A Reduced Toxicity Allogeneic Unrelated Donor Stem Cell Transplantation (SCT) for Severe Sickle Cell Disease

A Pilot Study of an Immunosuppressive and Myeloablative Preparative Regimen for Allogeneic Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT) for Severe Sickle Cell Disease

Majority of patients who are eligible for allogeneic HSCT for cure of severe sickle cell disease lack a matched family donor. This study aims for cure of sickle cell disease by performing unrelated donor (outside family) allogeneic HSCT. Donors or unrelated cord blood units will be selected from the NMDP database. It is designed to estimate the safety of a novel reduced toxicity, yet an immunosuppressive and myeloablative preparative regimen. This is meant for patients <21 years old who have severe complications from sickle cell and do not have matched sibling donors in the family to undergo stem cell transplant. Patients will undergo transplant using unrelated donor stem cells after receiving the protocol therapy. They will be followed for 1 year to monitor for engraftment of donor cells and complications like graft versus host disease (GVHD), infections and death.

The primary goal of this pilot study is to determine the safety and feasibility of the preparative regimen for HSCT using a novel reduced toxicity regimen for stem cell transplant with unrelated donors. Analysis will be geared to confirm if the study regimen, followed by an appropriately HLA-matched unrelated donor (MUD)or unrelated cord blood HSCT, can lead to durable donor engraftment with reasonable toxicity, inhibiting sickle erythropoiesis and limiting disease related organ toxicity in patients who are at high risk for morbidity and mortality associated with sickle cell disease (SCD).

Inclusion Criteria:

Patients must have sickle cell disease (genotype Hb SS or Sß° thalassemia), AND must have 1 or more of the following clinical complications related to Sickle cell disease:

1. A clinically significant neurologic event (stroke) or any neurologic defect lasting >24 hours, that is accompanied by an infarct on cerebral MRI.
2. Minimum of two episodes of acute chest syndrome (defined as new pulmonary alveolar consolidation involving at least 1 complete lung segment associated with acute symptoms including fever, chest pain, tachypnea, wheezing or cough) despite adequate supportive care measures (example: asthma therapy, hydroxyurea).
3. History of severe pain episodes defined as 3 or more severe pain events per year in the 2 years prior to enrollment despite adequate supportive care measures and hydroxyurea trial (i.e. Hydroxyurea non-responders). Pain may occur in typical sites associated with vaso-occlusive painful events and cannot be explained by causes other than vaso-occlusion mediated by sickle cell disease.
4. Recurrent priapism.
5. Osteo-necrosis of multiple joints
6. Evidence of Pulmonary Hypertension as evidenced by Tricuspid Regurgitation jet velocity (TRV) > 2.5 m/s on Echocardiogram.
7. Red cell allo-immunization (≥ 2 antibodies) during long term transfusion therapy.

Exclusion Criteria:

1. Invasive bacterial, viral or fungal infections within 1 month prior to starting conditioning therapy.
2. Female patients who are Pregnant (Beta HCG +) or breastfeeding.
3. HIV positive patients.
4. Patients with HLA-matched related family donors are not eligible for this study.
5. Prior myeloablative allogeneic HCT.
6. Patients on chronic transfusion therapy for ≥ 1 year with evidence of cirrhosis of liver on biopsy
7. Any significant concurrent disease, illness, severe cognitive delay or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.