The safety of CASGEVY™ in patients with TDT was evaluated in an open-label, single-arm trial (Trial 2), in which 52 adolescent and adult patients with TDT were treated with CASGEVY after undergoing myeloablative conditioning with busulfan.1
Grade 3 or 4 non-laboratory adverse reactions in ≥10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion1*
Grade 3 or 4 non-laboratory adverse reactions in ≥10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion1*
*Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSCT.1
| System organ class, preferred term | Patients with TDT (Trial 2) (N=52) n (%) |
|---|---|
| Blood and lymphatic system disorders | |
| Febrile neutropenia | 28 (54) |
| Gastrointestinal disorders | |
| Mucositis†‡ | 37 (71) |
| Hepatobiliary disorders | |
| Veno-occlusive liver disease | 5 (10) |
| Metabolism and nutrition disorders | |
| Decreased appetite | 12 (23) |
| Respiratory, thoracic, and mediastinal disorders | |
| Epistaxis | 7 (13) |
| System organ class, preferred term | Patients with TDT (Trial 2) (N=52) n (%) |
|---|---|
| Blood and lymphatic system disorders | |
| Febrile neutropenia | 28 (54) |
| Gastrointestinal disorders | |
| Mucositis†‡ | 37 (71) |
| Hepatobiliary disorders | |
| Veno-occlusive liver disease | 5 (10) |
| Metabolism and nutrition disorders | |
| Decreased appetite | 12 (23) |
| Respiratory, thoracic, and mediastinal disorders |
|
| Epistaxis | 7 (13) |
† Mucositis includes anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis.
‡ Encompasses preferred terms that belong to other system organ class.
Other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following1:
Immune system disorders: Hemophagocytic lymphohistiocytosis (1 [2%] patient).
Nervous system disorders: Cerebellar hemorrhage (intracranial hemorrhage) (1 [2%] patient).
Infusion-related reactions: 12 (23%) patients, including preferred terms of abdominal pain and nausea in 4 (8%) patients each; pruritus and vomiting in 2 (4%) patients each; and abdominal pain lower, chills, sinus tachycardia, and tachycardia in 1 (2%) patient each.
HSCT=hematopoietic stem-cell transplantation; TDT=transfusion-dependent β-thalassemia.
Grade 3 or 4 laboratory abnormalities in ≥10% of patients with TDT who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 2: Day 1 to Month 24 after CASGEVY infusion1§
§Table includes laboratory abnormalities associated with busulfan myeloablative conditioning and treatment with CASGEVY. Laboratory abnormalities were generally consistent with those expected from busulfan myeloablative conditioning and HSCT.1
| Laboratory abnormality | Patients with TDT (Trial 2) (N=52)||(%) |
|---|---|
| Neutropenia | 100 |
| Thrombocytopenia | 100 |
| Leukopenia | 98 |
| Anemia | 92 |
| Lymphopenia | 79 |
| CD4 lymphocytes decreased | 23 |
| Hyperbilirubinemia | 23 |
| Alanine aminotransferase increased | 19 |
| Hypokalemia | 19 |
| Gamma-glutamyltransferase increased | 17 |
| Activated partial thromboplastin time prolonged | 13 |
| Hypocalcemia | 12 |
| Laboratory abnormality | Patients with TDT (Trial 2) (N=52)||(%) |
|---|---|
| Neutropenia | 100 |
| Thrombocytopenia | 100 |
| Leukopenia | 98 |
| Anemia | 92 |
| Lymphopenia | 79 |
| CD4 lymphocytes decreased | 23 |
| Hyperbilirubinemia | 23 |
| Alanine aminotransferase increased | 19 |
| Hypokalemia | 19 |
| Gamma-glutamyltransferase increased | 17 |
| Activated partial thromboplastin time prolonged | 13 |
| Hypocalcemia | 12 |
|| The denominator for CD4 lymphocytes decreased is 48 and the denominator for all other laboratory data is 52, based on evaluable data at the time of the interim analysis.1
Neutrophil and platelet engraftment1
| Neutrophil engraftment (N=52)¶ | Platelet engraftment (N=52) #** | |
|---|---|---|
| Time to engraftment Median (min, max) (starting the day after infusion) |
29 days (12, 56) | 44 days (20, 200) |
|
|
|
| Median cell dose (N=52)†† CD34+ cells x 106/kg (min, max) |
7.5 (3.0, 19.7) | |
| Duration of follow-up (N=52) Median months (min, max) |
20.4 months (2.1, 48.1) | |
| Neutrophil engraftment (N=52)¶ |
Platelet engraftment (N=52)# |
|
|---|---|---|
| Time to engraftment Median (min, max) (starting day after infusion) |
29 days (12, 56) |
44 days (20, 200) |
|
|
|
| Median cell dose (N=52)†† CD34+ cells x 106/kg (min, max) |
7.5 (3.0,19.7) |
|
| Duration of follow-up (N=52) Median months (min, max) |
20.4 months (2.1, 48.1) |
|
¶Defined as 3 consecutive measurements of absolute neutrophil counts ≥500 cells/μL on 3 different days after CASGEVY infusion, without use of the unmodified backup CD34+ cells.1
#Defined as 3 consecutive measurements of platelet counts ≥20×109/L, obtained on 3 different days after CASGEVY infusion, without administration of platelet transfusions for 7 days.1
**While the use of thrombopoietin (TPO) mimetics was not specified in the trial protocol, 5 patients (10%) received a TPO mimetic at the time of platelet engraftment, per physician discretion. All 5 patients continued TPO mimetic use for thrombocytopenia beyond engraftment. The total duration of TPO mimetic use was 98-457 days.1
††A single dose of CASGEVY may consist of multiple lots.1
- A backup collection of ≥2x106 CD34+ cells/kg is required. These unmodified backup cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with CASGEVY. The unmodified cells may be needed for rescue treatment under any one of the following conditions1:
- Compromise of CASGEVY after initiation of myeloablative conditioning and before CASGEVY infusion
- Neutrophil engraftment failure, or
- Loss of engraftment after infusion with CASGEVY
- In the clinical trial, all treated patients achieved neutrophil engraftment and no patients received backup CD34+ cells1
Safety considerations from Trial 21
- The CASGEVY adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSCT
- Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 33% of patients
- The most common serious adverse reactions (≥2 patients) were veno‑occlusive liver disease, pneumonia, hypoxia, thrombocytopenia, viral infection, and upper respiratory tract infection
- No cases of graft-versus-host disease (GVHD), graft failure, or graft rejection
- In the clinical trial, all treated patients achieved neutrophil engraftment and no patients received backup CD34* cells
Warnings and Precautions
Neutrophil Engraftment Failure
There is potential risk of neutrophil engraftment failure after treatment with CASGEVY. In the clinical trials, all treated patients achieved neutrophil engraftment and no patients received rescue CD34+ cells.
Monitor absolute neutrophil counts (ANC) and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, patients should be infused with rescue CD34+ cells.
Delayed Platelet Engraftment
Delayed platelet engraftment has been observed with CASGEVY treatment. There is an increased risk of bleeding until platelet engraftment is achieved. In the clinical trials, there was no association observed between incidence of bleeding events and time to platelet engraftment.
Monitor patients for bleeding according to standard guidelines and medical judgement. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis can occur due to dimethyl sulfoxide (DMSO) or dextran 40 in the cryopreservative solution. Monitor patients for hypersensitivity reactions during and after infusion.
Off-Target Genome Editing Risk
Although off-target genome editing was not observed in the edited CD34+ cells evaluated from healthy donors and patients, the risk of unintended, off-target editing in an individual’s CD34+ cells cannot be ruled out due to genetic variants. The clinical significance of potential off-target editing is unknown.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Neutrophil Engraftment Failure
There is potential risk of neutrophil engraftment failure after treatment with CASGEVY. In the clinical trials, all treated patients achieved neutrophil engraftment and no patients received rescue CD34+ cells.
INDICATION
CASGEVY is indicated for the treatment of patients aged 12 years and older with:
Monitor absolute neutrophil counts (ANC) and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, patients should be infused with rescue CD34+ cells.
Delayed Platelet Engraftment
Delayed platelet engraftment has been observed with CASGEVY treatment. There is an increased risk of bleeding until platelet engraftment is achieved. In the clinical trials, there was no association observed between incidence of bleeding events and time to platelet engraftment.
Monitor patients for bleeding according to standard guidelines and medical judgement. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis can occur due to dimethyl sulfoxide (DMSO) or dextran 40 in the cryopreservative solution. Monitor patients for hypersensitivity reactions during and after infusion.
Off-Target Genome Editing Risk
Although off-target genome editing was not observed in the edited CD34+ cells evaluated from healthy donors and patients, the risk of unintended, off-target editing in an individual’s CD34+ cells cannot be ruled out due to genetic variants. The clinical significance of potential off-target editing is unknown.
ADVERSE REACTIONS
The most common Grade 3 or 4 non-laboratory adverse reactions (occurring in ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and patients with TDT, and decreased appetite in patients with SCD.
All (100%) of the patients with TDT and SCD experienced Grade 3 or 4 neutropenia and thrombocytopenia. Other common Grade 3 or 4 laboratory abnormalities (≥ 50%) include leukopenia, anemia, and lymphopenia.
DRUG INTERACTIONS
No formal drug interaction studies have been performed. CASGEVY is not expected to interact with the hepatic cytochrome P450 family of enzymes or drug transporters.
Use of Granulocyte-Colony Stimulating Factor (G-CSF): G-CSF must not be used for CD34+ HSC mobilization of patients with SCD.
Use of Hydroxyurea: Discontinue the use of hydroxyurea at least 8 weeks prior to start of each mobilization cycle and conditioning. There is no experience of the use of hydroxyurea after CASGEVY infusion.
Use of Voxelotor and Crizanlizumab: Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilization and conditioning, as their interaction potential with mobilization and myeloablative conditioning agents is not known.
Use of Iron Chelators: Discontinue the use of iron chelators at least 7 days prior to initiation of myeloablative conditioning, due to potential interaction with the conditioning agent. Some iron chelators are myelosuppressive. If iron chelation is required, avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. Phlebotomy can be used instead of iron chelation, when appropriate.
USE IN SPECIFIC POPULATIONS
Pregnancy/Lactation: CASGEVY must not be administered during pregnancy and breastfeeding should be discontinued during conditioning because of the risks associated with myeloablative conditioning. Pregnancy and breastfeeding after CASGEVY infusion should be discussed with the treating physician.
Females and Males of Reproductive Potential: A negative serum pregnancy test must be confirmed prior to the start of each mobilization cycle and reconfirmed prior to myeloablative conditioning.
Women of childbearing potential and men capable of fathering a child should use effective methods of contraception from start of mobilization through at least 6 months after administration of CASGEVY. Advise patients of the risks associated with conditioning agents.
Infertility has been observed with myeloablative conditioning therefore, advise patients of fertility preservation options before treatment, if appropriate.
Please see full Prescribing Information for CASGEVY.
Reference: 1. CASGEVY [prescribing information]. Vertex Pharmaceuticals Incorporated. Boston, MA; January 2024.
