Safety and additional considerations
Safety was based on 41 patients treated with ZYNTEGLO™ in 2 open-label,
single-arm clinical studies and 1 long-term follow-up study.1
Non-Laboratory Treatment Emergent Adverse Reactions in at Least 10% of Patients from Day 1—Month 24 After ZYNTEGLO Administration* (N=41)1
*Includes adverse events associated with busulfan myeloablative conditioning.
ADVERSE REACTION |
% Any Grade |
% Grade 3 or Higher |
Blood and lymphatic system disorders |
||
| Febrile neutropenia | 51 | 51 |
Gastrointestinal disorders |
||
| Mucositisa# | 95 | 63 |
| Vomiting | 49 | 0 |
| Abdominal painb | 39 | 2 |
| Diarrhea | 27 | 0 |
| Nausea | 24 | 2 |
| Constipation | 24 | 0 |
| Dyspepsia | 10 | 5 |
| Gingival bleeding | 10 | 2 |
General disorders and administration site conditions |
||
| Pyrexia | 49 | 12 |
| Fatigue | 12 | 0 |
Hepatobiliary disorders |
||
| Veno-occlusive liver disease | 10 | 7 |
Infections and infestations |
||
| Viral infectionc | 17 | 2 |
| Upper respiratory tract infectionsd# | 15 | 0 |
| Nasopharyngitis | 12 | 0 |
| Sepsise | 10 | 10 |
Injury, poisoning and procedural complications |
||
| Procedural pain | 15 | 0 |
| Transfusion reaction | 15 | 0 |
ADVERSE REACTION |
% Any Grade |
% Grade 3 or Higher |
Blood and lymphatic system disorders |
||
| Febrile neutropenia | 51 | 51 |
Gastrointestinal disorders |
||
| Mucositisa# | 95 | 63 |
| Vomiting | 49 | 0 |
| Abdominal painb | 39 | 2 |
| Diarrhea | 27 | 0 |
| Nausea | 24 | 2 |
| Constipation | 24 | 0 |
| Dyspepsia | 10 | 5 |
| Gingival bleeding | 10 | 2 |
General disorders and administration site conditions |
||
| Pyrexia | 49 | 12 |
| Fatigue | 12 | 0 |
Hepatobiliary disorders |
||
| Veno-occlusive liver disease | 10 | 7 |
Infections and infestations |
||
| Viral infectionc | 17 | 2 |
| Upper respiratory tract infectionsd# | 15 | 0 |
| Nasopharyngitis | 12 | 0 |
| Sepsise | 10 | 10 |
Injury, poisoning and procedural complications |
||
| Procedural pain | 15 | 0 |
| Transfusion reaction | 15 | 0 |
Metabolism and nutrition disorders |
||
| Decreased appetite | 24 | 15 |
Musculoskeletal and connective tissue disorders |
||
| Musculoskeletal painf# | 37 | 0 |
Nervous system disorders |
||
| Headacheg | 29 | 0 |
Respiratory, thoracic and mediastinal disorders |
||
| Epistaxis | 42 | 20 |
| Coughh | 34 | 0 |
| Oropharyngeal paini | 15 | 0 |
| Dyspnea | 12 | 0 |
| Hypoxia | 12 | 7 |
| Rhinitisj | 12 | 0 |
Skin and subcutaneous tissue disorders |
||
| Alopecia | 44 | 0 |
| Rashk# | 27 | 0 |
| Pigmentation disorderl | 24 | 0 |
| Pruritus | 22 | 0 |
Vascular disorders |
||
| Hypertension | 10 | 0 |
ADVERSE REACTION (CONT'D) |
% Any Grade |
% Grade 3 or Higher |
Metabolism and nutrition disorders |
||
| Decreased appetite | 24 | 15 |
Musculoskeletal and connective tissue disorders |
||
| Musculoskeletal painf# | 37 | 0 |
Nervous system disorders |
||
| Headacheg | 29 | 0 |
Respiratory, thoracic and mediastinal disorders |
||
| Epistaxis | 42 | 20 |
| Coughh | 34 | 0 |
| Oropharyngeal paini | 15 | 0 |
| Dyspnea | 12 | 0 |
| Hypoxia | 12 | 7 |
| Rhinitisj | 12 | 0 |
Skin and subcutaneous tissue disorders |
||
| Alopecia | 44 | 0 |
| Rashk# | 27 | 0 |
| Pigmentation disorderl | 24 | 0 |
| Pruritus | 22 | 0 |
Vascular disorders |
||
| Hypertension | 10 | 0 |
#Encompasses more than one system organ class.
aMucositis includes anal inflammation, mucosal inflammation, oral mucosal exfoliation, oral mucosal roughening, pharyngeal inflammation, stomatitis.
bAbdominal pain includes abdominal pain, abdominal pain lower, abdominal discomfort, abdominal pain upper.
cViral infection includes BK virus infection, human rhinovirus test positive, influenza, influenza like illness, parainfluenza virus infection, rhinovirus infection, SARS-CoV-2 test positive, viral infection.
dUpper respiratory tract infections include upper airway cough syndrome, upper respiratory tract infection, viral upper respiratory tract infection, pharyngitis, pharyngitis streptococcal.
eSepsis includes bacterial sepsis, neutropenic sepsis, fungal sepsis, sepsis.
fMusculoskeletal pain includes musculoskeletal pain, musculoskeletal chest pain, bone pain, musculoskeletal discomfort, chest pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain, tendon pain, back pain.
gHeadache includes headache, migraine.
hCough includes cough, upper-airway cough syndrome, productive cough.
iOropharyngeal pain includes oropharyngeal pain, oral pain, oropharyngeal discomfort, jaw pain.
jRhinitis includes rhinitis, rhinorrhea, rhinitis allergic.
kRash includes acne, dermatitis acneiform, dermatitis atopic, macule, petechiae, rash, rash follicular, rash macular, rash maculo-papular, rash pruritic, rash pustular, rash vesicular.
lPigmentation disorder includes oral pigmentation, pigmentation disorder, skin hyperpigmentation, skin hypopigmentation.
In the two trials, serious adverse reactions occurred in 37% of patients as of last follow-up. The most common serious adverse reactions (>3%) were pyrexia (fever), thrombocytopenia, liver veno-occlusive disease, febrile neutropenia, neutropenia, and stomatitis. There were no deaths.
Grade 3 or 4 Treatment Emergent Laboratory Abnormalities Occurring in ≥10% of Patients Following Treatment with ZYNTEGLO* from Day 1 to Month 24 (N=41)a1
LABORATORY ABNORMALITYb |
Grade 3 or 4 (%) |
| Neutropenia | 100 |
| Thrombocytopenia | 100 |
| Leukopenia | 100 |
| Anemia | 95 |
| Lymphopenia | 61 |
| ALT Increased | 24 |
| Hypophosphatemia | 20 |
LABORATORY ABNORMALITYb |
Grade 3 or 4 (%) |
| Neutropenia | 100 |
| Thrombocytopenia | 100 |
| Leukopenia | 100 |
| Anemia | 95 |
| Lymphopenia | 61 |
| ALT Increased | 24 |
| Hypophosphatemia | 20 |
| Hyperglycemia | 14 |
| Hypokalemia | 12 |
| Hyperbilirubinemia | 10 |
| Hyponatremia | 10 |
*Includes lab abnormalities associated with busulfan myeloablative conditioning.
aThe denominator is 36 for hyperglycemia, due to missing data.
bBaseline lab values were assessed prior to apheresis.
Abbreviations: ALT: alanine aminotransferase
LABORATORY ABNORMALITYb (CONT'D) |
Grade 3 or 4 (%) |
| Hyperglycemia | 14 |
| Hypokalemia | 12 |
| Hyperbilirubinemia | 10 |
| Hyponatremia | 10 |
*Includes lab abnormalities associated with busulfan myeloablative conditioning.
aThe denominator is 36 for hyperglycemia, due to missing data.
bBaseline lab values were assessed prior to apheresis.
Abbreviations: ALT: alanine aminotransferase
ADDITIONAL SAFETY CONSIDERATIONS1
The median duration of follow-up in the clinical trials was 27.2 months (min, max: 4.1, 48.2). All information is based on March 2021 data cut.
All patients remain alive at last follow-up
As an autologous therapy, there were no cases of graft-versus-host disease (GVHD)
As ZYNTEGLO is an autologous therapy, long-term immunosuppressive agents were not required in clinical studies
Delayed platelet engraftment* has been observed with ZYNTEGLO
- Median time to platelet engraftment was 46 days (min, max: 20, 94)
- Patients without a spleen reached platelet engraftment earlier compared to patients with an intact spleen: median Day 42 (range, 21–53 days) vs median Day 50 (range, 20–94 days), respectively
- Patients achieving platelet engraftment at ≥ Day 46 did not have an increased incidence of bleeding compared with patients with platelet engraftment at < Day 46
- Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100
- Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. 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
*Platelet engraftment was defined as three consecutive platelet values ≥ 20,000 cells/microliter, obtained on different days after ZYNTEGLO infusion, with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period.
There is a potential risk of neutrophil engraftment failure† after treatment with ZYNTEGLO
- There were no reports of neutrophil engraftment failure in clinical trials. 7% of patients remained dependent on G-CSF beyond Day 43, one through Day 77. G-CSF discontinuation was followed by transient decreases in neutrophil counts to < 500 cells/microliter after Day 43 in six (15%) patients
- Median time to neutrophil engraftment was 26 days (min, max: 13, 39)
- Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells
†Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO.
There is a potential risk of LVV-mediated insertional oncogenesis after treatment with ZYNTEGLO
- No cases of hematological malignancy have been seen in studies of ZYNTEGLO
- Patients may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted
- In the event that a malignancy occurs, contact bluebird bio at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for testing
for a total of 15 years after ZYNTEGLO infusion1
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