Pure Red Cell Aplasia, Red Blood Cell Disorder, Sickle Cell Disease, Stem Cell Transplant Complications
Conditions
Keywords
sickle cell disease, stem cell transplant, red blood cell engraftment, nonmyeloablative, pure red cell aplasia
Brief summary
The aim of this study to evaluate the safety and efficacy of a nonmyeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with sickle cell disease (SCD) who have a matched related major ABO-incompatible donor. The nonmyeloablative regimen will use alemtuzumab, total body irradiation (TBI) and sirolimus for immune suppression. This study will expand the access of HSCT for patients with SCD who are currently not eligible because of donor restrictions.
Detailed description
Sickle cell disease (SCD) is a debilitating chronic blood disorder with multi-system end-organ damage that leads to morbidity and early mortality. The only cure for SCD is hematopoietic stem cell transplantation (HSCT), which given the risks with unrelated HSCT, is only an option for a minority of patients who have a matched sibling donor. In the field of HSCT, blood group ABO incompatibility between donor and recipient is not a contraindication and several studies do not show compromised outcomes. However, in the context of nonmyeloablative (NMA) conditioning and major ABO-incompatibility, when the recipient has existing antibodies to donor red blood cells, pure red cell aplasia (PRCA) may occur. This phase II pilot study will enroll SCD patients with a matched related major ABO-incompatible donor to determine the safety and efficacy of NMA-HSCT. Biological studies will include a plan to study and monitor red cell engraftment in this population to facilitate early detection and interventional measures to prevent and treat PRCA.
Interventions
DRUGAlemtuzumab
Alemtuzumab, Day -7 to -3. Dose: 0.2mg/kg/dose SC once daily x 5 days
RADIATIONTotal Body Irradiation
TBI 300 cGy on Day -2
DRUGSirolimus
Sirolimus is used for GVHD prophylaxis
Sponsors
University of Calgary
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase II pilot, non-randomized, prospective study to evaluate the safety and efficacy of a nonmyeloablative conditioning allogeneic stem cell transplantation for patients with sickle cell disease who have a matched related major ABO-incompatible donor.
Eligibility
Sex/Gender
ALL
Age
1 Years to 19 Years
Healthy volunteers
No
Inclusion criteria
* Patients must be ≥ 12 months and \< 19 years of age at the time of study enrollment. * Patients must have sickle cell disease as defined by hemoglobin electropheresis, as follows: * homozygous Hb S disease (HbSS), * sickle-Hb C disease (HbSC), * sickle beta-plus-thalassemia (HbS/β+), or * sickle beta-null-thalassemia (HbS/βo) * Patients must meet standard eligibility criteria to undergo HSCT, including but not limited to one or more of the following: * history of repeated (more than 1) bony (vaso-occlusive) crisis * history of stroke * elevated transcranial Doppler velocity not eligible for hydroxyurea, as per TWiTCH trial (ie. severe vasculopathy) * history of acute chest crisis or splenic sequestration crisis * history of priapism in males * history of osteonecrosis * pulmonary hypertension as documented by tricuspid regurgitation jet velocity (TRV) \> 2.5 m/s on echocardiogram * red cell allo-immunization (≥ 2 antibodies) during long term transfusion therapy * Sickle complications should be present despite the use of hydroxyurea, but this is not an absolute requirement, if the treating team considers the patient to be at high risk for further crisis episodes.
Exclusion criteria
* Patients who are unable to comply with or follow the study protocol. * Patients with known hypersensitivity to sirolimus, its derivatives or to any of its components.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of pure red cell aplasia (PRCA) | 6 months from enrollment | Clinical definition: reticulocytopenia \< 10x109/L (\< 1%) lasting more than 60 days after HSCT, or Pathological definition: the absence of erythroid precursors in the marrow in the setting of adequate myeloid, lymphoid and megakaryocytic precursors |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| RBC chimerism measured by peripheral blood flow cytometry | 12 months | Peripheral blood for RBC chimerism on flow sorted erythroid precursor cells |
| RBC chimerism measured by bone marrow BFU-erythroid forming colonies | 2 months | Bone marrow will be performed between Day +45 and +60 |
| Primary graft failure | 6 weeks | Measured by donor chimerism from peripheral blood and bone marrow |
| Secondary graft failure | 24 months | Measured by donor chimerism in peripheral blood and bone marrow |
| Disease recurrence | 24 months | Measured by peripheral blood Hb S level |
| Incidence and severity of acute GVHD | 100 days | Acute GVHD grade will be accessed using modified CIBMTR criteria |
| Incidence and severity of chronic GVHD | 24 months | Chronic GVHD will be accessed using the NIH consensus criteria |
Countries
Canada
Contacts
CONTACTTony Truong, MD, MPH
CONTACTGreg Guilcher, MD
Outcome results
None listed