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Stem Cell Transplantation After Reduced-Dose Chemotherapy for Patients With Sickle Cell Disease or Thalassemia

Primary Purpose

Hemoglobinopathies, Anemia, Sickle Cell, Hemoglobin SC Disease

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Busulfan
Fludarabine
FK506
Prednisone
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemoglobinopathies

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria: All patients must: Have related donors who are identical at 6 human leukocyte antigens (HLA) loci (A, B and DR) by molecular typing Have a performance status from 0-2 Give written informed consent Patients with sickle cell disease should have 1 or more of the following: Acute chest syndrome requiring recurrent hospitalization or exchange transfusion Nonhemorrhagic stroke or central nervous system event lasting longer than 24 hours Recurrent vaso-occlusive pain (2 episodes or more per year) or recurrent priapism Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50 percent of normal predicted value) Bilateral proliferative retinopathy and major visual impairment in at least 1 eye Osteonecrosis of multiple joints Patients with thalassemia should have 1 or more of the following: Transfusion dependence, defined as a transfusion requirement of greater than or equal to 6 units of packed red blood cells over the past 12 months Iron overload, defined as serum ferritin greater than 500 mcg/L in the absence of infection or biopsy-proven iron overload Presence of 2 or more alloantibodies against red cell antigens Exclusion criteria: Pregnancy Acute hepatitis (transaminases greater than 3 times the normal value) Cardiac ejection fraction less than 30 percent Severe renal impairment (glomerular filtration rate less than 30 percent of predicted normal value) Severe residual functional neurologic impairment (other than hemiplegia alone) Seropositivity for the human immunodeficiency virus (HIV)

Sites / Locations

  • Dana-Farber Cancer Institute/Harvard Cancer Center, Brigham and Women's Hospital and Massachusetts General Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Allogeneic stem cell transplantation

Arm Description

Participants will receive a nonmyeloablative conditioning regimen of fludarabine and busulfan prior to allogeneic peripheral blood stem cell (CD34+) infusions. FK506 and prednisone will be administered for graft versus host disease (GVHD) prophylaxis.

Outcomes

Primary Outcome Measures

Evidence of engraftment of donor hematopoietic cells following administration of low doses of busulfan and fludarabine

Secondary Outcome Measures

Solid organ toxicity related to the conditioning regimen
Incidence of grade II, III, or IV acute graft versus host disease (GVHD)
Level of disease response

Full Information

First Posted
April 30, 2002
Last Updated
April 30, 2013
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00034528
Brief Title
Stem Cell Transplantation After Reduced-Dose Chemotherapy for Patients With Sickle Cell Disease or Thalassemia
Official Title
Allogeneic Stem Cell Transplantation Following Nonmyeloablative Chemotherapy in Patients With Hemoglobinopathies
Study Type
Interventional

2. Study Status

Record Verification Date
April 2013
Overall Recruitment Status
Terminated
Why Stopped
Due to slow recruitment
Study Start Date
September 2001 (undefined)
Primary Completion Date
November 2003 (Actual)
Study Completion Date
November 2003 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
The purpose of this study is to find out if using a lower dose of chemotherapy before stem cell transplantation can cure patients of sickle cell anemia or thalassemia while causing fewer severe side effects than conventional high dose chemotherapy with transplantation.
Detailed Description
Hemoglobinopathies, such as sickle cell disease and thalassemia major, are genetic diseases associated with significant morbidity and premature death. Allogeneic bone marrow transplantation (BMT) is the only potential cure for severe hemoglobinopathies. Typical regimens have used high doses of chemotherapy or chemo-radiotherapy to ablate recipient hematopoiesis and to prevent graft rejection. The widespread use of this treatment has been limited by toxicity, risk of end-organ damage, and donor availability. This study will use a nonmyeloablative regimen of fludarabine and busulfan to attempt to generate consistent engraftment with donor hematopoietic stem cells in patients with severe hemoglobinopathy. G-CSF mobilization of the donor's peripheral blood white blood cells will precede donor apheresis. A nonmyeloablative conditioning regimen of fludarabine and busulfan will be administered to patients prior to allogeneic peripheral blood stem cell infusions. FK506 and prednisone will be administered for graft versus host disease (GVHD) prophylaxis. Patients will be evaluated for engraftment, donor: host hematopoietic chimerism, toxicity, and hemoglobinopathy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemoglobinopathies, Anemia, Sickle Cell, Hemoglobin SC Disease, Thalassemia, Thalassemia Major

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Allogeneic stem cell transplantation
Arm Type
Experimental
Arm Description
Participants will receive a nonmyeloablative conditioning regimen of fludarabine and busulfan prior to allogeneic peripheral blood stem cell (CD34+) infusions. FK506 and prednisone will be administered for graft versus host disease (GVHD) prophylaxis.
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
Busulfex
Intervention Description
0.8 mg/kg/d administered as a single intravenous infusion over 3 hours for 4 days. All infusions are anticipated to be given in the outpatient clinic.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara, Oforta
Intervention Description
30 mg/m^2/d administered as a bolus infusion over 30 minutes for 4 days. All infusions are anticipated to be given in the outpatient clinic.
Intervention Type
Drug
Intervention Name(s)
FK506
Other Intervention Name(s)
Prograf, Tacromilus
Intervention Description
0.15 mg/kg taken orally daily for 12 to 14 weeks
Intervention Type
Drug
Intervention Name(s)
Prednisone
Intervention Description
0.5 mg/kg taken orally four times daily on Day 7 and increase to 1 mg/kg taken orally four times daily on Day 14. Participants will continue regimen until Day 30 before a 20-25% taper per week.
Primary Outcome Measure Information:
Title
Evidence of engraftment of donor hematopoietic cells following administration of low doses of busulfan and fludarabine
Time Frame
Throughout study
Secondary Outcome Measure Information:
Title
Solid organ toxicity related to the conditioning regimen
Time Frame
Throughout study
Title
Incidence of grade II, III, or IV acute graft versus host disease (GVHD)
Time Frame
Throughout study
Title
Level of disease response
Time Frame
Throughout study

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: All patients must: Have related donors who are identical at 6 human leukocyte antigens (HLA) loci (A, B and DR) by molecular typing Have a performance status from 0-2 Give written informed consent Patients with sickle cell disease should have 1 or more of the following: Acute chest syndrome requiring recurrent hospitalization or exchange transfusion Nonhemorrhagic stroke or central nervous system event lasting longer than 24 hours Recurrent vaso-occlusive pain (2 episodes or more per year) or recurrent priapism Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50 percent of normal predicted value) Bilateral proliferative retinopathy and major visual impairment in at least 1 eye Osteonecrosis of multiple joints Patients with thalassemia should have 1 or more of the following: Transfusion dependence, defined as a transfusion requirement of greater than or equal to 6 units of packed red blood cells over the past 12 months Iron overload, defined as serum ferritin greater than 500 mcg/L in the absence of infection or biopsy-proven iron overload Presence of 2 or more alloantibodies against red cell antigens Exclusion criteria: Pregnancy Acute hepatitis (transaminases greater than 3 times the normal value) Cardiac ejection fraction less than 30 percent Severe renal impairment (glomerular filtration rate less than 30 percent of predicted normal value) Severe residual functional neurologic impairment (other than hemiplegia alone) Seropositivity for the human immunodeficiency virus (HIV)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Catherine J. Wu, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dana-Farber Cancer Institute/Harvard Cancer Center, Brigham and Women's Hospital and Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
10706855
Citation
Walters MC, Storb R, Patience M, Leisenring W, Taylor T, Sanders JE, Buchanan GE, Rogers ZR, Dinndorf P, Davies SC, Roberts IA, Dickerhoff R, Yeager AM, Hsu L, Kurtzberg J, Ohene-Frempong K, Bunin N, Bernaudin F, Wong WY, Scott JP, Margolis D, Vichinsky E, Wall DA, Wayne AS, Pegelow C, Redding-Lallinger R, Wiley J, Klemperer M, Mentzer WC, Smith FO, Sullivan KM. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood. 2000 Mar 15;95(6):1918-24.
Results Reference
background
PubMed Identifier
10673669
Citation
Gomez-Almaguer D, Ruiz-Arguelles GJ, Ruiz-Arguelles A, Gonzalez-Llano O, Cantu OE, Hernandez NE. Hematopoietic stem cell allografts using a non-myeloablative conditioning regimen can be safely performed on an outpatient basis: report of four cases. Bone Marrow Transplant. 2000 Jan;25(2):131-3. doi: 10.1038/sj.bmt.1702100.
Results Reference
background
PubMed Identifier
11187121
Citation
Krishnamurti L, Blazar BR, Wagner JE. Bone marrow transplantation without myeloablation for sickle cell disease. N Engl J Med. 2001 Jan 4;344(1):68. doi: 10.1056/NEJM200101043440119. No abstract available.
Results Reference
background
PubMed Identifier
11071260
Citation
Andersson BS, Madden T, Tran HT, Hu WW, Blume KG, Chow DS, Champlin RE, Vaughan WP. Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant. 2000;6(5A):548-54. doi: 10.1016/s1083-8791(00)70064-4.
Results Reference
background
PubMed Identifier
16091448
Citation
Wu CJ, Krishnamurti L, Kutok JL, Biernacki M, Rogers S, Zhang W, Antin JH, Ritz J. Evidence for ineffective erythropoiesis in severe sickle cell disease. Blood. 2005 Nov 15;106(10):3639-45. doi: 10.1182/blood-2005-04-1376. Epub 2005 Aug 9.
Results Reference
background
PubMed Identifier
17910640
Citation
Wu CJ, Gladwin M, Tisdale J, Hsieh M, Law T, Biernacki M, Rogers S, Wang X, Walters M, Zahrieh D, Antin JH, Ritz J, Krishnamurti L. Mixed haematopoietic chimerism for sickle cell disease prevents intravascular haemolysis. Br J Haematol. 2007 Nov;139(3):504-7. doi: 10.1111/j.1365-2141.2007.06803.x. No abstract available.
Results Reference
background
PubMed Identifier
14550808
Citation
Wu CJ, Hochberg EP, Rogers SA, Kutok JL, Biernacki M, Nascimento AF, Marks P, Bridges K, Ritz J. Molecular assessment of erythroid lineage chimerism following nonmyeloablative allogeneic stem cell transplantation. Exp Hematol. 2003 Oct;31(10):924-33. doi: 10.1016/s0301-472x(03)00227-3.
Results Reference
result

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Stem Cell Transplantation After Reduced-Dose Chemotherapy for Patients With Sickle Cell Disease or Thalassemia

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