Transplanting stem cells from mismatched donors for sickle cell disease and other anemias

T-Cell Depleted, Alternative Donor Transplant in Pediatric and Adult Patients With Severe Sickle Cell Disease (SCD) and Other Transfusion-Dependent Anemias

This study is testing if using stem cells from mismatched donors can help people with severe sickle cell disease and other anemias who don't have matching donors.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 5 (estimated)
• Ages: 5 Years to 40 Years
• Sex: All
• Sponsor: University of Pittsburgh (Academic / other)
• Locations: 1 site (Pittsburgh, Pennsylvania)
• Trial ID: NCT03653338 on ClinicalTrials.gov

What this trial studies

This study evaluates the effects of using mismatched unrelated volunteer and haploidentical related donor stem cell transplants in patients with severe sickle cell disease and other transfusion-dependent anemias. It employs a T-cell depleted approach to minimize the risk of graft-versus-host disease while aiming for successful engraftment. The study focuses on patients who lack matched donor options and utilizes a reduced-intensity conditioning regimen to reduce treatment-related complications. The goal is to improve patient outcomes by increasing the availability of safe and effective stem cell transplants.

Who should consider this trial

Good fit: Ideal candidates include patients aged 5 to 40 with severe sickle cell disease or other specified anemias who have not responded adequately to standard treatments.

Not a fit: Patients with matched sibling donors or those who do not meet the eligibility criteria for the study may not benefit from this approach.

Why it matters

Potential benefit: If successful, this approach could provide a viable transplant option for patients with limited donor availability, potentially improving their quality of life and health outcomes.

How similar studies have performed: While the use of mismatched donors in stem cell transplantation is a developing area, this specific approach has not been widely tested, making it a novel investigation.

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.

Patient 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.

Where this trial is running

Pittsburgh, Pennsylvania

• Children's Hospital of Pittsburgh of UPMC — Pittsburgh, Pennsylvania, United States (Recruiting)

Study contacts

• Principal investigator: Paul Szabolcs, MD — University of Pittsburgh
• Study coordinator: Paul Szabolcs, MD

Conditions Sickle Cell Anemia; Beta-thalassemia Major; Diamond-blackfan Anemia; Sickle Cell; Diamond-Blackfan; Beta-thalassemia; Anemia; Stem cell transplantation