Long-term Follow-up of Subjects With Transfusion-Dependent β-Thalassemia (TDT) Treated With Ex Vivo Gene Therapy

Study Overview
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Brief Summary
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This is a multi-center, long-term safety and efficacy follow-up study for subjects with transfusion-dependent β-thalassemia (TDT) who have been treated with ex vivo gene therapy drug product in bluebird bio-sponsored parent clinical studies. After completing the parent clinical study (approximately 2 years), eligible subjects will be followed for an additional 13 years for a total of 15 years post-drug product infusion. No investigational drug product will be administered in the study.

Official Title
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Long-term Follow-up of Subjects With Transfusion-Dependent β-Thalassemia (TDT) Treated With Ex Vivo Gene Therapy Using Autologous Hematopoietic Stem Cells Transduced With a Lentiviral Vector

Conditions
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Transfusion-dependent Beta-Thalassemia

Intervention / Treatment
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* Other: Safety and efficacy assessments


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent for this study by subjects, or as applicable, subject's parent(s)/legal guardian(s) Treated with drug product for therapy of transfusion-dependent β-thalassemia in a bluebird bio-sponsored clinical study Exclusion Criteria: There are no exclusion criteria for this study

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Subjects with Transfusion-Dependent β-Thalassemia<br>Subjects treated with ex vivo gene therapy product in an applicable bluebird bio-sponsored clinical trial who agree to participate in this long-term follow-up study | Other: Safety and efficacy assessments<br>* Vector copy number (VCN) measurement, safety evaluations, disease-specific assessments, and assessments to monitor for long-term effects of autologous transplant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of subjects with malignancies |  | Up to 15 years post-drug product infusion | 
| The number of subjects with immune-related AEs |  | Up to 15 years post-drug product infusion | 
| The number of subjects with new or worsening hematologic disorders |  | Up to 15 years post-drug product infusion | 
| The number of subjects with new or worsening neurologic disorders |  | Up to 15 years post-drug product infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| βA-T87Q-globin expression | Median (min, max) βA-T87Q-globin expression | Up to 15 years post-drug product infusion | 
| Proportion of subjects treated with beti-cel who achieved Transfusion Independence (TI) | Proportion of subjects who achieved TI, defined as a weighted average Hb ≥ 9 g/dL without any packed red blood cell (pRBC) transfusions for a continuous period of ≥ 12 months at any time after drug product infusion in parent study and/or Study LTF-303 | Up to 15 years post-drug product infusion | 
| Proportion of subjects treated with beti-cel who achieved Transfusion Independence at yearly timepoints | Proportion of subjects treated with beti-cel who achieved TI at yearly timepoints including Year 5, Year 10, and Year 15 post-drug product infusion, and at last follow-up | Up to 15 years post-drug product infusion | 
| Time from drug product infusion to achievement of Transfusion Independence (in parent study or Study LTF-303) |  | Up to 15 years post-drug product infusion | 
| Duration of Transfusion Independence |  | Up to 15 years post-drug product infusion | 
| Weighted average Hb during Transfusion Independence |  | Up to 15 years post-drug product infusion | 
| Change in annualized pRBC transfusion volume (among subjects who achieved TI), from 6 months post-drug product infusion (parent study) through last follow-up | Reduction in annualized pRBC transfusion volume (mL/kg/year) from 6 months post-drug product infusion (parent study) through last follow-up of at least 50%, 60%, 75%, 90%, or 100% as compared to the annualized pRBC transfusion volume during the 2 years prior to parent study enrollment | Up to 15 years post-drug product infusion | 
| Annualized pRBC transfusion volume, from 6 months post-drug product infusion (parent study) through last follow-up | Annualized pRBC transfusion volume (mL/kg/year from 6 months post-drug product infusion (parent study) through last follow-up as compared to the annualized pRBC transfusion requirements during the 2 years prior to parent study enrollment | Up to 15 years post-drug product infusion | 
| pRBC transfusion frequency, from 6 months post-drug product infusion (parent study) through last follow-up | Annualized pRBC frequency (number/year) from 6 months post-drug product infusion (parent study) through last follow-up as compared to the annualized pRBC transfusion requirements during the 2 years prior to parent study enrollment | Up to 15 years post-drug product infusion | 
| Time from drug product infusion to last pRBC transfusion (in parent study or Study LTF-303) |  | Up to 15 years post-drug product infusion | 
| Time from last pRBC transfusion (in parent study or Study LTF-303) to last follow-up |  | Up to 15 years post-drug product infusion | 
| Weighted average nadir Hb from 6 months post-drug product infusion (parent study) through last follow-up | Weighted average nadir Hb from 6 months post-drug product infusion (parent study) through last follow-up as compared to the weighted average nadir Hb during the 2 years prior to parent study enrollment | Up to 15 years post-drug product infusion | 
| Unsupported total Hb levels over time through last follow-up | Unsupported total Hb level is defined as the total Hb measurement level without any acute or chronic pRBC transfusions within 60 days prior to the measurement date. | Up to 15 years post-drug product infusion | 
| Proportion of subjects with unsupported total Hb levels ≥ 10 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 |  | Up to 15 years post-drug product infusion | 
| Proportion of subjects with unsupported total Hb levels ≥ 11 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 |  | Up to 15 years post-drug product infusion | 
| Proportion of subjects with unsupported total Hb levels ≥ 12 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 |  | Up to 15 years post-drug product infusion | 
| Proportion of subjects with unsupported total Hb levels ≥ 13 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 |  | Up to 15 years post-drug product infusion | 
| Proportion of subjects with unsupported total Hb levels ≥ 14 g/dL over time through last follow-up, including Year 5, Year 10, and Year 15 |  | Up to 15 years post-drug product infusion | 
| Liver iron content (LIC) by magnetic resonance imaging (MRI)/Superconducting Quantum Interference Device (SQUID) over time at yearly timepoints through last follow-up |  | Up to 15 years post-drug product infusion | 
| Change from parent study baseline in LIC by MRI/SQUID over time at yearly timepoints through last follow-up |  | Up to 15 years post-drug product infusion | 
| Cardiac T2* by MRI over time at yearly timepoints through last follow-up |  | Up to 15 years post-drug product infusion | 
| Change from parent study baseline in cardiac T2* by MRI over time at yearly timepoints through last follow-up |  | Up to 15 years post-drug product infusion | 
| Serum ferritin over time at yearly timepoints through last follow-up |  | Up to 15 years post-drug product infusion | 
| Change from parent study baseline in serum ferritin over time at yearly timepoints through last follow-up |  | Up to 15 years post-drug product infusion | 
| Number of subjects who stopped iron chelation post-DP infusion | Defined as subjects who stopped iron chelation or never restarted chelation after DP infusion. | Up to 15 years post-drug product infusion | 
| Number of subjects who stopped iron chelation for at least 6 months post-drug product infusion |  | Up to 15 years post-drug product infusion | 
| Time from stopping chelation to last follow-up | Among subjects that never restart chelation after DP infusion. | Up to 15 years post-drug product infusion | 
| Proportion of subjects using phlebotomy therapy post-drug product infusion |  | Up to 15 years post-drug product infusion | 
| Annualized frequency of phlebotomy therapy usage | Annualized frequency of phlebotomy therapy usage is defined as the number of procedures per year, calculated from DP infusion through last follow-up. | Up to 15 years post-drug product infusion | 
| Reticulocyte counts over time at yearly timepoints through last follow-up |  | Up to 15 years post-drug product infusion | 
| Change from Baseline in reticulocyte counts at yearly timepoints through last follow-up | Baseline defined as value closest, but prior to, conditioning in parent study. | 15 years post-drug product infusion | 
| Proportion of subject with nucleated RBC over time at yearly timepoints through last follow-up |  | Up to 15 years post-drug product infusion | 
| Change from Baseline in patient reported outcome (PRO) as assessed by Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale (GCS) Score |  | 5 years post-drug product infusion | 
| Change from Baseline in PRO as assessed by EuroQol-5D Youth version (EQ-5D-Y) |  | 5 years post-drug product infusion | 
| Change from Baseline in PRO as assessed by EuroQol-5D (EQ-5D-3L) |  | 5 years post-drug product infusion | 
| Change From Baseline in PRO as assessed by Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score |  | 5 years post-drug product infusion | 
| Change from Baseline in PRO as assessed by Short Form-36 Health Survey (SF-36) |  | 5 years post-drug product infusion |