Early Human Leukocyte Antigen (HLA) Matched Sibling Hematopoietic Stem Cell Transplantation

The use of HLA matched sibling donor (MSD) hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD) is evolving. Because of the low risk for graft versus host disease (GVHD) associated with younger age, HSCT is increasingly being performed prior to adolescence. The use of less gonadotoxic reduced intensity regimens (RIC) are more commonly be utilized to lessen the risk for infertility. Finally, with the recognition that most children, even those who have asymptomatic to relatively mild courses, will develop debilitating morbidities as adults and ultimately suffer an early death, HSCT is being offered to children across a wider spectrum of SCD severity. Long reserved for severely affected children, HSCT is being performed for a growing number of less severely affected children, as well as children without disease manifestation.

This trial is designed to prospectively assess HSCT under these conditions. Eligibility will be limited to children less than 13 years of age who have an HLA MSD. A RIC regimen - fludarabine, alemtuzumab and melphalan (FAM) - will be employed. Finally, SCD severity criteria will be broadened to include less severely affected children as well as those who are severely affected.

This study has the following two specific aims:

Specific Aim #1: To prospectively assess the safety and efficacy of HSCT using FAM conditioning in children with SCD of varying severity who are under 13 years of age.

Specific Aim #2: To address current gaps in our understanding of the long-term effects of HSCT in children with SCD, by longitudinally assessing sickle cell related cerebrovascular disease, sickle cell related nephropathy and health related quality of life.

Inclusion criteria

• Patients must be at least 2 years and less than 13 years old and have a sickle hemoglobinopathy.
• Patient must have an HLA identical sibling donor who is less than 13 years old. Sibling donors must not have any form of SCD. It is acceptable for the donor to carry a hemoglobinopathy trait.
• Patients must meet criteria for symptomatic SCD as defined below.

• Severe disease:

• Previous clinical stroke, defined as a neurological deficit lasting longer than 24 hours plus new finding on head CT or brain MRI/MRA.
• Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent brain MRI/MRA) or the enlargement of a single lesion, initially measuring at least 3 mm). Lesions must be visible on T2-weighted MRI sequences.
• Abnormal TCD testing (confirmed elevated velocities in any single vessel of TAMMV > 200 cm/sec for non-imaging TCD)
• Significant vasculopathy on MRA (greater than 50% stenosis of > 2 arterial segments or complete occlusion of any single arterial segment).
• Frequent (at least 3 per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting at least 4 hours and requiring hospitalization or outpatient treatment with parenteral opioids). If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 2 years prior to the start of hydroxyurea.
• Recurrent (at least 3 in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy.
• Any combination of at least 3 acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above) yearly for 3 years. If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 3 years prior to the start of hydroxyurea.
• Less severe disease: to qualify as having less severe disease, patients must not meet criteria for severe disease and must have one of the following:

• Asymptomatic cerebrovascular disease, as evidenced by one the following: Silent cerebral infarction with at least one lesion measuring at least 3 mm in one dimension that is visible on two planes on the most recent brain MRI, or, cerebral arteriopathy, as evidenced by conditional TCD (TAMMV>170cm/sec but <200cm/sec) on two separate scans >2 weeks apart). If patient has a conditional TCD, then a brain MRI/MRA to evaluate for vasculopathy is required.
• 2 or more painful vaso-occlusive episodes (in lifetime) requiring hospitalization or outpatient treatment with parenteral opioids.
• 2 or more episodes of acute chest syndrome (in lifetime) irrespective of SCD modifying therapy administered.
• Any combination of at least 3 acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above, lifetime).
• Patients with HbSS and HbSβ°thalassemia who have no clinical complications of their sickle cell disease and do not meet the criteria for less severe or severe disease.
• Participant's parent or legal guardian must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Patient must have been evaluated and parent(s)/legal guardian, and the patient as age appropriate as determined by the treating center, adequately counseled regarding treatment options for SCD by a pediatric hematologist.
• Co-enrollment on STAR Project Sickle Cure (PSC) study is required for sites that are activated and participating in the study.

Exclusion criteria

• Bridging (portal to portal) fibrosis or cirrhosis of the liver.
• Parenchymal lung disease stemming from SCD or other process defined as a diffusing capacity of the lungs for carbon monoxide (DLCO; corrected for hemoglobin) or forced vital capacity of less than 45% of predicted. Children unable to perform pulmonary function testing will be excluded if they require daytime oxygen supplementation.
• Renal dysfunction with an estimated glomerular filtration rate (GFR) < 50% of predicted normal for age.
• Cardiac dysfunction with shortening fraction < 25%.
• Neurologic impairment other than hemiplegia, defined as full-scale intelligence quotient (IQ) of less than or equal to 70, quadriplegia or paraplegia, or inability to ambulate.
• Lansky functional performance score < 70%.
• Patient is HIV infected.
• Donor is HIV infected.
• Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate HSCT.
• Patient's parent(s) or legal guardian is unable to understand the nature and the risks inherent in the HSCT process.
• History of lack of adherence with medical care that would jeopardize transplant course.
• Donor who for psychological, physiologic, or medical reasons is unable to tolerate a bone marrow harvest or receive general anesthesia.
• Active viral, bacterial, fungal or protozoal infection.

• Patients with viral upper respiratory tract infections should be asymptomatic for at least 7 days prior to enrollment. PCR testing for respiratory viruses (nasopharyngeal sample) should be negative at the start of the conditioning regimen. Exceptions may be made in patients with prolonged carriage (repeatedly positive over many weeks) of rhinovirus. These exceptions should be discussed with and approved by both study co-chairs and STAR Medical Director.