Sickle Cell Disease Conditioning for Bone Marrow Transplant

NCT00968162 | Completed Phase 1 DMC

• 2 other identifiers: IRB00011048BMT for SCD
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 10

Brief Summary

Most bone marrow transplants for children with sickle cell disease are performed using high doses of two chemotherapy agents: busulfan and cyclophosphamide for the pre-transplant conditioning. This approach produces cure in most cases (approximately 95%). It, however, has serious side effects, including seizures and infertility. The primary goal of this study is to determine how much we can lower the dosages of busulfan and cyclophosphamide by incorporating fludarabine, a safer chemotherapy agent, into conditioning. The secondary goal is to develop a better understanding of how bone marrow transplants cause neurologic problems like seizures.

Conditions

Bone Marrow Transplantation; Sickle Cell Disease

Keywords

Bone Marrow Transplant; Sickle Cell Disease

Outcome Measures

Primary Outcomes (1)

• Modify the standard dose of busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen by adding fludarabine in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg.

  1 year after last patient enrolled

Secondary Outcomes (1)

• To gain insight into the processes that give rise to neurologic problems following bone marrow transplantation and to develop surrogate outcomes.

  1 year after last patient enrolled

Study Arms (1)

Dose de-escalation

EXPERIMENTAL

Drug: fludarabine

Interventions

fludarabine DRUG

Conduct a pilot trial using a transplant protocol, in which the standard busulfan, cyclophosphamide and anti-thymocyte globulin conditioning regimen is modified by adding fludarabine, a highly immunosuppressive agent, in order to determine the feasibility of reducing the total dose of cyclophosphamide from its present standard of 200 mg/kg to 90 mg/kg and of busulfan from its present standard of 12.8 mg/kg (IV) to 6.4 mg/kg, using a four step dose de-escalation schema.

Dose de-escalation

Eligibility Criteria

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

You may qualify if:

• Up to and including the age of 18 years at time of admission for transplant
• Hemoglobin SS, or hemoglobin S0 thalassemia
• HLA-identical sibling donor (any age) available without HgbSS, SC or S0 thalassemia. As an alternative, HLA identical sibling umbilical cord blood can be used as long as the unit has a pre-cryopreservation TNC dose of greater than 5.0 x 107 TNC/kg recipient weight.
• Clinically severe SCD, defined by one of the following:
• Previous clinical stroke, as evidenced by a neurological deficit lasting longer than 24 hours, which is accompanied by radiographic evidence of ischemic brain injury and cerebral vasculopathy.
• Asymptomatic cerebrovascular disease, as evidenced by one the following:
• (i)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 scan) or the enlargement of a single lesion, initially measuring at least 3 mm). Lesions must be visible on T2-weighted MRI sequences.
• (ii) Cerebral arteriopathy, as evidenced by abnormal TCD testing (confirmed elevated velocities in any single vessel of TAMMV \> 200 cm/sec for non-imaging TCD or TAMX \> 185 cm/sec for imaging TCD) or by significant vasculopathy on MRA (greater than 50% stenosis of \> 2 arterial segments or complete occlusion of any single arterial segment).
• (c) Frequent (≥ 3 per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting ≥ 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 this drug.
• (d) Recurrent (≥ 3 in lifetime) acute chest syndrome events that have necessitated erythrocyte transfusion therapy.
• (e) Any combination of ≥ 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 this drug.
• Must have been evaluated and adequately counseled regarding treatment options for severe sickle cell disease by a pediatric hematologist.

You may not qualify if:

• Biopsy proven chronic active hepatitis, portal fibrosis (greater than score I), or cirrhosis, or serologic evidence of active hepatitis.
• SCD chronic lung disease stage III (see appendix 1).
• Severe renal dysfunction defined as \< 50% of predicted normal GFR for age.
• Severe cardiac dysfunction defined as shortening fraction \< 25%.
• Severe residual neurologic impairment other than hemiplegia alone, defined as full-scale IQ 70, quadriplegia or paraplegia, inability to ambulate, inability to communicate without assistive device, or any impairment resulting in decline of Lansky performance score to \< 70%.
• CNS event occurring within 6 months prior to transplant.
• Karnofsky or Lansky functional performance score \< 70%.
• Confirmed HIV seropositivity.
• Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate bone marrow transplantation.
• Patient or patient's guardian(s) unable to understand the nature and risks inherent in the BMT process.
• History of lack of compliance 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.
• Donor is HIV infected.
• Donor is pregnant.

Sponsors & Collaborators

• Emory University: lead

Study Sites (10)

University of Alabama-Birmingham

Birmingham, Alabama, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, United States

Location

All Children's Research Institute Inc.

St. Petersburg, Florida, 33701, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Tulane University

New Orleans, Louisiana, 70112, United States

Location

Wayne State University

Detroit, Michigan, 48202, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, United States

Location

Montefiore Medical Center

The Bronx, New York, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27516, United States

Location

University of Texas Southwestern

Dallas, Texas, United States

Location

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

fludarabine

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

Study Officials

• John Horan, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 11, 2009
• First Posted: August 28, 2009
• Study Start: February 1, 2009
• Primary Completion: March 1, 2014
• Study Completion: January 11, 2016
• Last Updated: July 25, 2017

Record last verified: 2017-07

Locations

US (10)