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

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00034528

Purpose

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.

Condition	Intervention	Phase
Hemoglobinopathies Anemia, Sickle Cell Hemoglobin SC Disease Thalassemia Thalassemia Major	Drug: Busulfex Drug: Fludarabine Drug: FK506 Drug: Prednisone	Phase II

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Allogeneic Stem Cell Transplantation Following Non-Myeloablative Chemotherapy in Patients With Hemoglobinopathies

Resource links provided by NLM:

Genetics Home Reference related topics: beta thalassemia sickle cell disease

MedlinePlus related topics: Anemia Sickle Cell Anemia Thalassemia

Drug Information available for: Prednisone Busulfan Fludarabine Fludarabine monophosphate Tacrolimus anhydrous Tacrolimus

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Evidence of engraftment of donor hematopoietic cells following administration of low doses of Busulfex and fludarabine [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Solid organ toxicity related to the conditioning regimen [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Incidence of grade II, III, or IV acute graft versus host disease (GVHD) [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Level of disease response [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Enrollment:	20
Study Start Date:	January 2005
Primary Completion Date:	December 2005 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 Participants will receive a non-myeloablative conditioning regimen of fludarabine and Busulfex prior to allogeneic peripheral blood stem cell infusions. FK506 and prednisone will be administered for graft versus host disease prophylaxis.	Drug: Busulfex 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. Drug: Fludarabine 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. Drug: FK506 0.15 mg/kg taken orally daily for 12 to 14 weeks Other Name: Tacromilus Drug: Prednisone 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.

Arms

Assigned Interventions

Experimental: 1

Participants will receive a non-myeloablative conditioning regimen of fludarabine and Busulfex prior to allogeneic peripheral blood stem cell infusions. FK506 and prednisone will be administered for graft versus host disease prophylaxis.

Drug: Busulfex

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.

Drug: Fludarabine

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.

Drug: FK506

0.15 mg/kg taken orally daily for 12 to 14 weeks

Other Name: Tacromilus

Drug: Prednisone

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.

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 non-myeloablative regimen of fludarabine and Busulfex 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 non-myeloablative conditioning regimen of fludarabine and Busulfex will be administered to patients prior to allogeneic peripheral blood stem cell infusions. FK506 and prednisone will be administered for graft versus host disease prophylaxis. Patients will be evaluated for engraftment, donor:host hematopoietic chimerism, toxicity, and hemoglobinopathy.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

All patients must:
- Have related donors who are identical at 6 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 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 HIV

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00034528

Locations

United States, Massachusetts
Dana-Farber Cancer Institute/Harvard Cancer Center, Brigham and Women's Hospital and Massachusetts General Hospital
Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Principal Investigator:

Catherine J. Wu, MD

Dana Farber Cancer Institute/Harvard Medical School

More Information

Publications:

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.

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.

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. No abstract available.

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.

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.

Responsible Party:	Associate Director, Clinical Research Program, DAIT/NIAID
ClinicalTrials.gov Identifier:	NCT00034528 History of Changes
Other Study ID Numbers:	DAIT DF/HCC 01-098, P01 A 129530
Study First Received:	April 30, 2002
Last Updated:	September 26, 2008
Health Authority:	United States: Federal Government

Additional relevant MeSH terms:

Anemia
Beta-Thalassemia
Anemia, Sickle Cell
Hemoglobin SC Disease
Hemoglobinopathies
Thalassemia
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Genetic Diseases, Inborn
Busulfan
Fludarabine monophosphate
Tacrolimus
Fludarabine
Prednisone

Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Anti-Inflammatory Agents

ClinicalTrials.gov processed this record on February 09, 2012