Minimizing Toxicity in HLA-identical Related Donor Transplantation for Children With Sickle Cell Disease

This is a prospective, multicenter phase II study of HLA-identical sibling donor HSCT in 30
pediatric patients with SCD using nonmyeloablative conditioning with alemtuzumab, total-body
irradiation, and sirolimus. The primary Objective of this study is to determine if the SUN
regimen can decrease the incidence of grade II-IV acute graft-versus host disease (GVHD) by
day +100 while maintaining similar disease-free survival compared to establish HLA-identical
donor hematopoietic stem cell transplant (HSCT) regimens in children with SCD. The secondary
Objective is to determine if health-related quality of life (HRQoL) for children undergoing
SUN HSCT is preserved during the early post-transplant time period. To determine if the SUN
regimen can decrease the number of platelet transfusions compared to established
HLA-identical HSCT regimens in children with SCD. The tertiary/Exploratory Objectives: To
describe other markers of toxicity (duration of neutropenia, mucositis, length of
hospitalization) and indicators of a successful HSCT (HRQoL at 1 year, proportion needing
additional immunosuppression during the first year, proportion able to wean sirolimus at 1
year).

Inclusion criteria:

Patients with genotypes hemoglobin SS and Sβ0 thalassemia must have at least one of the
following:

- History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥200
cm/sec by the non-imaging technique (or ≥185 cm/sec by the imaging technique) measured
at a minimum of two separate occasions.

- History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm
in one dimension, visible in two planes on fluid-attenuated inversion recovery
T2-weighted images).

- History of two or more episodes of acute chest syndrome (ACS) in lifetime.

- History of three or more SCD pain events requiring treatment with an opiate or IV pain
medication (inpatient or outpatient) in lifetime.

- History of any hospitalization for SCD pain or ACS while receiving hydroxyurea
treatment.

- History of two or more episodes of priapism (erection lasting ≥4 hours or requiring
emergent medical care).

- Administration of regular RBC transfusions (≥8 transfusions in the previous 12
months).

- At least two episodes of splenic sequestration requiring red blood cell transfusion or
splenectomy after at least one episode of splenic sequestration.

Patients with all other sickle genotypes (hemoglobin SC, Sβ+ thalassemia) must have at
least one of the following:

- Clinically significant neurologic event (overt stroke).

- History of two or more episodes of ACS in the 2-years period preceding enrollment.

- History of three or more SCD pain events requiring treatment with an opiate or IV pain
medication (inpatient or outpatient) in the 1-year period preceding enrollment.

- History of any hospitalization for SCD pain or ACS while receiving hydroxyurea
treatment.

- History of two or more episodes of priapism (erection lasting ≥4 hours or requiring
emergent medical care).

- Administration of regular RBC transfusions (≥8 transfusions in the previous 12
months).

- At least two episodes of splenic sequestration requiring red blood cell transfusion or
splenectomy after at least one episode of splenic sequestration.

Exclusion Criteria:

- • General: Life expectancy less than 6 months. Pregnant or breastfeeding patients.

- Infection Disease: Uncontrolled bacterial, viral or fungal infections (undergoing
appropriate treatment and with progression of clinical symptoms) within 1 month prior
to conditioning. Patients with febrile illness or suspected minor infection should
await clinical resolution prior to starting conditioning. Patients with confirmed
seropositivity for HIV and patients with active Hepatitis B or C determined by
serology and/or NAAT are excluded.

- Liver: Direct (conjugated) bilirubin > 1.5 mg/dL, transaminases >5x upper limit of
normal for age.

- Cardiac: Left ventricular shortening fraction <25% or ejection fraction <50% by ECHO.

- Kidney: Estimated creatinine clearance less than 60 mL/min/1.73m2.

- Pulmonary function: Diffusion capacity of carbon monoxide (DLCO) <35% (adjusted for
hemoglobin). Baseline oxygen saturation <85% or PaO2 <70.

- Heme: History of RBC alloantibodies against donor RBC antigens (even if current
antibody screen is negative). Major ABO incompatibility with donor.