Thal-Fabs: Reduced Toxicity Conditioning for High Risk Thalassemia

Inclusion Criteria: In order to be eligible to participate in this study, the recipient must meet all of the following criteria: 1. Patients with a diagnosis of transfusion dependent beta or alpha thalassemia (3 or 4 gene 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 measurement of serum ferritin, MRI of the heart and liver (within the previous 6 months prior to referral). Liver elastography (within the preceding 3 months) will be also obtained but not required. 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 prior to transplantation. 6\. Patients who are acceptable candidates for marrow transplantation based on their pre-BMT evaluation. 7\. Patients who have histocompatibility sibling or HLA haplo identical family member and have 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 the Research Ethical Board of the Hospital for Sick Children/University of Toronto. Exclusion Criteria: The recipient who meets any of the following criteria will be excluded from 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 major organs, which could interfere with the outcome following bone marrow transplant, including: * Cardiac: Evidence of significant cardiac dysfunction (resting left ventricular ejection fraction of \< 50% with absence of improvement with exercise), marked cardiomegaly 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 the patient demonstrates a FEV1 \< 50% or carbon monoxide diffusing capacity (DLCO) of \< 50% predicted value (adjusted for hemoglobin). The patient should not require ventilation 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/g liver dry weight. If iron chelation were optimized and reassessment within 6 months shows a decrease of LIC to \<15 with no evidence of cardiomyopathy, patient may still be 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 are currently 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 transplant immunosuppression (fludarabine), conditioning (treosulfan, cyclophosphamide or anti-thymocyte globulin) or graft versus host prophylactic regimen (abatacept, sirolimus). 14. Any condition or diagnosis, that could in the opinion of the Principal Investigator or delegate 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 is standard 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 the following criteria: 1. May have thalassemia or sickle trait. 2. Will also consider ABO match and lack of donor specific anti-HLA antibodies. 3. Donors must be minimal of 15 kg weight and have completed routine donor evaluations as per our standard of care. 4. Donors must have signed (by patient or legal guardian) informed consent for the protocol approved by the Research Ethical Board of the Hospital for Sick Children/University of Toronto. 5. No evidence of transmissible diseases in compliance with the Health Canada CTO regulations 6. Not pregnant or lactating 7. Must not be allergic to granulocyte colony stimulating factor (G-CSF)