Nonmyeloablative Stem Cell Transplant in Children With Sickle Cell Disease and a Major ABO-Incompatible Matched Sibling Donor

Study Overview
=================
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.

Official Title
-----------------
A Phase II Pilot Study of Nonmyeloablative Conditioning Hematopoietic Stem Cell Transplantation in Children With Sickle Cell Disease Who Have a Matched Related Major ABO-Incompatible Donor (Sickle-AID)

Conditions
-----------------
Sickle Cell Disease, Stem Cell Transplant Complications, Red Blood Cell Disorder, Pure Red Cell Aplasia

Intervention / Treatment
-----------------
* Drug: Alemtuzumab
* Radiation: Total Body Irradiation
* Drug: Sirolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-myeloablative conditioning<br>Non-myeloablative conditioning | Drug: Alemtuzumab<br>* Alemtuzumab, Day -7 to -3. Dose: 0.2mg/kg/dose SC once daily x 5 days<br>* Other names: Campath;Radiation: Total Body Irradiation<br>* TBI 300 cGy on Day -2<br>* Other names: TBI;Drug: Sirolimus<br>* Sirolimus is used for GVHD prophylaxis<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of pure red cell aplasia (PRCA) | 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 | 6 months from enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RBC chimerism measured by peripheral blood flow cytometry | Peripheral blood for RBC chimerism on flow sorted erythroid precursor cells | 12 months | 
| RBC chimerism measured by bone marrow BFU-erythroid forming colonies | Bone marrow will be performed between Day +45 and +60 | 2 months | 
| Primary graft failure | Measured by donor chimerism from peripheral blood and bone marrow | 6 weeks | 
| Secondary graft failure | Measured by donor chimerism in peripheral blood and bone marrow | 24 months | 
| Disease recurrence | Measured by peripheral blood Hb S level | 24 months | 
| Incidence and severity of acute GVHD | Acute GVHD grade will be accessed using modified CIBMTR criteria | 100 days | 
| Incidence and severity of chronic GVHD | Chronic GVHD will be accessed using the NIH consensus criteria | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
sickle cell disease, stem cell transplant, red blood cell engraftment, nonmyeloablative, pure red cell aplasia