Addition of JSP191 (C-kit Antibody) to Nonmyeloablative Hematopoietic Cell Transplantation for Sickle Cell Disease and Beta-Thalassemia

• INCLUSION CRITERIA:

Recipient: patients must fulfill one disease category (criteria 1) and all of criteria 2

1. Patients with sickle cell disease at high risk for disease related morbidity ormortality, defined by having an end-organ damage (A, B, C, D, or E) orcomplication(s) not ameliorated by SICKLE CELL-SPECIFC THERAPIES (F):

A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination (>=200 cm/s); OR

B. Sickle cell related renal insufficiency defined by a creatinine level >=1.5 times the upper limit of normal (see table below) 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) Upper limit of normal serum creatinine (mg/dl)

<= 5 0.8

5 < age <= 10 1.0

10 < age <= 15 1.2

> 15 1.3

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

D. Recurrent tricorporal priapism defined as at least two episodes of an erection lasting >=4 hours involving the corpora cavernosa and corpus spongiosa; OR

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

F. Any one of the below complications:

• Complication || Eligible for HSCT

• Vaso-occlusive crises || More than 1 hospital admission per year while on atherapeutic dose of sickle cell treatment /medication

• Acute chest syndrome (ACS) || Any ACS while on sickle cell treatment /medication

• Osteonecrosis of 2 or more joints || And on sickle cell treatment /medication wheretotal hemoglobin increase less than 1 g/dL or fetal hemoglobin increases <2.5 timesthe baseline level

• Red cell alloimmunization || Total hemoglobin increase <1 g/dL while on therapeuticdoses of 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 compliancewith chelation with deferoxamine initiated within 18 months of the first transfusionand administered subcutaneously for 8-10 hours at least 5 days each week)

• hepatomegaly of greater than 2 cm below the costochondral margin or by other imagingscans

2. Non disease specific

• Ages >=4 years (>=18 years for phase 1 portion of the study)

• 6/6 HLA matched family donor available

• Ability to comprehend and willing to sign an informed consent, assent obtainedfrom minors

• Negative serum or urine beta-HCG, when applicable

• Agree to use birth control throughout the study and 12 months after drugproduct infusion.

• Female subjects must agree to use a medically acceptable method of birth controlsuch as oral contraceptive, intrauterine device, barrier and spermicide, orimplant/injection from start of screening through 12 months after drug productinfusion.

• Male subjects must agree to use effective contraception (including condoms) fromstart of screening through 12 months after drug product infusion.

3. Patients and Capacity to Consent

• Subject provides informed consent prior to initiation of any study procedures.

• Subject understands and agrees to comply with planned study procedures.

4. 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 >=20 kg, eligible to donate hematopoietic stem cells, who are additionally willing to donate blood for research 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. 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.

EXCLUSION CRITERIA:

Recipient exclusion criteria:

• ECOG performance status of 3 or more, or Lanksy performance status of <40 (SeeAppendix A).

• Diffusion capacity of carbon monoxide (DLCO) <35% predicted (corrected forhemoglobin and alveolar volume). This criterion may be omitted in young children (e.g. near age 5) or other individuals who may have difficulty understanding orcomplying with instructions of testing.

• Baseline oxygen saturation of <85% or PaO2 <70

• Left ventricular ejection fraction: <35% estimated by ECHO

• Transaminases >5x upper limit of normal for age

• Evidence of uncontrolled bacterial, viral, or fungal infections (currently takingmedication and progression of clinical symptoms) within one month prior to startingthe conditioning regimen

• Major anticipated illness or organ failure incompatible with survival from PBSCtransplant.

• Pregnant or breastfeeding

Donor exclusion criteria:

• Pregnant or breastfeeding

• Cognitively impaired subjects