Transplant for Sickle Cell Disease Using a Nonmyeloablative Approach

Sickle Cell Disease Transplant Using a Nonmyeloablative Approach: Adding Daratumumab for Patients With Anti-donor Red Cell AntibodY

This study is testing a new way to help people with sickle cell disease who have certain antibodies receive a safer type of stem cell transplant from a sibling to see if it can improve their chances of recovery.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 12 (estimated)
• Ages: 2 Years to 25 Years
• Sex: All
• Sponsor: Children's National Research Institute (Academic / other)
• Drugs / interventions: daratumumab, alemtuzumab
• Locations: 1 site (Washington D.C., District of Columbia)
• Trial ID: NCT06358638 on ClinicalTrials.gov

What this trial studies

This multicenter prospective study investigates the use of daratumumab prior to HLA-identical sibling donor transplantation in patients with sickle cell disease who have anti-donor red blood cell antibodies. The aim is to prevent pure red blood cell aplasia while maintaining an acceptable safety profile and achieving event-free survival comparable to patients without such antibodies. The study employs a nonmyeloablative conditioning regimen that includes alemtuzumab, low dose total-body irradiation, and sirolimus. By including patients previously excluded from nonmyeloablative hematopoietic cell transplant due to their antibody status, the study seeks to expand access to less toxic curative therapies.

Who should consider this trial

Good fit: Ideal candidates are patients aged 2-24.99 years with sickle cell disease and a healthy HLA-identical sibling donor, particularly those with major ABO incompatibility or other red blood cell alloantibodies.

Not a fit: Patients who do not have sickle cell disease or those without a suitable HLA-identical sibling donor may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could provide a safer transplant option for patients with sickle cell disease who have limited donor options due to red blood cell antibodies.

How similar studies have performed: Other studies have shown success with nonmyeloablative approaches in hematopoietic cell transplantation, but this specific use of daratumumab in patients with anti-donor antibodies is novel.

Eligibility criteria

Inclusion Criteria:

General:

* Patients with SCD age 2-24.99 years who have a healthy HLA-identical sibling donor with major ABO incompatibility OR patients with RBC alloantibodies against other donor RBC antigens.
* Patients must have an absolute neutrophil count of 1 x 109/L and a platelet count of 100 x 109/L.
* Lansky/Karnofsky score of, at least, 70.

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 measured at a minimum of two separate occasions.
* Progression of CNS vasculopathy on MRA determined to be secondary to SCD.
* 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 in lifetime.
* History of any hospitalization for a complication secondary to SCD (does NOT include empiric hospitalizations for fever only).
* History of two or more episodes of priapism.
* Administration of regular RBC transfusions (≥8 transfusions episodes 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 (e.g. hemoglobin SC, Sβ+ thalassemia, etc.) 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-year 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:

* Life expectancy less than 6 month
* Pregnant or breastfeeding patients.
* Infectious 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 or resolved 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. Uncontrolled cardiac arrhythmia.
* 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 \<94% at rest or PaO2 \<70. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification.
* Heme: Available, medically suitable, and equivalent HLA-matched sibling donor, who does not have major ABO incompatibility or express RBC antigens against which the patient is alloimmunized.

Where this trial is running

Washington D.C., District of Columbia

• Children's National Hospital — Washington D.C., District of Columbia, United States (Recruiting)

Study contacts

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

Conditions Sickle Cell Disease; ABO Mismatch; SUN-RAY; Matched Sibling Donor