Prepare for Mobilization and Apheresis

Prepare patients for mobilization with at least 2 cycles of scheduled transfusions (one each month) with erythrocytapheresis being preferred. For at least 60 days prior to mobilization and through myeloablative conditioning, patients should undergo a transfusion regimen to reach a target Hb of 8-10 g/dL, not to exceed 12 g/dL, and HbS of less than 30% to reduce the risk of SCD-related complications. Perform erythrocytapheresis within a recommended 4 days preceding mobilization to reach the target of less than 30% HbS.

Manage other concomitant medications (as applicable) as described below:

• Hydroxyurea: Discontinue at least 2 months prior to mobilization. Patients should not resume hydroxyurea until all cycles of apheresis are completed.
• Disease-modifying agents (e.g., L-glutamine, voxelotor and crizanlizumab): Discontinue at least 2 months prior to mobilization as the interaction between disease modifying agents and mobilization agents is unknown.
• Erythropoietin: Discontinue at least 2 months prior to mobilization.
• Iron chelation: Discontinue at least 7 days prior to mobilization.
• Granulocyte-colony stimulating factor (G-CSF): Do not administer G-CSF prior to or with mobilization agents.
• Anti-retrovirals: Discontinue prophylactic HIV anti-retroviral medications at least one month prior to mobilization and do not resume until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication.

Mobilization and Apheresis

Perform HSC mobilization followed by apheresis to obtain CD34+ cells for product manufacturing. Administer plerixafor to mobilize stem cells prior to the apheresis procedure at a dose of 0.24 mg/kg/day.¹

Begin apheresis approximately 4 to 6 hours after plerixafor administration. If more than one apheresis day is required, confirm platelet counts to be ≥ 75 × 10⁹/L within 24 hours of subsequent apheresis sessions, prior to administration of plerixafor on that day. If platelet counts do not meet these criteria, defer mobilization and apheresis until the platelet counts recover to ≥ 75 × 10⁹/L. For patients undergoing more than 1 mobilization cycle, separate each cycle by at least 14 days. Administer daily plerixafor 4 to 6 hours prior to each apheresis collection. If a sufficient number of cells are collected after the first mobilization cycle, no further mobilization/apheresis is required. In clinical studies, the minimum number of CD34+ cells to manufacture LYFGENIA was collected in most patients with 1 or 2 cycles of mobilization and apheresis which typically required 2 consecutive collection days per cycle.

Maximize CD34+ cell collection to obtain as many CD34+ stem cells as possible for product manufacturing during each mobilization and apheresis cycle. Target a minimum collection of 16.5 × 10⁶ CD34+ cells/kg for manufacturing and back-up. If, after manufacturing, the minimum dose of 3 × 10⁶ CD34+ cells/kg is not achieved, the patient may undergo additional cycles of mobilization and apheresis, separated by at least 14 days, to obtain more cells for additional manufacture. Multiple drug product lots may be administered to comprise the final dose.

Retain ≥ 1.5 × 10⁶ CD34+ cells/kg from the collection for back-up. These cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning. The back-up collection may be needed for rescue treatment if there is: 1) compromise of hematopoietic stem cells or LYFGENIA before infusion, 2) primary engraftment failure, or 3) loss of engraftment after infusion with LYFGENIA.

Manage concomitant medications (as applicable) between apheresis and conditioning as described below:

• Transfusions: Scheduled transfusions can be continued between apheresis and conditioning. Patients should maintain total hemoglobin (Hb) levels of 8 to 10 g/dL. Hb levels should not exceed 12 g/dL. A scheduled transfusion should be performed within 2 days prior to conditioning.
• Hydroxyurea: If administered after apheresis, discontinue hydroxyurea at least 2 days prior to myeloablative conditioning.
• Disease-modifying agents (e.g., L-glutamine, voxelotor and crizanlizumab): Discontinue disease modifying agents at least 2 months prior to conditioning as the interaction between disease modifying agents and conditioning agents are unknown.
• Iron chelation: If administered after apheresis, discontinue iron chelation at least 7 days prior to myeloablative conditioning.
• G-CSF: Do not administer G-CSF between mobilization and conditioning.
• Anti-retrovirals and erythropoietin: There are no data regarding use of anti-retrovirals or erythropoietin between apheresis and conditioning.

Myeloablative Conditioning

Do not begin myeloablative conditioning until the complete set of infusion bag(s) constituting the dose of LYFGENIA has been received and stored at the treatment center and the availability of the back-up collection is confirmed.

Myeloablative conditioning with busulfan must be administered before infusion of LYFGENIA.

Busulfan should be administered via a central venous line. For patients weighing less than 35 kg, administer every 6 hours; for patients weighing 35 kg or more, busulfan can be administered either once daily or every 6 hours. Calculate the dose on the basis of the lower of the ideal versus actual body weight.

The recommended initial dose of busulfan is 3.2 mg/kg/day for 4 consecutive days as a 3-hour infusion for a total of 4 doses.² To achieve myeloablation, the busulfan target AUC is 5000 (range 4400 to 5400) μM*min for a once daily dosing regimen.

For divided dosing, initial dose of busulfan is 0.8 mg/kg/dose every 6 hours as a 2-hour infusion for 16 consecutive doses. Target AUC is 1250 (range 1100 to 1350) μM*min for a q6h dosing regimen.

Perform pharmacokinetic (PK) monitoring after the first dose and adjust dose to achieve the target AUC. Adjust sample collection based on whether a 2-hour or 3-hour infusion is used. If feasible, daily busulfan PK measurement is recommended.

Administer seizure prophylaxis with agents other than phenytoin at least 12 hours prior to initiating busulfan. Do not use phenytoin because of its induction of cytochrome P450 and resultant increased clearance of busulfan.

Consider prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome with ursodeoxycholic acid or defibrotide.

After completion of the myeloablative conditioning, allow a minimum of 48 hours of washout before LYFGENIA infusion.

Receipt and Storage of LYFGENIA

• LYFGENIA is shipped in the vapor phase of liquid nitrogen shipper.
• Confirm patient identifiers on the product label(s) and Lot Information Sheet within the shipper.
• If there are any concerns about the product or packaging upon receipt, contact bluebird bio at 1-833-999-6378.
• Keep the infusion bag(s) in the metal cassette(s) and transfer LYFGENIA from the vapor phase of liquid nitrogen shipper to the treatment center vapor phase of liquid nitrogen storage at ≤ -140°C (-220°F). Store in the vapor phase of liquid nitrogen at ≤ -140°C (-220°F) until ready for thaw and administration.

Preparation of LYFGENIA for Infusion

Coordinate the timing of LYFGENIA thaw and infusion. Confirm the infusion time in advance and adjust the start time of LYFGENIA thaw such that it will be available for infusion when the patient and healthcare providers are ready. Note that each infusion bag must be completely administered within 4 hours after thawing.

• Remove each metal cassette from liquid nitrogen storage and remove each infusion bag from the metal cassette.
• Confirm that LYFGENIA is printed on the infusion bag(s).
• Confirm that patient identity matches the unique patient identifiers located on the LYFGENIA infusion bag(s). Do not infuse LYFGENIA if the information on the patient-specific label on the infusion bag does not match the intended patient and contact bluebird bio at 1-833-999-6378.
• 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.
• Inspect each infusion bag for any breaches of integrity before and after thawing and before infusion. If an infusion bag is compromised, follow the local guidelines and contact bluebird bio immediately at 1-833-999-6378.
• If more than one infusion bag is provided, thaw and administer each infusion bag completely before proceeding to thaw the next infusion bag. Maintain any additional infusion bag(s), if applicable, at less than or equal to -140°C (-220°F) until time to thaw.
• Thaw LYFGENIA at 37°C (98.6°F) in a water bath or dry bath. Thawing of each infusion bag takes approximately 2 to 4 minutes. Do not leave LYFGENIA unattended. Do not submerge the infusion ports in a water bath.
• After thaw, mix the contents gently by massaging the infusion bag to disperse clumps of cellular material until all of 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 LYFGENIA in new media prior to infusion.
• Do not sample, alter, irradiate or refreeze LYFGENIA.

After LYFGENIA Administration

Standard procedures for patient management after HSC transplantation should be followed after LYFGENIA infusion.

• Irradiate any blood products required for at least the first 3 months after LYFGENIA infusion and per transplant physician's recommendation.
• There is no experience regarding the use of hydroxyurea, anti-retrovirals, erythropoietin or disease-modifying agents, such as voxelotor or crizanlizumab, after LYFGENIA infusion.
• Avoid use of myelosuppressive iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation when appropriate.
• G-CSF is not recommended for 21 days after LYFGENIA infusion.
• Patients should not donate blood, organs, tissues, or cells at any time in the future.

LYFGENIA contains human blood stem cells that are genetically modified with a replication-incompetent, self-inactivating lentiviral vector (LVV). Follow universal precautions and local biosafety guidelines (Biosafety Level 2) for handling and disposal of LYFGENIA to avoid potential transmission of infectious diseases.

Post-Marketing Long Term Follow-Up Study

Patients who intend to receive treatment with LYFGENIA are encouraged to enroll in the study, as available, to assess the long-term safety of LYFGENIA and the risk of malignancies occurring after treatment with LYFGENIA by calling bluebird bio at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion.

Anemia

Two patients developed anemia following LYFGENIA treatment; one patient continues to require monthly packed red blood cell (pRBC) transfusions. The other patient has been diagnosed with MDS. Both subjects had α-thalassemia trait (-α3.7 /-α3.7) [see Limitations of Use (1)].

Infusion-related reactions to LYFGENIA

Pre-medication for infusion reactions was managed at physician discretion. Infusion-related reactions to LYFGENIA were observed in 2 patients on the day of LYFGENIA infusion. Both infusion-related reactions resolved and were Grade 1. Events included hot flush and decreased diastolic blood pressure.

Platelet engraftment delay

Platelet engraftment, defined as having 3 consecutive platelet values ≥ 50 × 10⁹/L obtained on different days after the initial post-transplant nadir without receiving any platelet transfusions for 7 days immediately preceding and during the evaluation period, was achieved in all patients (median [min, max] Day 37 [19, 235]) after LYFGENIA infusion. Two patients treated with LYFGENIA achieved platelet engraftment after Day 100; one of these patients was administered eltrombopag until Day 234 [see Warnings and Precautions (5.2)].

Neutrophil engraftment

All patients achieved neutrophil engraftment. Neutrophil engraftment, defined as having 3 consecutive ANC laboratory values ≥ 0.5 × 10⁹ cells/L obtained on 3 different days by Day 43, was reported on median (min, max) Day 20 (12, 35) after LYFGENIA infusion.

Risk Summary

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

No reproductive and developmental toxicity studies in animals have been conducted with LYFGENIA to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known whether LYFGENIA has the potential to be transferred to the fetus. Therefore, LYFGENIA should not be administered to women who are pregnant, and pregnancy after LYFGENIA infusion should be discussed with the treating physician.

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

Risk Summary

There is no information regarding the presence of LYFGENIA in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LYFGENIA and any potential adverse effects on the breastfed child from LYFGENIA. Therefore, LYFGENIA is not recommended for women who are breastfeeding, and breastfeeding after LYFGENIA infusion should be discussed with the treating physician.

Pregnancy Testing

A negative serum pregnancy test must be confirmed prior to the start of mobilization and re‑confirmed prior to conditioning procedures and before LYFGENIA administration.

Contraception

There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with LYFGENIA.

Women of childbearing potential and men capable of fathering a child 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 LYFGENIA. Advise patients of the risks associated with conditioning agents.

Infertility

There are no data on the effects of LYFGENIA on fertility.

Data are available on the risk of infertility with myeloablative conditioning. Advise patients of the risks and the options for fertility preservation.