Exagamglogene autotemcel interacts in the following cases:
The safety of immunisation with live viral vaccines during or following exagamglogene autotemcel treatment has not been studied. As a precautionary measure, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of the conditioning regimens, during exagamglogene autotemcel treatment, and until haematological recovery following treatment.
Exagamglogene autotemcel has not been studied in patients who have received a prior allogeneic or autologous HSC transplant. Treatment with exagamglogene autotemcel is not recommended in these patients.
There are no clinical data from the use of exagamglogene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause foetal harm when administered to a pregnant woman. It is not known whether exagamglogene autotemcel has the potential to be transferred to the foetus. Exagamglogene autotemcel must not be administered during pregnancy because of the risk associated with myeloablative conditioning. Pregnancy after exagamglogene autotemcel infusion should be discussed with the treating physician.
It is unknown whether exagamglogene autotemcel is excreted in human milk or transferred to the breast-feeding child. There are no data available.
Refer to the Summary of Product Characteristics of the mobilisation and myeloablative conditioning medicinal product(s) for guidance on their use during breast-feeding. Because of the potential risks associated with myeloablative conditioning, breast-feeding should be discontinued during conditioning.
The decision to breast-feed after exagamglogene autotemcel treatment should be discussed with the treating physician, taking into account the benefit of breast-feeding for the child versus any potential adverse events from exagamglogene autotemcel or from the underlying maternal condition.
A negative serum pregnancy test must be confirmed prior to the start of each mobilisation cycle and re-confirmed prior to myeloablative conditioning. There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with exagamglogene autotemcel. Women of childbearing potential and men capable of fathering a child must use effective method of contraception from start of mobilisation through at least 6 months after administration of myeloablative conditioning. Please also refer to the Summary of Product Characteristics for the myeloablative conditioning medicinal product.
There are no data on the effects of exagamglogene autotemcel on human fertility. Effects on male and female fertility have not been evaluated in animal studies. Data are available on the risk of infertility with myeloablative conditioning. It is therefore advised to consider fertility preservation options such as cryopreservation of semen or ova before treatment if possible.
Exagamglogene autotemcel has no influence on the ability to drive or use machines.
The effect of mobilisation and myeloablative conditioning medicinal products on the ability to drive or use machines must be considered.
The safety of exagamglogene autotemcel was evaluated in two open-label, single-arm studies (study 111 and study 121) and one long-term follow-up study (study 131), in which 97 adolescent and adult patients with TDT or SCD were treated with exagamglogene autotemcel.
Treatment with exagamglogene autotemcel was preceded by peripheral blood mobilisation with granulocyte colony-stimulating factor (G-CSF) and plerixafor in patients with TDT and plerixafor only in patients with SCD, followed by apheresis and myeloablative conditioning with busulfan.
The safety profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant after mobilisation and apheresis.
The median (min, max) duration of follow-up after being administered exagamglogene autotemcel was 22.8 (2.1, 51.1) months for patients with TDT (N=54), and 17.5 (1.2, 46.2) months for patients with SCD (N=43).
Serious adverse reactions attributed to exagamglogene autotemcel occurred in 2 (3.7%) patients with TDT: 1 (1.9%) patient with haemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, idiopathic pneumonia syndrome, and headache; 1 (1.9%) patient with delayed engraftment and thrombocytopenia. No patient with SCD had serious adverse reactions attributed to exagamglogene autotemcel.
A life-threatening serious adverse reaction of cerebellar haemorrhage occurred in 1 (1.9%) patient with TDT and was attributed to busulfan myeloablative conditioning.
One (2.3%) patient with SCD died due to a COVID-19 infection and subsequent respiratory failure. The event was not related to exagamglogene autotemcel.
Adverse reactions are listed by MedDRA body system organ class and by frequency. Frequencies are defined as: very common (≥1/10) and common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Tables 1, 2, 3, and 4 are lists of adverse reactions attributed to mobilisation/apheresis with G-CSF and plerixafor, mobilisation/apheresis with plerixafor only, myeloablative conditioning with busulfan, and exagamglogene autotemcel, respectively, experienced by patients with TDT and SCD in clinical studies with exagamglogene autotemcel.
Table 1. Adverse reactions attributed to mobilisation/apheresis in patients with TDT receiving G-CSF and plerixafor (N=59):
| System organ class (SOC) | Very common | Common |
|---|---|---|
| Blood and lymphatic system disorders | Leukocytosis, thrombocytopenia | |
| Metabolism and nutrition disorders | Hypokalaemia | |
| Nervous system disorders | Headache | |
| Respiratory, thoracic and mediastinal disorders | Oropharyngeal pain | |
| Gastrointestinal disorders | Nausea | Abdominal pain, vomiting, diarrhoea, oral hypoaesthesia |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain* | |
| General disorders and administration site conditions | Pain, pyrexia |
* Musculoskeletal pain included back pain, bone pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, pain in extremity.
Table 2. Adverse reactions attributed to mobilisation/apheresis in patients with SCD receiving plerixafor (N=58):
| System organ class (SOC) | Very common | Common |
|---|---|---|
| Blood and lymphatic system disorders | Sickle cell anaemia with crisis | |
| Metabolism and nutrition disorders | Hyperphosphataemia, hypomagnesaemia | |
| Nervous system disorders | Headache | |
| Respiratory, thoracic and mediastinal disorders | Acute chest syndrome | |
| Gastrointestinal disorders | Abdominal pain*, nausea, Vomiting | Diarrhoea |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain† | Arthralgia |
| General disorders and administration site conditions | Pain, fatigue |
* Abdominal pain included abdominal pain upper.
† Musculoskeletal pain included back pain, bone pain, chest pain, neck pain, non-cardiac chest pain, and pain in extremity.
Table 3. Adverse reactions attributed to myeloablative conditioning with busulfan in patients with TDT and SCD (N=97)*:
| System organ class (SOC) | Very common | Common |
|---|---|---|
| Infections and infestations | Pneumonia, sepsis, klebsiella | |
| Blood and lymphatic system disorders | Thrombocytopenia, febrile neutropenia, neutropenia, anaemia, lymphopenia†, leukopenia | Pancytopenia, reticulocytopenia, splenomegaly |
| Metabolism and nutrition disorders | Decreased appetite, hypokalaemia, hyperphosphataemia, hypomagnesaemia, fluid retention, hypophosphataemia | Hypoalbuminaemia, hypocalcaemia |
| Nervous system disorders | Headache | Cerebellar haemorrhage, hydrocephalus, peripheral sensory neuropathy, peripheral neuropathy, neuralgia, dysgeusia |
| Eye disorders | Vision blurred, dry eye | |
| Cardiac disorders | Tachycardia | |
| Vascular disorders | Hypotension, hot flush | |
| Respiratory, thoracic and mediastinal disorders | Epistaxis, oropharyngeal pain | Respiratory failure, idiopathic pneumonia syndrome, hypoxia, dyspnoea, cough |
| Gastrointestinal disorders | Mucositis‡, nausea, vomiting, abdominal pain§, diarrhoea, constipation, gastritis | Colitis, dyspepsia, gingival bleeding, gastrooesophageal reflux disease, haematemesis, oesophagitis, dysphagia, gastrointestinal inflammation, haematochezia, mouth ulceration |
| Hepatobiliary disorders | Venoocclusive liver disease, hyperbilirubinaemia, alanine aminotransferase increased | Aspartate aminotransferase increased, hepatomegaly, gamma-glutamyltransferase increased |
| Skin and subcutaneous tissue disorders | Pigmentation disorder#, skin exfoliation, alopecia, petechiae, dry skin, rash** | Pruritus, erythema |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain†† | Arthralgia |
| Renal and urinary disorders | Dysuria, haematuria | |
| Reproductive system and breast disorders | Amenorrhoea, intermenstrual bleeding, vulvovaginal pain, dysmenorrhoea, menstruation irregular, premature menopause | |
| General disorders and administration site conditions | Pyrexia, fatigue | Pain |
| Investigations | Weight decreased | International normalised ratio increased, C-reactive protein increased, weight increased |
| Injury, poisoning procedural complications | Delayed engraftment, subcutaneous haematoma, skin abrasion, skin laceration |
* Frequency is based on the highest incidence from study 111 in patients with TDT or from study 121 in patients with SCD.
† Lymphopenia included CD4 lymphocytes decreased and lymphocyte count decreased.
‡ Mucositis included anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis.
§ Abdominal pain included abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and epigastric discomfort.
# Pigmentation disorder included nail pigmentation, skin hyperpigmentation, and skin hypopigmentation.
** Rash included dermatitis, rash erythematous, rash macular, rash maculo-papular, and rash papular.
†† Musculoskeletal pain included back pain, bone pain, chest pain and pain in extremity.
Table 4. Adverse reactions attributed to exagamglogene autotemcel in patients with TDT and SCD (N=97):
| System organ class (SOC) | Very common | Common |
|---|---|---|
| Blood and Lymphatic system disorders | Lymphopenia†,‡ | Thrombocytopenia†, neutropenia†, anaemia†, leukopenia† |
| Immune system disorders | Haemophagocytic lymphohistiocytosis | |
| Metabolism and nutrition disorders | Hypocalcaemia† | |
| Nervous system disorders | Headache†, paraesthesia | |
| Cardiac disorders | Tachycardia† | |
| Respiratory, thoracic and mediastinal disorders | Acute respiratory distress syndrome, idiopathic pneumonia syndrome†, epistaxis† | |
| Skin and subcutaneous tissue disorders | Rash†,§, petechiae† | |
| General disorders and administration site conditions | Chills†, pyrexia† | |
| Injury, poisoning and procedural complications | Delayed engraftment†, infusion related reactions# |
* Frequency is based on the highest incidence from study 111 in patients with TDT or from study 121 in patients with SCD.
† At least one event was also attributed to busulfan myeloablative conditioning.
‡ Lymphopenia included CD4 lymphocytes decreased and lymphocyte count decreased.
§ Rash included dermatitis.
# Infusion related reactions included chills, sinus tachycardia, and tachycardia.
Platelet engraftment was defined as 3 consecutive measurements of platelet counts ≥20 × 109/L in patients with TDT and 3 consecutive measurements of platelet counts ≥50 × 109/L in patients with SCD, obtained on 3 different days after exagamglogene autotemcel infusion without administration of platelet transfusions for 7 days. All patients achieved platelet engraftment.
In study 111, the median (min, max) time to platelet engraftment in patients with TDT was 44 (20, 200) days (n=53), with one remaining patient achieving platelet engraftment after the time of the interim analysis. The median (min, max) time to platelet engraftment was 45 (20, 199) days in adolescent patients and 40 (24, 200) days in adult patients. Patients without a spleen had an earlier median time to platelet engraftment than patients with an intact spleen. Median (min, max) time to platelet engraftment was 34.5 (20, 78) days in patients without a spleen and 46 (27, 200) days in patients with an intact spleen.
In study 121, the median (min, max) time to platelet engraftment for patients with SCD was 35 (23, 126) days (n=43). The median (min, max) time to platelet engraftment was 44.5 (23, 81) days in adolescent patients and 32 (23, 126) days in adult patients.
There was no association observed between bleeding events and time to platelet engraftment after exagamglogene autotemcel treatment.
Neutrophil engraftment was defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥500 cells/µL on 3 different days after exagamglogene autotemcel infusion, without use of the unmodified rescue CD34+ cells. All patients achieved neutrophil engraftment, and no patients received rescue CD34+ cells.
In study 111, the median (min, max) time to neutrophil engraftment in patients with TDT was 29 (12, 56) days (n=54). The median (min, max) time to neutrophil engraftment was 31 (19, 56) days in adolescent patients and 29 (12, 40) days in adult patients.
In study 121, the median (min, max) time to neutrophil engraftment in patients with SCD was 27 (15, 40) days (n=43). The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in adolescent patients and 26 (15, 38) days in adult patients.
There was no association observed between infections and time to neutrophil engraftment.
The safety of exagamglogene autotemcel was evaluated in 31 adolescent patients aged 12 to less than 18 years with TDT or SCD. The median (min, max) age of adolescent TDT patients was 14 (12, 17) years, and for SCD patients was 15 (12, 17) years. The median (min, max) duration of follow-up was 19.6 (2.1, 26.6) months for adolescent TDT patients and 14.7 (2.5, 18.7) months for adolescent SCD patients. The safety profile was generally consistent among adolescent and adult patients. Engraftment times were similar in adolescent and adult patients.
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