RecruitingPhase 2NCT03587272

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

Sponsor

Robert Nickel

Enrollment

100 participants

Start Date

Apr 17, 2018

Study Type

INTERVENTIONAL

Conditions

Sickle Cell Disease

Summary

This multisite prospective study seeks to determine if HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus (Sickle transplant Using a Nonmyeloablative approach, "SUN") can decrease the toxicity of transplant while achieving a high cure rate for children with sickle cell disease (SCD).

Eligibility

Min Age: 2 YearsMax Age: 25 Years

Inclusion Criteria17

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 Criteria7

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.

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Interventions

DRUGAlemtuzumab, low dose total body irradiation, Sirolimus

The conditioning regimen (SUN regimen) will consist of alemtuzumab daily for 5 days (total dose 1 mg/kg) and low dose total body irradiation (TBI) 300 cGY on Day -2 with gonadal shielding if possible. The HSCT graft will be G-CSF mobilized PBSCs with minimum CD34+ of 5 x106/kg recipient weight, goal of 10 x 106/kg (no upper limit). A peripheral blood stem cell (PBSC) graft was selected as it engrafts faster than bone marrow and would lead to shorter period of neutropenia and infection and less thrombocytopenia and need for platelet transfusion. GVHD prophylaxis will be sirolimus with a loading dose 3 mg/m2 on day -1. Sirolimus will be continued at 1 mg/m2/day starting on day 0 and dose adjusted to maintain a target trough level 5-15 ng/mL for the first 3 months and 5-10 ng/mL for the remainder of the first year.