TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Non-Malignant Hematological Disorders in Children

Launched by JOHNS HOPKINS ALL CHILDREN'S HOSPITAL · Apr 21, 2020

Keywords

ClinConnect Summary

This clinical trial is exploring a new method of stem cell transplantation to treat certain blood disorders in children, specifically conditions like severe sickle cell disease, thalassemia major, and various bone marrow failure syndromes. The study will use stem cells collected from a parent or a close family member and will be processed through a special device to improve safety and effectiveness. Researchers want to find out if this new approach is safe and can help improve the health of children with these serious conditions.

To participate in this trial, children must meet specific criteria, such as having severe forms of sickle cell disease or thalassemia, or certain types of bone marrow failure that haven’t responded to standard treatments. Participants will need to have a close family member who can donate stem cells and must also be in good overall health. Throughout the trial, participants will be closely monitored by doctors to ensure their safety and to see how well this new treatment works. If you think your child might be eligible and could benefit from this study, it’s important to discuss it with your healthcare provider.

Gender

ALL

Eligibility criteria

• Inclusion Criteria:
• 1. Severe sickle cell disease (HbSS, HbSC, HbSB0, HbSB+, HbSD, HbSE) with at least one of the following criteria:
• • 1. Cerebrovascular accident lasting longer than 24 hours
• • 2. Impaired neuropsychological function with abnormal brain MRI/MRA
• • 3. Patients with frequent (≥ 3 per year for preceding 2 years) painful vaso-occlusive episodes
• • 4. Recurrent (≥ 3 in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy
• • 5. Any combination of ≥ 3 acute chest syndrome episodes and vaso-occlusive pain episodes yearly for 3 years and have failed treatment with hydroxyurea (HU) (at least 6 months on maximum tolerated dose) or who are intolerant to HU therapy
• 2. Thalassemia major with at least one of the following criteria:
• • 1. Transfusion dependency defined as receiving 8 or more transfusions per year
• • 2. Thalassemia diagnosis documented by clinical assessment, laboratory evidence with microcytic anemia and absence of HbA (\< 10%) on electrophoresis and or confirmation by DNA analysis of alpha and beta gene loci
• • 3. Genotypically proven thalassemia major for children \< 2 years of age even in the absence of transfusion dependency
• • 4. Lucarelli class 1 or 2 risk status (i.e. with only 0-2 of the following factors: hepatomegaly, portal fibrosis, or poor response to chelation therapy)
• 3. Bone marrow failure syndromes and autoimmune cytopenias:
• • 1. Severe Aplastic Anemia refractory to immunosuppressive therapy
• • 2. Diamond Blackfan Anemia refractory to conventional therapy
• • 3. Inherited Bone Marrow Failure Syndromes such as Fanconi anemia and Shwachman-Diamond syndrome with progressive marrow failure (without cytogenetic evidence of MDS/AML)
• • 4. Severe Congenital Neutropenia
• • 5. Congenital Amegakaryocytic Thrombocytopenia
• • 6. Glanzmann Thrombasthenia
• • 7. Autoimmune Cytopenias refractory to conventional treatment (including Pure red cell aplasia, Evan's syndrome, Immune thrombocytopenia, autoimmune hemolytic anemia)
• • 8. Other marrow failure disorders not otherwise specified
• Inclusion Criteria:
• • 1. Patient has a suitable genotypic identical match of 5/10. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1.
• 2. Patients must have adequate organ function measured by:
• • 1. Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 40% or SF ≥ 26%
• • 2. Pulmonary: asymptomatic or if symptomatic DLCO ≥ 40% of predicted (corrected for hemoglobin) or pulse oximetry ≥ 92% on room air if the patient is unable to perform pulmonary function testing.
• • 3. Renal: Creatinine clearance (CrCl) or glomerular filtration rate (GFR) must be \> 50 mL/min/1.73 m2.
• • 4. Hepatic: Serum conjugated (direct) bilirubin \< 2.0 x ULN for age as per local laboratory unless attributable to Gilbert's syndrome; AST and ALT \< 5.0 x ULN for age as per local laboratory. Patients with hyperbilirubinemia as a consequence of hyperhemolysis, or a profound change in serum hemoglobin post blood transfusion, are not excluded.
• • 5. Karnofsky or Lansky (age-dependent) performance score ≥ 50
• • 3. Signed written informed consent
• Exclusion Criteria:
• • 1. Participants who have an HLA-matched sibling who is able and willing to donate bone marrow. Patients with a HLA-matched unrelated donors are not excluded.
• • 2. Pregnant or breastfeeding females.
• • 3. Patient has HIV or uncontrolled fungal, bacterial or viral infections.
• • 4. Patient has received prior solid organ transplant.
• • 5. Patient has active GVHD (\> grade II) or chronic extensive GVHD due to a previous allograft at the time of inclusion.
• • 6. For patients with hemoglobinopathy, liver biopsy is necessary if the patient has received chronic transfusions for over a year and has two ferritin levels of ≥ 1000 ng/ml. Patients with cirrhosis, extensive bridging hepatic fibrosis, or active hepatitis are excluded from enrollment.