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

J
Jodi Skiles

Primary Investigator

Enrolling By Invitation
2-13 years
All
Phase 2
58 participants needed
1 Location

Overview

This study aims to enroll 58 pre-adolescent (<13 years) pediatric participants with sickledisease (SCD) who have a pre-adolescent sibling bone marrow donor. All participants will go through a pre-transplant evaluation to find out if there are health problems that will keep them from being able to receive the transplant. It usually takes 2 to 3 months tohe pre-transplant evaluation and make the arrangements for the transplant. Oncehey are found to be eligible for transplant, participants will be admitted to the hospitald will start transplant conditioning. Conditioning is the chemotherapy and other medicines given to prepare them to receive donor cells. It prevents the immune system from rejecting donor cells. Conditioning will start 21 days before transplant. Once they completeditioning, participants will receive the bone marrow transplant. After the transplant,will stay in the hospital for 4-6 weeks. After they leave the hospital,will be followed closely in the clinic. Outpatient treatment and frequent clinic visits usually last 6 to 12 months. Routine medical care includes at least a yearlyy years after transplant by doctors and nurses familiar with sickle cell disease and transplant. The researchers will collect and study information about participants5 years after transplant.

Description

The use of HLA matched sibling donor (MSD) hematopoietic stem cell transplantation (HSCT) forkle 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 todolescence. 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 mosthildren, even those who have asymptomatic to relatively mild courses, will develop debilitating morbidities as adults and ultimately suffer an early death, HSCT is beingd to children across a wider spectrum of SCD severity. Long reserved for severelyd children, HSCT is being performed for a growing number of less severely affectedhildren, 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 -udarabine, alemtuzumab and melphalan (FAM) - will be employed. Finally, SCD severitywill be broadened to include less severely affected children as well as those whoverely affected.
This study has the following two specific aims:
Specific Aim #1: To prospectively assess the safety and efficacy of HSCT using FAMditioning 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.

Eligibility

You may be eligible for this study if you meet the following criteria:

  • Conditions:
    Sickle Cell Disease
  • Age: Between 2 Years - 13 Years
  • Gender: All

Inclusion Criteria:
  • Patients must be at least 2 years and less than 13 years old and have a sicklehemoglobinopathy.
  • Patient must have an HLA identical sibling donor who is less than 13 years old.bling donors must not have any form of SCD. It is acceptable for the donor to carryhemoglobinopathy trait.
  • Patients must meet criteria for symptomatic SCD as defined below.
    • Severe disease:
      • Previous clinical stroke, defined as a neurological deficit lasting longerhan 24 hours plus new finding on head CT or brain MRI/MRA.
      • Progressive silent cerebral infarction, as evidenced by serial MRI scanshat demonstrate the development of a succession of lesions (at least twoy discreet lesions, each measuring at least 3 mm in greatestdimension on the most recent brain MRI/MRA) or the enlargement of a singley measuring at least 3 mm). Lesions must be visible onT2-weighted MRI sequences.
      • Abnormal TCD testing (confirmed elevated velocities in any single vessel ofTAMMV > 200 cm/sec for non-imaging TCD)
      • Significant vasculopathy on MRA (greater than 50% stenosis of > 2 arterialgments or complete occlusion of any single arterial segment).
      • Frequent (at least 3 per year for preceding 2 years) painful vaso-occlusivedes (defined as episode lasting at least 4 hours and requiringhospitalization or outpatient treatment with parenteral opioids). If patienthydroxyurea and its use has been associated with a decrease in thequency of episodes, the frequency should be gauged from the 2 years priorhe start of hydroxyurea.
      • Recurrent (at least 3 in lifetime) acute chest syndrome events which haved erythrocyte transfusion therapy.
      • Any combination of at least 3 acute chest syndrome episodes andvaso-occlusive pain episodes (defined as above) yearly for 3 years. Ifhydroxyurea and its use has been associated with a decrease inhe frequency of episodes, the frequency should be gauged from the 3 yearshe 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:bral infarction with at least one lesion measuring at least 3 mmdimension that is visible on two planes on the most recent brain MRI,bral arteriopathy, as evidenced by conditional TCD (TAMMV>170cm/secbut <200cm/sec) on two separate scans >2 weeks apart). If patient has aditional TCD, then a brain MRI/MRA to evaluate for vasculopathy isquired.
      • 2 or more painful vaso-occlusive episodes (in lifetime) requiringhospitalization or outpatient treatment with parenteral opioids.
      • 2 or more episodes of acute chest syndrome (in lifetime) irrespective of SCDdifying therapy administered.
      • Any combination of at least 3 acute chest syndrome episodes andvaso-occlusive pain episodes (defined as above, lifetime).
    • No clinical manifestations of HbSS and HbSβ°thalassemia
  • 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 agedetermined by the treating center, adequately counseled regardingCD by a pediatric hematologist.
  • Co-enrollment on STAR Project Sickle Cure (PSC) study is required for sites that arevated 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 diffusingy of the lungs for carbon monoxide (DLCO; corrected for hemoglobin) or forcedvital capacity of less than 45% of predicted. Children unable to perform pulmonaryunction testing will be excluded if they require daytime oxygen supplementation.
  • Renal dysfunction with an estimated glomerular filtration rate (GFR) < 50% ofdicted normal for age.
  • Cardiac dysfunction with shortening fraction < 25%.
  • Neurologic impairment other than hemiplegia, defined as full-scale intelligencequotient (IQ) of less than or equal to 70, quadriplegia or paraplegia, or inability tobulate.
  • Lansky functional performance score < 70%.
  • Patient is HIV infected.
  • Donor is HIV infected.
  • Patient with unspecified chronic toxicity serious enough to detrimentally affect they to tolerate HSCT.
  • Patient's parent(s) or legal guardian is unable to understand the nature and the risksherent in the HSCT process.
  • History of lack of adherence with medical care that would jeopardize transplanturse.
  • Donor who for psychological, physiologic, or medical reasons is unable to tolerate abone marrow harvest or receive general anesthesia.
  • Active viral, bacterial, fungal or protozoal infection.
    • Patients with viral upper respiratory tract infections should be asymptomatic for7 days prior to enrollment. PCR testing for respiratory viruses(nasopharyngeal sample) should be negative at the start of the conditioninggimen. Exceptions may be made in patients with prolonged carriage (repeatedlyve over many weeks) of rhinovirus. These exceptions should be discussedwith and approved by both study co-chairs and STAR Medical Director.

Updated on 15 May 2024. Study ID: IRB00093513
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