Reducing toxicity in sibling donor transplants for children with sickle cell disease

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

This study is testing a gentler transplant method for children with sickle cell disease using cells from their siblings to see if it reduces side effects while still helping them stay healthy.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 100 (estimated)
• Ages: 2 Years to 25 Years
• Sex: All
• Sponsor: Children's National Research Institute (Academic / other)
• Drugs / interventions: alemtuzumab
• Locations: 7 sites (Washington D.C., District of Columbia and 6 other locations)
• Trial ID: NCT03587272 on ClinicalTrials.gov

What this trial studies

This multicenter phase II study aims to evaluate the effectiveness of HLA-identical sibling donor transplantation using a nonmyeloablative approach with alemtuzumab, low dose total-body irradiation, and sirolimus in children with sickle cell disease. The primary goal is to reduce the incidence of acute graft-versus-host disease while maintaining disease-free survival rates. Secondary objectives include assessing health-related quality of life and the need for platelet transfusions post-transplant. The study will also explore additional markers of toxicity and indicators of successful transplantation.

Who should consider this trial

Good fit: Ideal candidates are pediatric patients with sickle cell disease who have specific high-risk medical histories, such as abnormal transcranial Doppler measurements or recurrent acute chest syndrome.

Not a fit: Patients who do not have HLA-identical siblings or those with milder forms of sickle cell disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly reduce transplant-related toxicity and improve outcomes for children with sickle cell disease.

How similar studies have performed: Other studies have shown promise with nonmyeloablative approaches in similar patient populations, suggesting potential for success in this novel application.

Eligibility criteria

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.

Where this trial is running

Washington D.C., District of Columbia and 6 other locations

• Children's National Health System — Washington D.C., District of Columbia, United States (Recruiting)
• Ann & Robert H. Lurie Children's Hospital of Chicago — Chicago, Illinois, United States (Recruiting)
• Columbia University — New York, New York, United States (Recruiting)
• Levine Children's Hospital — Charlotte, North Carolina, United States (Recruiting)
• Nationwide Children's Hospital — Columbus, Ohio, United States (Recruiting)
• Alberta Children's Hospital — Calgary, Alberta, Canada (Recruiting)
• The Hospital for Sick Children — Toronto, Ontario, Canada (Recruiting)

Study contacts

• Principal investigator: Robert Nickel, MD — Children's National Research Institute
• Study coordinator: Robert Nickel, MD

Conditions Sickle Cell Disease