Haploidentical stem cell transplantation for sickle cell disease

A Phase II Stratified Trial to Assess Haploidentical T-depleted Stem Cell Transplantation in Patients With Sickle Cell Disease With no Available Sibling Donor

This study is testing a new type of stem cell transplant for people with sickle cell disease to see if it can cure the disease while causing fewer complications.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 212 (estimated)
• Ages: 2 Years to 35 Years
• Sex: All
• Sponsor: University of Regensburg (Academic / other)
• Locations: 9 sites (Vienna and 8 other locations)
• Trial ID: NCT04201210 on ClinicalTrials.gov

What this trial studies

This trial investigates the safety and efficacy of haploidentical T-depleted stem cell transplantation as a potential curative treatment for patients with sickle cell disease (SCD). It aims to determine if this approach can provide disease-free survival comparable to matched sibling donor transplants while minimizing complications such as graft-versus-host disease (GvHD) and rejection. The study will assess various outcomes including immune reconstitution, fertility, and the incidence of severe infections. By utilizing a less aggressive conditioning regimen, the trial seeks to improve patient outcomes and reduce transplantation-related mortality.

Who should consider this trial

Good fit: Ideal candidates for this study are patients aged 2 to 35 years with severe forms of sickle cell disease and significant related complications.

Not a fit: Patients with mild sickle cell disease or those without significant complications may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could provide a viable curative option for the majority of patients with sickle cell disease who lack a matched donor.

How similar studies have performed: While haploidentical stem cell transplantation is a novel approach for sickle cell disease, similar strategies have shown promise in other hematological conditions.

Eligibility criteria

Inclusion Criteria:

* Age 2yrs to 35yrs
* Homozygous hemoglobin S disease or heterozygous hemoglobin SC or S 0/+
* Study specific consent given
* Preexisting severe or moderate SCD related complications:

  * Clinically significant neurological event (stroke) or deficit
  * Silent crisis, neurocognitive deficit
  * Pathological angio-MRI with TOF Sequence
  * TCD velocity \>200 cm/s at 2 occasions \>1 month apart
  * More than 5 vaso-occlusive crises (VOC) in the past 1 year or more than 20 VOC in a lifetime
  * Two or more episodes of acute chest syndrome (ACS) in a lifetime or one episode of ACS in the past 24 months
  * Chronic transfusion requirement or more than 8 transfusions or one exchange transfusion in a lifetime
  * Transfusion-refractory allo-immunization
  * More than five SCD-related hospitalizations in a lifetime
  * Beginning pulmonary hypertension
  * Osteonecrosis at more than 2 sites
  * Beginning SCD Nephropathy
  * Recurrent priapism (\>2)

Exclusion Criteria:

* Karnofsky or Lansky Performance Score \< 70%
* Patients with donor-specific antibodies (DSA) against the potential stem cell donor by either

  * Cell-based crossmatched assays (Complement-dependent cytotoxicity; CDC) or
  * Flow cytometry crossmatch test or
  * Solid-phase immunoassays (SPI) or
  * Modified SPI such as C4d and C1q assays Whichever method the participating center is experienced in.
* Patients with major AB0 incompatibility defined according to EBMT Handbook, Edition 2019 Tab 23.1.:

ABO incompatibility Recipient Donor Major O A O B O AB A AB B AB

* Cardiac function:

  * Ejection fraction at rest \<45.0% on echocardiography or
  * Shortening fraction of \<27.0% by echocardiogram or radionuclide scan (MUGA)
  * Patients with \> grade II hypertension by Common Toxicity Criteria (CTC)
* Renal function:

  * Estimated creatinine clearance (for patients \> 12 years) greater than 50.0 mL/minute
  * for pediatric patients (\> 1 year to 12 years), GFR estimated by the updated Schwartz formula ≥ 90.0 mL/min/1.73 m2. If \< 90 mL/min/1.73 m2, renal function must be measured by 24-hour creatinine clearance or nuclear GFR and must be \> 70.0 mL/min/1.73 m2 or
  * Creatinine clearance below threshold defined for stem cell transplantation according to local clinical standard
* Pulmonary function:

  * DLCO \>50% (adjusted for hemoglobin), and FVC and FEV1≥50%; children unable to perform for PFTs, O2 saturation \<92% on room air.
* Liver function:

  * Total bilirubin \> 2x the upper limit of normal (unless elevated bilirubin is attributed to Gilbert's Syndrome) and ALT/AST \> 2.5x the upper limit of normal.
  * Chronic active viral hepatitis
* Women who are pregnant (positive serum or urine βHCG) or breastfeeding. Note: Women of childbearing potential must have a negative serum pregnancy test at study entry.
* Adults of reproductive potential not willing to use an effective method of birth control during study treatment and for at least 12 months thereafter,
* History of uncontrolled autoimmune disease or on active treatment
* Patient unable to comply with the treatment protocol
* Prior autologous or allogeneic hematopoietic stem cell transplant
* Vaccination with a live virus vaccine during the trial
* HIV infection
* Patients with a history of psychiatric illness or a condition which could interfere with their ability to understand the requirements of the study (this includes alcoholism/drug addiction)
* Patients unwilling or unable to comply with the protocol or unable to give informed consent.
* Concurrent severe or uncontrolled medical disease (e.g. uncontrolled diabetes, congestive heart failure, myocardial infarction within 6 months prior to the study, unstable and uncontrolled hypertension, chronic renal disease, or active uncontrolled infection) which by assessment of the treating physician could compromise participation in the study

Where this trial is running

Vienna and 8 other locations

• St. Anna Kinderspital — Vienna, Austria (Not_yet_recruiting)
• University Hospital Aachen, Children's Hospital — Aachen, Germany (Not_yet_recruiting)
• Charité University medicine, Clinic for Hematology, Oncology — Berlin, Germany (Not_yet_recruiting)
• University Hospital Duesseldorf, Clinic for Pediatric Oncology, - Hemtaology and Clinical Immunology — Düsseldorf, Germany (Not_yet_recruiting)
• University Hospital of Frankfurt, Clinic for Paediatrics and Adolescent Medicine — Frankfurt, Germany (Not_yet_recruiting)
• University Hospital Heidelberg, Department of Pediatric Hematology, Oncology and Immunology — Heidelberg, Germany (Recruiting)
• University Hospital Regensburg, Dept. of Ped. Hematology, Oncology and Stem Cell Transplantation — Regensburg, Germany (Recruiting)
• University Children's Hospital Tübingen — Tübingen, Germany (Recruiting)
• University Children's Hospital Würzburg — Würzburg, Germany (Recruiting)

Study contacts

• Principal investigator: Selim Corbacioglu, MD — University Hospital of Regensburg
• Study coordinator: Selim Corbacioglu, MD

Conditions HbS Disease; Hemoglobin S Disease; Sickle Cell Anemia; Sickle Cell Disorders; Sickling Disorder Due to Hemoglobin S; Sickle Cell Disease