Sickle Cell Disease Transplant Using a Nonmyeloablative Approach for Patients With Anti-donor Red Cell Antibody

NCT06358638 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: STUDY00000859
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

This multicenter prospective study seeks to determine if daratumumab given, prior to HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus, can prevent pure red blood cell aplasia with an acceptable safety profile in patients with anti-donor red blood cell antibodies, achieving an event-free survival similar to transplanted patients without such antibodies.

Conditions

Sickle Cell Disease

Keywords

Sickle Cell Disease; ABO Mismatch; SUN-RAY; Matched Sibling Donor (MSD)

Outcome Measures

Primary Outcomes (1)

• To determine the event-free survival of children and adolescents with SCD undergoing nonmyeloablative HCT who received 4 doses of pre-HCT daratumumab for donor-directed red blood cell antibodies.

  Event-free survival rate at 1 year with events including death, graft failure (donor myeloid chimerism \<10% or second HCT), grade II-IV GVHD, and serious pure red blood cell aplasia (persistent reticulocytopenia and need for red blood cell transfusion support after day +100).

  1-year post-transplant

Secondary Outcomes (2)

• To evaluate changes in antibodies to red blood cell antigens pre and post exposure to daratumumab and HCT.

  100 days post-transplant

• To characterize the safety of adding pre-HCT daratumumab to the conditioning regimen, as defined by adverse events grade 3 or greater.

  1-year post-transplant

Other Outcomes (3)

• To compare alemtuzumab levels, in mcg/mL, post-HCT among patients treated with daratumumab, with patients not treated with daratumumab on the SUN study.

  Through end of study

• To compare immune reconstitution among patients treated with daratumumab, with patients not treated with daratumumab on the SUN study.

  Through end of study

• To compare donor chimerism (lymphoid vs myeloid) post-HCT among patients treated with daratumumab, with patients not treated with daratumumab on the SUN study.

  Through end of study

Study Arms (2)

Recipients with a major ABO incompatible donor

EXPERIMENTAL

Patients in this cohort are treated pre-HCT with Daratumumab, intravenously, on days -49, -42, -35 and -28. The conditioning regimen will consist of alemtuzumab, given subcutaneously, daily for 5 days (days -7 to -3) and low dose total body irradiation (TBI) 300 cGY on day -2 with gonadal shielding. Sirolimus will be given as GVHD prophylaxis for the first year with weaning thereafter based on donor T-cell chimerism. G-CSF, at 5 mcg/kg/day, will be given post stem cell infusion until neutrophil engraftment is achieved.

Drug: Daratumumab; Drug: Alemtuzumab; Drug: Sirolimus; Radiation: Total Body Irradiation

Recipients with red cell alloantibodies (non-ABO) against donor antigens

EXPERIMENTAL

Patients in this cohort are treated pre-HCT with Daratumumab, intravenously, on days -49, -42, -35 and -28. The conditioning regimen will consist of alemtuzumab, given subcutaneously, daily for 5 days (days -7 to -3) and low dose total body irradiation (TBI) 300 cGY on day -2 with gonadal shielding. Sirolimus will be given as GVHD prophylaxis for the first year with weaning thereafter based on donor T-cell chimerism. G-CSF, at 5 mcg/kg/day, will be given post stem cell infusion until neutrophil engraftment is achieved.

Drug: Daratumumab; Drug: Alemtuzumab; Drug: Sirolimus; Radiation: Total Body Irradiation

Interventions

Daratumumab DRUG

Daratumumab is a cytotoxic monoclonal antibody (IgG1k) to CD38 and is commercially approved to treat multiple myeloma. CD38 is expressed on several types of blood cells including B-cells, antibody-secreting plasma blasts and plasma cells. As a result, it has been used to treat antibody-mediated diseases, including children with antibody-mediated cytopenias post-HCT.

Also known as: Darzalex

Recipients with a major ABO incompatible donor; Recipients with red cell alloantibodies (non-ABO) against donor antigens

Alemtuzumab DRUG

Alemtuzumab is a humanized monoclonal antibody specific to lymphocyte antigens. It is a recombinant DNA-derived humanized monoclonal antibody (Campath-1H) that is directed against the 21-28 kD cell surface glycoprotein, CD52.

Also known as: Campath-1H

Recipients with a major ABO incompatible donor; Recipients with red cell alloantibodies (non-ABO) against donor antigens

Sirolimus DRUG

Sirolimus is an mTOR inhibitor immunosuppressant used to prevent organ transplant rejections as well as treat lymphangioleiomyomatosis and adults with perivascular epithelioid cell tumors.

Also known as: Rapamune

Recipients with a major ABO incompatible donor; Recipients with red cell alloantibodies (non-ABO) against donor antigens

Total Body Irradiation RADIATION

Total body irradiation is a form of radiotherapy used primarily as part of the preparative regimen for haematopoietic stem cell transplantation. The radiation is given in a low dose so that normal tissues can repair themselves.

Also known as: TBI

Recipients with a major ABO incompatible donor; Recipients with red cell alloantibodies (non-ABO) against donor antigens

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• Children's National Research Institute: lead
• Alberta Children's Hospital: collaborator
• The Hospital for Sick Children: collaborator
• Levine Children's Hospital: collaborator
• Ann & Robert H Lurie Children's Hospital of Chicago: collaborator
• Nationwide Children's Hospital: collaborator
• Children's Hospital at Montefiore: collaborator
• Doris Duke Charitable Foundation: collaborator
• Janssen Pharmaceuticals: collaborator

Study Sites (1)

Children's National Hospital

Washington D.C., District of Columbia, 20010, United States

RECRUITING

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

daratumumab; Alemtuzumab; Sirolimus; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Macrolides; Lactones; Organic Chemicals; Radiotherapy; Therapeutics; Investigative Techniques

Study Officials

• Robert Nickel, MD

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Robert Nickel, MD

CONTACT

202-476-3122; rnickel@childrensnational.org

Maryanne Odinakachukwu

CONTACT

202-476-2957; modinakach@childrensnational.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Model Details: Sickle cell patients, who have matched sibling donors with anti-donor RBC antibodies.

Study Record Dates

• First Submitted: April 2, 2024
• First Posted: April 10, 2024
• Study Start: April 3, 2024
• Primary Completion (Estimated): September 1, 2044
• Study Completion (Estimated): September 1, 2054
• Last Updated: September 26, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)