T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias
- Conditions
- Diamond-blackfan AnemiaSickle Cell AnemiaBeta-thalassemia Major
- Interventions
- Biological: CD3/CD19 depleted leukocytesBiological: CD45RA depleted leukocytes
- Registration Number
- NCT03653338
- Lead Sponsor
- Paul Szabolcs
- 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
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 5
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Hematopoietic Stem Cell Transplantation CD3/CD19 depleted leukocytes 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. Hematopoietic Stem Cell Transplantation CD45RA depleted leukocytes 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. Hematopoietic Stem Cell Transplantation Hydroxyurea 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. Hematopoietic Stem Cell Transplantation Rituximab 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. Hematopoietic Stem Cell Transplantation Fludarabine 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. Hematopoietic Stem Cell Transplantation Alemtuzumab 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. Hematopoietic Stem Cell Transplantation Thiotepa 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.
- Primary Outcome Measures
Name Time Method Graft rejection Day -30 through study completion, an average of 2 years How frequent, if any, graft rejection occurs
Post Transplant treatment related mortality 1 year Number of deaths that occurred from treatment
Acute Graft versus host disease Day 0 through study completion, an average of 2 years The number of patients who develop acute graft versus host disease (GVHD)post transplant
Chronic Graft versus host disease Day 0 through study completion, an average of 2 years The number of patients who develop chronic graft versus host disease (GVHD) post transplant
- Secondary Outcome Measures
Name Time Method Neutrophil recovery Day 0 through study completion, an average of 2 years ≥ 0.5 x 103/μL neutrophils for three consecutive days tested on different days.
Donor Cell Engraftment From Day 0, Day 42, Day 100 and Day 180. Further testing can be done if clinically indicated up to 2 years post transplant ≥ 5% donor cells on day +42 and ≥ 10% donor cells on day +100. We will record if subjects have attained robust donor cell engraftment (\> 50% donor chimerism at 180 days).
Neurological complications Day 0 through study completion, an average of 2 years To evaluate the incidence of neurological complications
Immune reconstitution Day 0 through study completion, an average of 2 years The pace of systemic immune reconstitution
Cytomegalovirus (CMV) infection Day 0 through study completion, an average of 2 years Incidence of CMV infection by Polymerase chain reaction (PCR) as clinically indicated
Donor Lymphocyte Infusions response Day 0 through study completion, an average of 2 years Evaluate for delayed immune reconstitution, mixed chimerism or viral reactivation
Response to donor-derived virus-specific cytotoxic T-cell therapy Day 0 through study completion, an average of 2 years Activation or reactivation of Cytomegalovirus (CMV), Epstein-Barr Virus (EBV) or adenovirus testing by PCR
Sickle Cell disease phenotype recurrence Day 0 through study completion, an average of 2 years The incidence of Sickle Cell recurrence as clinical evidence of vaso occlusive crisis, detection of HgbS\>25% and acute chest syndrome.
Recurrence of transfusion-dependence Day 0 through study completion, an average of 2 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.
Organ toxicity Day 0 through study completion, an average of 2 years Incidence of Grade 3-4
Long-term complications-Sterility, endocrinopathy, and secondary malignancy Day 0 through study completion, an average of 2 years Incidence of long term complications
Pediatric Quality of Life Inventory Baseline through study completion, an average of 2 years Measures Pain/Hurt ,Pain Impact,Pain Management/Control ,Worry ,Emotions ,Treatment , Communication
Platelet Recovery Day 0 through study completion, an average of 2 years Platelet count of ≥ 20,000/μL without platelet transfusion in the previous 7 days.
Adult Sickle Cell Quality of Life Measurement System (ASCQ) Baseline through study completion, an average of 2 years Patient reported outcome measurement system that assesses the physical, social and emotional impact of Sickle Cell Disease.
Trial Locations
- Locations (1)
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States