HLA-Identical Sibling Donor Bone Marrow Transplantation for Individuals With Severe Sickle Cell Disease Using a Reduced Intensity Conditioning Regimen

NCT02776202 | Unknown Phase 2

• 1 other identifier: RC15/043/R
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

Sickle cell disease (SCD) is the most common inherited blood disorder in Saudi Arabia . Its clinical severity is widely heterogeneous among patients who share the same genetic mutation . Severe frequent pain crisis, recurrent acute chest syndrome and stroke are features of severe SCD. Hydroxyurea is an effective treatment of SCD as it ameliorates the severity and frequency of pain crisis and acute chest syndrome and decreases mortality, however, it is less effective in the prevention and treatment of stroke and other end organ dysfunctions . The only readily available cure of SCD is by hematopoietic stem cell transplantation (HSCT) . Most children with SCD who are treated by HSCT receive myeloablative conditioning with excellent results. The application of reduced intensity (RIC) and non-myeloablative (NMA) conditioning regimens are reserved for patients older than 16 years of age because of the increased risks of morbidity and mortality after HSCT6. However, infertility and gonadal failure after myeloablative conditioning are important barriers to the willingness of patients and their families to undergo HSCT . The development of an effective RIC HSCT in SCD that might spare the fertility of SCD patients would have obvious merit. With the ultimate goal of expanding this curative therapy to SCD patients, we propose to investigate HSCT with a RIC conditioning regimen. We will carry out a pilot study of HSCT from HLA matched sibling donors using thymoglobulin/fludarabine/melphalan conditioning and sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in SCD patients with severe complications such as stroke and other severe complications. We hypothesize that HSCT from HLA matched sibling using thymoglobulin/fludarabine/melphalan conditioning in SCD will maintain a level of stable donor chimerism that is sufficient to cure SCD with minimal toxicity.

Conditions

Sickle Cell Disease

Outcome Measures

Primary Outcomes (1)

• to determine event-free survival (EFS) at 1 year after HLA-Identical sibling donor hematopoietic stem cell transplantation (HCT) using bone marrow (BM) in patients with sickle cell disease (SCD).

  3 years

Secondary Outcomes (2)

• 1. To determine the effect of HCT on clinical and laboratory manifestations of severe sickle cell disease including stroke.

  3 years

• determine the incidence of other transplant-related outcomes.

  3 years

Study Arms (1)

Reduced-intensity conditioning regimen

EXPERIMENTAL

The HSCT preparative regimen will consist of * Thymoglobulin: 2.5 mg /kg/day intravenously (IV) on Days -8 through -5 * Fludarabine: 35 mg/m2/day IV on Days -8 through -4 * Melphalan: 140 mg/m2 IV on Day -3 * Rest on Day -2 and -1 * Day 0 is the day of transplant * GVHD prophylaxis: sirolimus beginning on Day -1 for at least one year and mycophenolate mofetil (MMF) from Day -3 to +45 or to 7 days after neutrophil engraftment, whichever is later.

Drug: Fludarabine monophosphate

Interventions

Fludarabine monophosphate DRUG

The HSCT preparative regimen will consist of * Thymoglobulin: 2.5 mg /kg/day intravenously (IV) on Days -8 through -5 * Fludarabine: 35 mg/m2/day IV on Days -8 through -4 * Melphalan: 140 mg/m2 IV on Day -3 * Rest on Day -2 and -1 * Day 0 is the day of transplant * GVHD prophylaxis: sirolimus beginning on Day -1 for at least one year and mycophenolate mofetil (MMF) from Day -3 to +45 or to 7 days after neutrophil engraftment, whichever is later.

Also known as: Melphalan, Mycophenolate Mofetil, Sirolimus

Reduced-intensity conditioning regimen

Eligibility Criteria

• Age: 3 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• \. SCD patients who are 3-18 years old. 2. SCD (HbSS, HbSβ° thalassemia or any genotype) with at least one of the following conditions:
• Clinically significant neurologic event (stroke) or any neurologic defect lasting \> 24 hours and accompanied by an infarct on cerebral magnetic resonance imaging (MRI)
• Minimum of two episodes of acute chest syndrome within the preceding 2-year period defined as new pulmonary alveolar consolidation involving at least one complete lung segment (associated with acute symptoms including fever, chest pain, tachypnea, wheezing, rales or cough that is not attributed to asthma or bronchiolitis) despite adequate supportive care measures
• History of 3 or more severe pain events per year in the 2 years prior to enrollment.
• \. Availability of 10/10 genotypically HLA identical related donor 4. In patients who have been treated by regular RBC transfusions \>12 months, with a liver biopsy that shows no evidence of cirrhosis or active hepatitis 5. Patients must have a Karnofsky score ≥ 50 or WHO/ECOG ≥ 2 for patients age ≥ 16, Lansky score ≥ 50 for patients age \< 16.
• \. Adequate cardiac function: shortening fraction of \> 25% or ejection fraction of \> 55% by echocardiogram 7. Adequate renal function: serum creatinine within normal limits or creatinine clearance \>70 ml/min/1.73 m2 8. Adequate liver function: Total bilirubin within normal limits and AST/ALT \<2.5x upper limit of normal

You may not qualify if:

• \. Patients with symptomatic cardiac insufficiency or arrhythmia. 2. Patients with cirrhosis on liver biopsy. 3. Hepatitis B, hepatitis C, or HIV seropositive patients. 4. Patients with other disease that would increase toxicity of transplant.

Sponsors & Collaborators

• National Guard Health Affairs: lead

Study Sites (1)

King Abdul Aziz Medical City for National Guard

Riyadh, Saudi Arabia

RECRUITING

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

fludarabine phosphate; Melphalan; Mycophenolic Acid; Sirolimus

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Macrolides; Lactones

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2016
• First Posted: May 18, 2016
• Study Start: May 1, 2016
• Primary Completion: December 1, 2019
• Study Completion: December 1, 2019
• Last Updated: May 19, 2016

Record last verified: 2016-05

Locations

SA (1)