Version May 2024
Dosage Guidance:
Safety: For autologous use only; confirm patient identity matches unique patient identifiers on the vial(s). Exagamglogene autotemcel is provided as a single dose for infusion containing a suspension of CD34+ cells in 1 or more vials; confirm correct number of vials are present (see lot information sheet). Administer an antipyretic (eg, acetaminophen) and an antihistamine (eg, diphenhydramine) prior to infusion.
Clinical considerations: A treatment course consists of multiple phases: 1) Plerixafor-only mobilization and apheresis to collect CD34+ cells for manufacturing, 2) myeloablative conditioning (eg, busulfan-based), and 3) exagamglogene autotemcel infusion (48 hours to 7 days after myeloablative conditioning).
Preparation for mobilization: Patients should be maintained at hemoglobin S (HbS) concentrations <30% of total Hb while maintaining total hemoglobin ≤11 g/dL prior to apheresis and for ≥8 weeks prior to initiation of myeloablative conditioning. Discontinue disease-modifying therapies for sickle cell disease (eg, hydroxyurea, crizanlizumab, voxelotor) 8 weeks before the planned start of mobilization and conditioning.
Mobilization: Plerixafor was used for mobilization in clinical trials; G-CSF should not be used in patients with sickle cell disease. A target CD34+ cell collection is ≥20 × 106 CD34+ cells/kg. If the minimum dose (3 × 106 CD34+ cells/kg) is not collected following 2 consecutive days of apheresis, the patient may undergo additional cycles of mobilization and apheresis, separated by ≥14 days. A collection of ≥2 × 106 CD34+ cells/kg for back-up unmodified rescue cells should also be collected and cryopreserved prior to myeloablative conditioning; a third day of collection may be used to obtain the back-up rescue cells.
Myeloablative conditioning preparation: Discontinue iron chelation therapy ≥7 days prior to myeloablative conditioning. Busulfan was used for myeloablative conditioning in clinical trials. Consider antiseizure prophylaxis (using agents other than phenytoin) and prophylaxis for hepatic sinusoidal syndrome (veno-occlusive disease) during treatment with busulfan. Confirm availability of autologous exagamglogene autotemcel and back-up cell collection at the infusion center prior to initiating myeloablative therapy. Refer to manufacturer labeling for specific protocols.
Sickle cell disease: Children ≥12 years and Adolescents: IV: Minimum recommended dose: 3 × 106 CD34+ cells/kg; administer after a washout period of between 48 hours and 7 days after the last dose of the myeloablative conditioning regimen.
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 <60 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 hepatic impairment; evaluate patient to ensure appropriateness of therapy.
(For additional information see "Exagamglogene autotemcel: Drug information")
Dosage guidance:
Safety: For autologous use only; confirm patient identity matches unique patient identifiers on the vial(s). Exagamglogene autotemcel is provided as a single dose for infusion containing a suspension of CD34+ cells in 1 or more vials; confirm correct number of vials are present (see lot information sheet provided with product shipment). Administer an antipyretic (eg, acetaminophen) and an antihistamine (eg, diphenhydramine) prior to exagamglogene autotemcel infusion.
Clinical considerations: A treatment course consists of multiple phases: 1) Plerixafor-only mobilization and apheresis to collect CD34+ cells for manufacturing, 2) myeloablative conditioning (eg, busulfan-based), 3) exagamglogene autotemcel infusion administered after a washout period between 48 hours and 7 days after the last dose of the myeloablative conditioning.
Preparation for mobilization: Patients should be maintained at a goal hemoglobin S level <30% while maintaining total hemoglobin ≤11 g/dL prior to apheresis and for at least 8 weeks prior to initiation of myeloablative conditioning. Discontinue disease-modifying therapy for sickle cell disease (eg, hydroxyurea, crizanlizumab, voxelotor) 8 weeks prior to the planned start of mobilization and myeloablative conditioning.
Mobilization: Plerixafor was used for mobilization in clinical trials; granulocyte-colony stimulating factor should not be used in patients with sickle cell disease. A target CD34+ cell dose of ≥20 × 106 CD34+ cells/kg is recommended for product manufacture. If the minimum dose (3 × 106 CD34+ cells/kg) is not met following initial product manufacturing, the patient will require additional cycles of mobilization and apheresis, separated by ≥14 days. A collection of ≥2 × 106 CD34+ cells/kg for backup unmodified rescue cells should also be collected and cryopreserved prior to myeloablative conditioning; a third day of collection may be used to obtain the backup rescue cells.
Myeloablative conditioning preparation: Discontinue iron chelation therapy at least 7 days prior to myeloablative conditioning. Busulfan was used for myeloablative conditioning in clinical trials. Consider antiseizure prophylaxis (using agents other than phenytoin), and prophylaxis for hepatic sinusoidal syndrome (veno-occlusive disease) during treatment with busulfan. Confirm availability of autologous exagamglogene autotemcel vials at the infusion center (and availability of backup collection) prior to initiating myeloablative therapy. Refer to product labeling for further information.
Sickle cell disease: Adults: IV: Minimum recommended dose: 3 × 106 CD34+ cells/kg; administer after a washout period between 48 hours and 7 days after the last dose of the 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 <60 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 exagamglogene autotemcel treatment.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); evaluate hepatic function to ensure appropriateness of exagamglogene autotemcel treatment.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adolescents and adults after undergoing myeloablative conditioning.
>10%:
Dermatologic: Pruritus (grades 3/4)
Gastrointestinal: Abdominal pain (grades 3/4, including upper abdominal pain), cholelithiasis (grades 3/4), decreased appetite (grades 3/4), stomatitis (grades 3/4)
Hematologic & oncologic: Anemia (grades 3/4), febrile neutropenia (grades 3/4), leukopenia (grades 3/4), lymphocytopenia (grades 3/4, including decreased CD4 lymphocytes), neutropenia (grades 3/4), prolonged partial thromboplastin time (grades 3/4), thrombocytopenia (grades 3/4)
Hepatic: Hyperbilirubinemia (grades 3/4)
Neuromuscular & skeletal: Musculoskeletal pain (grades 3/4, including noncardiac chest pain)
1% to 10%:
Cardiovascular: Sinus tachycardia
Gastrointestinal: Constipation, nausea, vomiting
Hepatic: Hepatic sinusoidal obstruction syndrome
Hypersensitivity: Infusion-related reaction
Infection: Sepsis
Nervous system: Pain
Respiratory: Oropharyngeal pain, pneumonia
Miscellaneous: Fever
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Gene editing (off-target): The risk of unintended, off-target editing of individual CD34+ cells with exagamglogene autotemcel treatment cannot be ruled out due to genetic variants (effects of off-target editing are unknown). Off-target genome editing has not been observed in cells from healthy donors or patients treated with exagamglogene autotemcel.
• Hypersensitivity: Serious hypersensitivity reactions, including anaphylaxis, may occur with exagamglogene autotemcel, and are due to the dimethyl sulfoxide (DMSO) and dextran 40 components of the cryopreservative solution.
• Neutrophil engraftment failure: There is a potential risk of neutrophil engraftment failure after treatment with exagamglogene autotemcel. Neutrophil engraftment failure is defined as not achieving neutrophil engraftment (3 consecutive measurements of ANC ≥500 cells/mm3 on 3 different days) after exagamglogene autotemcel infusion and requiring use of unmodified rescue CD34+ cells. In the clinical trial, all patients achieved neutrophil engraftment (none required unmodified rescue cells); the median time to neutrophil engraftment was 27 days (range: 15 to 40 days).
• Platelet engraftment delay: Delayed platelet engraftment has been observed with exagamglogene autotemcel treatment (when compared to allogeneic hematopoietic cell transplant). Platelet engraftment is defined as 3 consecutive measurements of platelets ≥50,000 cells/mm3 on 3 different days without administration of platelet transfusion for 7 days. In the clinical trial, median time to platelet engraftment was 35 days (range: 23 to 126 days). Bleeding risk is increased prior to platelet engraftment and until platelet engraftment is achieved; however, in the clinical trial, no correlation between serious bleeding and time to platelet engraftment was seen.
Disease-related concerns:
• Patients with HIV, hepatis B, or hepatitis C: Exagamglogene autotemcel has not been studied in patients with HIV-1, HIV-2, hepatis B (HBV), or hepatitis C (HCV). Exagamglogene autotemcel should not be used in patients with active HIV-1, HIV-2, HBV, or HCV.
• Prior hematopoietic cell transplant: Exagamglogene autotemcel has not been studied in patients who have received a prior autologous or allogeneic hematopoietic cell transplant. Treatment with exagamglogene autotemcel should not be used in this setting.
Concurrent drug therapy issues:
• Immunizations: Follow institutional guidelines for vaccine administration. The safety of immunization with live viral vaccines during or following exagamglogene autotemcel has not been studied.
Dosage form specific issues:
• Cryopreservative solution: Exagamglogene autotemcel contains DMSO and dextran 40, which have been associated with serious hypersensitivity reactions, including anaphylaxis.
• Universal precautions: Exagamglogene autotemcel contains genetically modified human cells; follow universal precautions and facility biosafety guidelines for handling and disposal to avoid potential transmission of infectious diseases.
Other warnings/precautions:
• Appropriate use: After exagamglogene 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 exagamglogene autotemcel infusion. If possible, avoid the use of nonmyelosuppressive iron chelators for 3 months and myelosuppressive iron chelators for 6 months after exagamglogene autotemcel infusion; restarting iron chelation after exagamglogene autotemcel infusion may be necessary and should be based on clinical practice; phlebotomy can be used in lieu of iron chelation, when appropriate. 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:
Casgevy: (1 ea) [contains dextran 40]
No
Note: For autologous use only; confirm patient identity matches unique patient identifiers on the cassette and infusion bag(s). Exagamglogene autotemcel is provided as a single dose for infusion containing a suspension of CD34+ cells in 1 or more vials; confirm correct number of vials are present (see lot information sheet).
IV: For IV use only. Administer IV push through a central IV catheter within 20 minutes of thawing. The total volume administered within 1 hour should not exceed 2.6 mL/kg; do not administer via infusion pump or an in-line blood filter. After infusing the contents of each vial, flush the primary line with NS with sufficient volume to flush the tubing and the length of the IV catheter.
If more than one vial is required, administer each vial completely before thawing and administering the next vial. Ensure all vials are administered.
Follow universal precautions and facility biosafety guidelines for handling and disposal.
IV: Before infusion, confirm patient identity matches unique identifiers on the exagamglogene autotemcel vial(s) (do not infuse if patient-specific label does not match).
Coordinate the timing of administration with thawing. If more than 1 vial is required, administer the contents of each vial completely before proceeding to thaw and infusing the contents of the next vial. Infuse as soon as possible after thawing; must be administered within 20 minutes after thawing.
Administer the contents of each exagamglogene autotemcel vial as an IV push through a central IV catheter; the total volume of exagamglogene administered within 1 hour should not exceed 2.6 mL/kg. Ensure all vials are administered. After infusing the contents of each vial, flush the primary line with a sufficient volume of NS to flush the tubing and the length of the IV catheter. Do not use an inline blood filter or an infusion pump.
Follow universal precautions and facility biosafety guidelines for handling and disposal.
Store intact vial(s) in the vapor phase of liquid nitrogen at ≤−135°C (≤−211°F) until ready for thaw and administration. Thaw prior to administration. Thaw and infuse one vial at a time, keeping remaining vials for the dose at ≤−135°C (≤−211°F) until ready to thaw. Do not refreeze after thawing. Do not irradiate. Product must be administered within 20 minutes after thawing.
Treatment of sickle cell disease in patients with recurrent vaso-occlusive crises (FDA approved in ages ≥12 years and adults).
Exagamglogene autotemcel may be confused with axicabtagene ciloleucel, betibeglogene autotemcel, brexucabtagene autoleucel, ciltacabtagene autoleucel, elivaldogene autotemcel, etranacogene dezaparvovec, idecabtagene vicleucel, lisocabtagene maraleucel, lovotibeglogene autotemcel, 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.
Crizanlizumab: May diminish the therapeutic effect of Exagamglogene Autotemcel. Risk X: Avoid combination
Granulocyte Colony-Stimulating Factors: May enhance the adverse/toxic effect of Exagamglogene Autotemcel. Risk X: Avoid combination
Hydroxyurea: May diminish the therapeutic effect of Exagamglogene Autotemcel. Risk X: Avoid combination
Iron Chelators: May enhance the myelosuppressive effect of Exagamglogene Autotemcel. Iron Chelators may diminish the therapeutic effect of Exagamglogene Autotemcel. Risk X: Avoid combination
Voxelotor: May diminish the therapeutic effect of Exagamglogene Autotemcel. Risk X: Avoid combination
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.
Patients who could become pregnant and patients with a partner who could become pregnant should use effective contraception prior to beginning mobilization through at least 6 months after administration of exagamglogene 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.
Prior to therapy: Screen for HIV (1 and 2), hepatitis B virus, and hepatitis C virus prior to collection of cells for manufacturing. Evaluate pregnancy status prior to therapy; patients who could become pregnant should have a negative serum pregnancy test prior to beginning mobilization and prior to conditioning procedures.
During and after therapy: ANCs until neutrophil engraftment; platelet counts until platelet engraftment and recovery; CBC and other appropriate testing if any clinical symptoms suggestive of bleeding arise; monitor for fever and other signs/symptoms of infection. Monitor for hypersensitivity reaction during and after infusion.
Exagamglogene autotemcel is a cellular gene therapy consisting of autologous CD34+ hematopoietic cells edited by CRISPR/Cas9 technology to create a DNA double-strand break at a critical transcription binding site of the erythroid-specific enhancer region of the BCL11A gene. This modification reduces BCL11A expression in the erythroid lineage, allowing for increased γ-globin expression and fetal hemoglobin (HbF) production in erythroid cells. After exagamglogene autotemcel infusion, the edited CD34+ cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. In patients with severe sickle cell disease, HbF expression reduces intracellular hemoglobin S concentration, preventing the RBCs from sickling and addressing the underlying cause of disease, thereby eliminating veno-occlusive crises.
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