Clinical trial NCT03214354: Nonmyeloablative Stem Cell Transplant in Children with Sickle Cell Disease and a Major ABO-Incompatible Matched Sibling Donor
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Sickle Cell Disease
Stem Cell Transplant Complications
Red Blood Cell Disorder
Pure Red Cell Aplasia
Keywords: sickle cell disease
stem cell transplant
red blood cell engraftment
nonmyeloablative
pure red cell aplasia
Lead sponsor: University of Calgary
Sponsor class: OTHER
First posted: 2017-07-11
Enrollment: 12
Sex: ALL
Minimum age (years): 1
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Incidence of pure red cell aplasia (PRCA)
timeFrame: 6 months from enrollment
Secondary outcomes:
measure: RBC chimerism measured by peripheral blood flow cytometry
timeFrame: 12 months
measure: RBC chimerism measured by bone marrow BFU-erythroid forming colonies
timeFrame: 2 months
measure: Primary graft failure
timeFrame: 6 weeks
measure: Secondary graft failure
timeFrame: 24 months
measure: Disease recurrence
timeFrame: 24 months
measure: Incidence and severity of acute GVHD
timeFrame: 100 days
measure: Incidence and severity of chronic GVHD
timeFrame: 24 months
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
Study officials:
References: