T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias

NCT ID: NCT03653338

Last Updated: 2025-08-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-02
• Study Completion Date: 2027-08-01

Brief Summary

The purpose of this study is to evaluate what effect, if any, mismatched unrelated volunteer donor and/or haploidentical related donor stem cell transplant may have on severe sickle cell disease and other transfusion dependent anemias. By using mismatched unrelated volunteer donor and/or haploidentical related donor stem cells, this study will increase the number of patients who can undergo a stem cell transplant for their specified disease. Additionally, using a T-cell depleted approach should reduce the incidence of graft-versus-host disease which would otherwise be increased in a mismatched transplant setting.

Detailed Description

CD3/CD19 depletion of mismatched donor grafts in the setting of reduced intensity, immune-ablative conditioning for patients with sickle cell disease and other transfusion-dependent anemias should sufficiently achieve engraftment while decreasing the incidence of treatment-related toxicities and achieving an acceptable incidence of graft versus host disease. Utilizing mismatched unrelated volunteer donors and haploidentical related donors will increase the number of patients able to undergo hematopoietic stem cell transplant (HSCT) for these diseases. Additionally, the institutional availability of virus-specific, donor-derived cytotoxic T lymphocytes should address complicated viral infections refractory to standard anti-viral therapy.

The purpose is to:

• To provide alternate donor transplantation from cryopreserved stem cell grafts that are fully characterized for safety and potency to patients with severe sickle cell disease, beta-thalassemia major, or Diamond-Blackfan anemia who do not have matched sibling donor, matched unrelated donor or cord blood donor options.
• To utilize a reduced-intensity conditioning regimen to achieve minimal treatment-related morbidity and mortality while attaining sustained donor engraftment and donor chimerism >20% in order to rescue disease phenotype, specifically in SCD patients.
• To utilize ex-vivo T-cell depletion methods to prevent graft-versus-host disease in the setting of mismatched donor transplantation.
• To utilize additional donor cell products to ensure sufficient immune reconstitution in the immediate post-transplant period, to improve mixed chimerism or provide non-specific anti-viral activity in patients with virus reactivation in the post-transplant period.
• To utilize calcineurin inhibitor-free regimen in an effort to minimize/prevent central nervous system toxicity

Conditions

Sickle Cell Anemia; Beta-thalassemia Major; Diamond-blackfan Anemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Hematopoietic Stem Cell Transplantation

All patients will receive a CD3+/CD19+ depleted stem cell transplant. In this study, the investigators will use HLA mismatched unrelated or haploidentical related donor peripheral blood stem cells. Prior to transplantation, the marrow (90-95%) will be negatively selected for CD3/CD19 using the ClinicMACs® depletion device. The remaining (5-10%) will undergo CD45+RA+ depletion and be frozen for future use as an immune boost.

Subjects will undergo hematopoietic stem cell transplant utilizing CD3+/CD19+ depleted cells following conditioning therapy.

Group Type: EXPERIMENTAL

CD3/CD19 depleted leukocytes

Intervention Type: BIOLOGICAL

Negative selection for CD3+/CD19+ cells will be performed on the CliniMACS® depletion device.

CD45RA depleted leukocytes

Intervention Type: BIOLOGICAL

Negative selection for CD45RA will be performed on the CliniMACS® depletion device.

Hydroxyurea

Intervention Type: DRUG

Sickle Cell Disease Conditioning

Rituximab

Intervention Type: DRUG

Sickle Cell Disease Conditioning

Alemtuzumab

Intervention Type: DRUG

Sickle Cell Disease Conditioning

Fludarabine

Intervention Type: DRUG

Sickle Cell Disease Conditioning

Thiotepa

Intervention Type: DRUG

Sickle Cell Disease Conditioning

Interventions

CD3/CD19 depleted leukocytes

Negative selection for CD3+/CD19+ cells will be performed on the CliniMACS® depletion device.

Intervention Type: BIOLOGICAL

CD45RA depleted leukocytes

Negative selection for CD45RA will be performed on the CliniMACS® depletion device.

Intervention Type: BIOLOGICAL

Hydroxyurea

Sickle Cell Disease Conditioning

Intervention Type: DRUG

Rituximab

Sickle Cell Disease Conditioning

Intervention Type: DRUG

Alemtuzumab

Sickle Cell Disease Conditioning

Intervention Type: DRUG

Fludarabine

Sickle Cell Disease Conditioning

Intervention Type: DRUG

Thiotepa

Sickle Cell Disease Conditioning

Intervention Type: DRUG

Other Intervention Names

HU, Hydrea; Rituxan; Campath-1H; Fludara

Eligibility Criteria

Inclusion Criteria

1. Patient, parent, or legal guardian must have given written informed consent and/or assent according to FDA guidelines.

2. Ages 5 years to 40 years, at time of consent.

3. Diagnosis of Sickle Cell Disease (Hemoglobin SS, Sβ0-thalassemia) complicated by any of the following:

• Recurrent acute painful episodes (also known as vaso-occlusive crises; VOC) despite supportive care, minimum of 2 new pain events per year requiring hospitalization for parenteral pain management in the previous 2 years.
• Recurrent acute chest syndrome (ACS) despite supportive care, minimum of 2 episodes in preceding 2-year period.
• Stroke or neurologic event lasting > 24 hours with an accompanying infarct on MRI in any patient for all ages; Brain MRI with silent infarct without clinical event in patients ≤ 16 years.
• Chronic transfusion therapy defined as > 8 packed red blood cell transfusions per year in the year prior to enrollment and/or evidence of red blood cell alloimmunization.
• Elevated transcranial Doppler velocities - > 200 cm/s, via the non-imaging technique or > 185 cm/s by the imaging technique measured on 2 separate occasions ≥ 1-month apart
• Elevated TRV > 2.6m/s in patients ≥ 16 years old.
• Sickle-related renal insufficiency and/or sickle hepatopathy and/or any irreversible end-organ damage in patients ≥ 16 years old.

OR Diagnosis of beta-thalassemia or Diamond-Blackfan anemia complicated by transfusion dependence with evidence of iron overload.

4. A minimum donor match of 4/8 via high resolution HLA typing at HLA-A, -B, -C, -DRB1 loci in the related setting or minimum donor match of 6/8 via high resolution HLA typing at HLA-A, -B, -C, -DRB1 loci (with the DRB1 locus as a full match requirement). An unrelated donor and cord blood search must have been completed without an eligible 8/8 matched unrelated donor or 6/8 cord blood unit available. Patients who may have acceptable cord blood donor options (4/6 or better) but are limited by cell dose of a single cord will also be eligible for the proposed study.

5. Adequate function of other organ systems as measured by:

• Creatinine clearance or GFR ≥ 45 ml/min/1.73m.
• Hepatic transaminases (ALT/AST) ≤ 3 x upper limit of normal.
• Liver MR imaging for iron content should be performed in all patients with Ferritin > 500 ng/mL. If hepatic iron content > 10mg Fe/g liver should have hepatology consultation and liver biopsy to confirm absence of cirrhosis, fibrosis or hepatitis.
• Adequate cardiac function as measure by echocardiogram (shortening fraction > 26% or ejection fraction > 40% or >80% of age-specific normal).
• Pulmonary evaluation testing demonstrating FEV1/FVC ≥ 60% of predicted for age and/or resting pulse oximeter ≥ 92% on room air.
• Cardiology clearance to proceed with conditioning regimen and HSCT.
• Pulmonology clearance to proceed with conditioning regimen and HSCT.

6. Subjects must be human immunodeficiency virus (HIV) negative by PCR.

7. Negative pregnancy test for females ≥10 years old or who have reached menarche, unless surgically sterilized.

8. All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect.

9. Subject and/or parent guardian will also be counseled regarding the potential risks of infertility following BMT and advised to discuss sperm banking or oocyte harvesting (Refer to section,

10. Hydroxyurea must have been trialed and failed in patients with sickle cell disease.

Exclusion Criteria

1. Patients with alternate, superior donor options (matched sibling donor or matched unrelated donor).

2. Patients who have undergone stem cell transplantation in the 6 months prior to anticipated conditioning.

3. Patients with history of a central nervous system (CNS) event within six months prior to start of conditioning (patient will be delayed until eligible).

4. Patients who are pregnant or lactating

5. Patients with uncontrolled bacterial, viral or fungal infection

6. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Paul Szabolcs

OTHER

Sponsor Role: lead

Responsible Party

Paul Szabolcs

Chief, Division of Blood and Marrow Transplantation and Cellular Therapy

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Paul Szabolcs, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Paul Szabolcs, MD

Role: CONTACT

paul.szabolcs@chp.edu

412-692-6225

Shawna McIntyre, RN

Role: CONTACT

mcintyresm@upmc.edu

412-692-5552

Other Identifiers

STUDY19050050

Identifier Type: -

Identifier Source: org_study_id