Donor Stem Cell Transplant with Personalized Conditioning Regimens for the Treatment of Sickle Cell Disease and Other Transfusion Dependent Red Blood Cell Disorders

Inclusion Criteria

• Sickle cell disease (SCD) * If diagnosis of SCD (any genotype) must meet one or more of the following disease characteristics: ** Stroke, central nervous system (CNS) hemorrhage or a neurologic event lasting longer than 24 hours, or abnormal cerebral MRI or cerebral arteriogram or MRI angiographic study and impaired neuropsychological testing ** Acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions ** Recurrent vaso-occlusive pain crisis 2 or more episodes per year for 2 years or more years or recurrent priapism, ** Impaired neuropsychological function and/or abnormal cerebral MRI scan ** Stage I or II sickle lung disease, ** Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate [GFR] 30-50% of the predicted normal value) ** Bilateral proliferative retinopathy or concern for major visual impairment in at least one eye ** Osteonecrosis of multiple joints with documented destructive changes ** Requirement for chronic transfusions ** Red blood cell (RBC) alloimmunization * SCD patients with a fully matched sibling donor (MSD) irrespective of the frequency or severity of symptoms MSD transplant can be considered. Parents/patient must be counseled as to the risks and benefits and provide their voluntary informed consent
• Transfusion dependent alpha- or beta-thalassemia
• Diamond Blackfan anemia
• Other non-malignant hematologic disorders * Transfusion dependent or involve other potential life-threatening cytopenias, including but not limited to paroxysmal nocturnal hemoglobinuria, Glanzmann’s thrombasthenia, severe congenital neutropenia and Shwachman-Diamond syndrome
• Age: 0-55 years
• Performance Status: Karnofsky ≥ 60%, Lansky play score ≥ 60. Patients with lower performance score can be considered based on study team's evaluation
• Consent: voluntary written consent (adult), parents will sign parental consent, and minors will be given information sheets
• Creatinine < 2.0 mg/dl for adults or glomerular filtration rate > 50 ml/min for children
• Direct bilirubin < 5 times the upper limit of institutional normal. Patients with elevated total and indirect bilirubin or transaminases can be considered per principal investigator's (PI’s) discretion as baseline is often elevated in SCD patients
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 5 times the upper limit of institutional normal. Patients with elevated total and indirect bilirubin or transaminases can be considered per PI’s discretion as baseline is often elevated in SCD patients
• Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction > 40%
• Sexually active persons of childbearing potential or persons with partners of childbearing potential must agree to use a highly effective form of contraception during study treatment and for at least 4 months after the transplant. Non-childbearing is defined as pre-pubertal, > 1 year post-menopausal or surgically sterilized. Examples of highly effective birth control methods include but are not limited to the following: * Using twice the normal protection of birth control (i.e., double-barrier) by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam. A spermicidal jelly or foam must be used in addition to a barrier method (e.g., condom or diaphragm). * Oral contraceptive pills * Depot or injectable birth control * Intrauterine device (IUD) * Transdermal contraceptive patch * Vaginal contraceptive ring * Contraceptive implants ** Note: Rhythm method or abstinence alone is not considered an adequate method of contraception
• Patients considered for transplantation must have a sufficient graft as based on current criteria of the University of Minnesota Blood and Marrow Transplantation Program. Transplantation using sufficiently matched related donors (such as matched siblings) or unrelated donors will be considered. Both granulocyte-colony stimulating factor (G-CSF) stimulated peripheral blood grafts and bone marrow grafts will be considered, although bone marrow will be the priority

Exclusion Criteria

• Pregnant, breastfeeding or intending to become pregnant during the study. Persons of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days of the start of treatment
• HIV positive
• Active, uncontrolled infection - infection that is stable or improving after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections) will be permitted
• Known allergy to any of the study components
• Psychiatric illness/social situations that, in the judgement of the enrolling investigator, would limit compliance with study requirements
• Other illness or a medical issue that, in the judgement of the enrolling Investigator, would exclude the patient from participating in this study