment and platelet recovery are achieved. When clinical symptoms suggestive of bleeding are observed, perform blood cell count determination and other appropriate testing.
Advise patients to avoid cell, organ, tissue, and blood donation after receiving treatment with betibeglogene autotemcel. Irradiate any blood products required within the first 3 months after betibeglogene autotemcel infusion.
Do not administer betibeglogene autotemcel during pregnancy. Advise females of reproductive potential who wish to become pregnant or think that they may be pregnant after treatment with betibeglogene autotemcel to discuss pregnancy with their care team. It is not known if betibeglogene autotemcel has the potential to be transferred to the fetus. There are no available data with betibeglogene autotemcel administration in pregnant women. Animal reproductive and developmental toxicity studies have not been conducted. No nonclinical germline transmission studies have been conducted.
Breast-feeding is not recommended for women who are being treated with betibeglogene autotemcel. Advise mothers who wish to breast-feed after betibeglogene autotemcel treatment to discuss breast-feeding with their care team. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for betibeglogene autotemcel and any potential adverse effects on the breast-fed child from betibeglogene autotemcel. There is no information on the presence of betibeglogene autotemcel in human milk, the effect on the breast-fed infant, or the effects on milk production.
Betibeglogene autotemcel may be associated with reproductive risk. Confirm the absence of pregnancy with serum pregnancy testing before the start of mobilization, and reconfirm with a negative serum pregnancy test before conditioning procedures and before betibeglogene autotemcel administration. Discuss contraception requirements with the patient. Advise persons of childbearing potential and their partners capable of fathering a child to use an effective method of contraception (i.e., intra-uterine device or combination of hormonal and barrier contraception) from start of mobilization though at least 6 months after betibeglogene autotemcel administration. There are insufficient data to recommend a duration of contraception after betibeglogene autotemcel treatment. There are no data on the effect of betibeglogene autotemcel on fertility; however, data are available on the risk of infertility with myeloablative conditioning. Advise persons of reproductive potential of the option to cryopreserve semen or ova before treatment, if appropriate.
General dosing information
-Allow a minimum of 48 hours after completion of myeloablative conditioning before betibeglogene autotemcel infusion.
For the treatment of beta thalassemia:
NOTE: Betibeglogene autotemcel has been designated an orphan drug by the FDA for the treatment of beta-thalassemia.
Intravenous dosage:
Adults: 5 x 10 to the 6th power CD34+ cells/kg IV as a single dose is the minimum recommended dose. In clinical trials, 9.4 x 10 to the 6th power CD34+ cells/kg IV was the median dose and 42.1 x 10 to the 6th power CD34+ cells/kg IV was the maximum dose.
Children and Adolescents 4 to 17 years: 5 x 10 to the 6th power CD34+ cells/kg IV as a single dose is the minimum recommended dose. In clinical trials, 9.4 x 10 to the 6th power CD34+ cells/kg IV was the median dose and 42.1 x 10 to the 6th power CD34+ cells/kg IV was the maximum dose.
Maximum Dosage Limits:
-Adults
42.1 x 106 CD34+ cells/kg IV as a single dose.
-Geriatric
42.1 x 106 CD34+ cells/kg IV as a single dose.
-Adolescents
42.1 x 106 CD34+ cells/kg IV as a single dose.
-Children
4 to 12 years: 42.1 x 106 CD34+ cells/kg IV as a single dose.
1 to 3 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Colony Stimulating Factors: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after betibeglogene autotemcel infusion.
Deferasirox: (Major) Avoid use of deferasirox for 6 months after betibeglogene autotemcel infusion due to risk of myelosuppression. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators (i.e., deferoxamine). Phlebotomy can be used instead of iron chelation, when appropriate.
Deferiprone: (Major) Avoid use of deferiprone for 6 months after betibeglogene autotemcel infusion due to risk of myelosuppression. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators (i.e., deferoxamine). Phlebotomy can be used instead of iron chelation, when appropriate.
Eflapegrastim: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after betibeglogene autotemcel infusion.
Filgrastim, G-CSF: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after betibeglogene autotemcel infusion.
Pegfilgrastim: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after betibeglogene autotemcel infusion.
Tbo-Filgrastim: (Major) Avoid administration of granulocyte-colony stimulating factors for 21 days after betibeglogene autotemcel infusion.
Betibeglogene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy that adds functional copies of a modified beta-globin gene into subjects' HSCs through transduction of autologous CD34+ cells with BB305 lentiviral vector (LVV), a cellular, non-viral promoter that controls gene expression for red blood cells (RBCs) and their precursors. After betibeglogene autotemcel infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce RBCs containing biologically active betaA-T87Q -globin. BetaA-T87Q-globin is a modified beta-globin protein that combines with alpha-globin to produce functional adult hemoglobin (Hb) containing betaA-T87Q-globin (HbAT87Q). BetaA-T87Q-globin expression corrects the beta/alpha-globin imbalance in erythroid cells of persons with beta thalassemia and has the potential to increase functional adult HbA and total Hb to normal concentrations and eliminate the need for regular RBC transfusions. To produce this autologous HSC-based gene therapy, HSCs are collected from the blood via apheresis procedure(s); the autologous cells are enriched for CD34+ cells, then transduced ex vivo with BB305 LVV. The transduced CD34+ cells are washed, formulated into a suspension, and then cryopreserved.
Betibeglogene autotemcel is administered intravenously. Conventional pharmacokinetic parameters of absorption, distribution, metabolism, and elimination are not applicable to betibeglogene autotemcel as this medication is an autologous gene therapy which includes hematopoietic stem cells that have been genetically modified ex vivo.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
In clinical trials (n = 35), HbAT87Q increased steadily after betibeglogene autotemcel infusion and stabilized by approximately month 6 after infusion. Subjects had a 6-month median HbAT87Q of 8.7 g/dL. HbAT87Q remained durable with a median of 8.8 g/dL at month 24 (n = 30) and continued to remain durable at last follow-up through month 36.