Hematopoietic Stem Cell Transplant for Sickle Cell Disease

Inclusion Criteria: * Patients must have one of the following inherited hemoglobin gene disorders: * a. Hemoglobin SS * b. Hemoglobin SC * c. Hemoglobin S-Beta-zero-Thalassemia or * d. Hemoglobin S-Beta-plus Thalassemia with an episode of multi-organ failure within 5 years of eligibility Patients must meet one of the following risk criteria: * Low Risk (Red Light. Stop and consider therapy closely): Must have matched sibling donor grafts, failed conventional therapy as determined by the PI, and evidence for morbid disease (one of the following): * a. 2 or more painful episode/year (requiring Emergency Department or inpatient care) x 2 years or * b. 1 or more diagnoses of Acute Chest Syndrome within 5 years, or * c. 2-year mortality 5-10% or * d. Baseline LDH\>600 IU or * e. History of sepsis, with or without a WBC\>13.5, or * f. On chronic transfusions * Moderate Risk (Yellow Light. Reasonable to proceed, but with caution): May have alternate donor grafts (haploidentical or matched unrelated donor), if MSD is not available. Must have history of high-level vasculopathy, as defined by at least one of the criteria below: * a. Urine Albumin to Creatinine Ratio of \>300mg/g or eGFR 50-90 ml/min x 2 evaluations within 3 months or * b. History of overt clinical stroke, or progressive cerebral vasculopathy radiographically or * c. 1 or more diagnoses of Acute Chest Syndrome, multi-organ failure, or sickle hepatopathy within 7 years, or * d. Excessively morbid disease manifest as VOCs at a rate of 2 or more per year x 2-years or uncontolled retinal disease attributed to SCD. These patients can be considered for moderate-risk alternate donor transplants. The palliative nature of the transplant will be explicit in the consent. * e. 2-year mortality \>10-15% * i. Baseline WBC\>13.5 and on chronic transfusions or baseline LDH\>600 or age \>35 years old, * ii. Baseline TRV ≥3 m/s, * iii. Chronic transfusion therapy and age \>35 years old or male gender, * iv. Baseline LDH\>600 and age \>35 years old or history of sepsis * v. History of sepsis and age \>35 years old or male gender. * f. History of multi-organ failure * High Risk (Green light, proceed if possible): All donor types are eligible. Must have high risk disease and a \>15% risk of 2-year mortality as defined by at least one of the criteria below. * a. Baseline TRV ≥3 m/s and baseline WBC \>13.5 or on chronic transfusions or history of sepsis or age \>35 years old, * b. Baseline WBC\>13.5 and chronic transfusions or baseline LDH\>600 or age \>35 years old * c. Age \>35 years old and chronic transfusions To determine eligibility as a bone marrow transplant patient: * Available suitable donor * a. 6/6 HLA-matched sibling donor (HLA A, B, and DRB1), bone marrow only * b. 8/8 HLA-matched unrelated donor (HLA A, B, C, DRB1), bone marrow only * c. 4/8, 5/8, 6/8, 7/8 Haploidentical donor, bone marrow only * Patients must have adequate hematologic, hepatic, and renal function as defined below: * Direct bilirubin within 3 X normal institutional limits * ALT (SGPT) \< 3 X institutional upper limit of normal * Creatinine clearance \>21 mL/min/1.73 m\^2 for subjects with creatinine clearance values below 50 mL/min/1.73 m\^2, the principal investigator may use discretion for appropriate fludarabine dose adjustment as noted. * Patients must have adequate pulmonary function as defined by Pulmonary function: DLCO r40% (adjusted for hemoglobin) and FEV1r50%. * Contraception/Child Bearing The effects of Fludarabine, cytoxan, ATG, tacrolimus/sirolimus and MTX are cumulatively known to be deleterious to the health of the developing human fetus. For this reason, and because of teratogenic potential, all women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) for the duration of study participation and for 12 months after completing treatment. * Performance Status: Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2 * Subjects must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Red cell alloimmunization to a degree that precludes extended transfusion * Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Subjects must not have evidence of impaired liver function due to iron overload, +/- hepatitis. Patients will be evaluated by liver consult if ferritin \>1500, history of hepatitis,or ALTis ≥3 X Upper limit of normal (ULN). Recommended evaluations could include liver biopsy if there is evidence for significant hepatic iron deposition or fibrosis/cirrhosis on T2\* MRI of the liver. * eGFR \<21 ml/min * ≥2.0 liter-per-minute pm home oxygen requirement * An estimated Left Ventricular Ejection Fraction ≤40% (echo or MUGA) * Hepatic cirrhosis (Biopsy Proven) * HIV positive, ineligible because of the increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated * Pregnant or breastfeeding women are excluded from this study because the immunomodulatory treatment, preparative regimen, and anti-GVHD therapy contain agents with the potential for teratogenic or abortifacient effects. * Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within 1 month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen. * Prior allogeneic marrow or stem cell transplantation.