Thalassemia Clinical Trials

‣ RECIPIENT:

‣ Participants must fulfill one disease category (1 or 2) and 3

⁃ Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having an end-organ damage (A, B, C, D, OR E) or complication(s) not ameliorated by sickle cell-specific therapies (F):

⁃ A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI ORb

⁃ B. Abnormal trans-cranial Doppler examination (\>=200 cm/s); OR

⁃ C. Silent cerebral infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2- weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination, or an abnormality on examination that could not be explained by the location of the brain lesion(s); OR

⁃ D. Sickle cell related renal insufficiency defined by a creatinine level \>=1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome OR creatinine clearance \<60mL/min/1.73m2 for patients \<16 years of age or \<50mL/min for patients \>16 years of age OR requiring peritoneal or hemodialysis; OR

⁃ Age (Years): \<= 5 / Upper limit of normal serum creatinine (mg/dl): 0.8

⁃ Age (Years): 5 \< age \<= 10 / Upper limit of normal serum creatinine (mg/dl): 1.0

⁃ Age (Years): \> 15 / Upper limit of normal serum creatinine (mg/dl): 1.3

⁃ E. Tricuspid regurgitant jet velocity (TRV) of \>=2.5 m/s in patients at least 3 weeks after a vaso-occlusive crisis; OR

⁃ F. Recurrent severe priapism defined as at least two episodes of an erection lasting \>=4 hours requiring medical intervention (e.g. aspiration, injection of vasoconstrictor, prior penile surgery.); OR

⁃ G. Sickle hepatopathy defined as EITHER ferritin \>1000mcg/L OR direct bilirubin \>0.4 mg/dL at baseline; OR

⁃ H. Vaso-occlusive crises: more than 1 hospital admission per year while on a therapeutic dose of sickle cell treatment /medication; OR

⁃ I. Acute chest syndrome (ACS): any ACS while on sickle cell treatment /medication

⁃ Patients with beta-thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following:

∙ Portal fibrosis by liver biopsy

‣ Inadequate chelation history (defined as failure to maintain adequate compliance with chelation with deferoxamine initiated within 18 months of the first transfusion and administered at least 5 days each week)

‣ Hepatomegaly of greater than 2 cm below the costochondral margin or by other imaging scans

⁃ Non disease specific

∙ Ages \>=4 years and less than 65 years old

‣ Fully matched human leukocyte antigen (HLA) donors at A, B, C, and DR loci (8 of 8 or 10 of 10

‣ Ability to comprehend and willing to sign an informed consent, assent obtained from minors when applicable. Negative serum or urine beta-HCG, when applicable

‣ Agree to use birth control throughout the study and 3 months after abatacept or sirolimus administration.

⁃ Female subjects must agree to use a medically acceptable method of birth control such as oral contraceptive, intrauterine device, barrier and spermicide, or implant/injection from start of screening until immunosuppression is stopped.

• Male subjects must agree to use effective contraception (including condoms) from start of screening until immunosuppression is stopped.

‣ DONOR:

• Fully matched human leukocyte antigen (HLA) donors at A, B, C, and DR loci (8 of 8 or 10 of 10) are intended for this study.

• Donors age 4 or older and \>=15 kg (or weight deemed acceptable by IR for line placement, DTM for apheresis, and pediatric consult service) eligible to donate hematopoietic stem cells, are eligible for this study.

• Donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation. Donors will sign on a separate protocol, 20-H-0099 NHLBI standard of care protocol for the mobilization and collection of HSCs. Note that participation in this study is offered to all eligible donors, but is not required for a donor to make a stem cell donation, so it is possible that not all donors will enroll onto this study.