Thal-Fabs: Reduced Toxicity Conditioning for High Risk Thalassemia

Inclusion Criteria: In order to be eligible to participate in this study, the recipientmust meet all of the following criteria:

1. Patients with a diagnosis of transfusion dependent beta or alpha thalassemia (3 or 4gene deletion) between the age of 1-18 years.
2. Thalassemia genotype must be confirmed by molecular genetic testing.
3. Patients with thalassemia must have at least one of the high-risk features:

• Age >7 years
• Hepatomegaly (2 cm below costal margin)
• Inadequate iron chelation (liver iron content >7mg/g dry weight)
• Severe alloimmunization
• Unable to tolerate iron chelation

3. Patients must have had a complete evaluation of their iron status including measurementof serum ferritin, MRI of the heart and liver (within the previous 6 months prior toreferral). Liver elastography (within the preceding 3 months) will be also obtained but notrequired.
4. Ability to take oral medication and be willing to adhere to the study regimen.
5. Patients who have a performance status of at least 70% Karnofsky or Lansky status priorto transplantation.
6. Patients who are acceptable candidates for marrow transplantation based on their pre-BMTevaluation.
7. Patients who have histocompatibility sibling or HLA haplo identical family member andhave been medically approved as hematopoietic progenitor cell donors.
8. Patients who are not candidates for gene therapy.
9. Patients/legal guardians who sign informed consent for the protocol approved by theResearch Ethical Board of the Hospital for Sick Children/University of Toronto.

Exclusion Criteria: The recipient who meets any of the following criteria will be excludedfrom participation in this study:

1. Patients will not be excluded based on sex, race, or ethnic background.
2. Patients will be excluded if they demonstrate significant functional deficits in majororgans, which could interfere with the outcome following bone marrow transplant,including:

• Cardiac: Evidence of significant cardiac dysfunction (resting left ventricularejection fraction of < 50% with absence of improvement with exercise), markedcardiomegaly or uncontrollable hypertension.
• Renal: Evidence of > 50% reduction in expected creatinine clearance or GFR < 60mL/min/1.73m2
• Hepatic: Evidence of hepatic dysfunction evidenced by a serum direct (conjugate)bilirubin of > 2.5 mg/dl, or ALT > 5 times the upper limit of normal for age.
• Pulmonary: Evidence of focal or diffuse active infection or pneumonitis and thepatient demonstrates a FEV1 < 50% or carbon monoxide diffusing capacity (DLCO) of < 50% predicted value (adjusted for hemoglobin). The patient should not requireventilation support.

3. Presence of donor specific antibody (DSA) with mean fluorescence intensity (MFI)greater than 3,000.
4. Previous stem cell transplant or gene therapy.
5. Presence of cardiomyopathy with a T2* < 10ms per Cardiac MRI.
6. Presence of significant liver iron deposition defined as liver iron content >15mg/gliver dry weight. If iron chelation were optimized and reassessment within 6 monthsshows a decrease of LIC to <15 with no evidence of cardiomyopathy, patient may stillbe considered for enrollment.
7. Active HIV, hepatitis B or hepatitis C disease.
8. Severe liver cirrhosis or bridging fibrosis on liver biopsy if previously done.
9. Prior or current malignancy or myeloproliferative or immunodeficiency disorder.
10. Evidence of active, deep seated, life-threatening infections despite therapy (e.g.,certain fungal species, HIV, etc.).
11. Patients will be excluded if they are women of childbearing potential who arecurrently pregnant (b-HCG+) or who are not practicing adequate contraception.
12. Any condition that would preclude serial follow up.
13. Patients with a known life-threatening allergy to components of the pre transplantimmunosuppression (fludarabine), conditioning (treosulfan, cyclophosphamide oranti-thymocyte globulin) or graft versus host prophylactic regimen (abatacept,sirolimus).
14. Any condition or diagnosis, that could in the opinion of the Principal Investigator ordelegate interfere with the participant's ability to comply with study instructions,might confound the interpretation of the study results, or put the participant at risk Donor Eligibility: Donors will not be considered research subjects as the stem cell collection procedure isstandard of care and will not be considered part of the research. In order to be eligible to participate in this study, the donor must meet all of thefollowing criteria:
15. May have thalassemia or sickle trait.
16. Will also consider ABO match and lack of donor specific anti-HLA antibodies.
17. Donors must be minimal of 15 kg weight and have completed routine donor evaluations asper our standard of care.
18. Donors must have signed (by patient or legal guardian) informed consent for theprotocol approved by the Research Ethical Board of the Hospital for SickChildren/University of Toronto.
19. No evidence of transmissible diseases in compliance with the Health Canada CTOregulations
20. Not pregnant or lactating
21. Must not be allergic to granulocyte colony stimulating factor (G-CSF)