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

Thalassemia Clinical Trial

Official title:

Allogeneic Stem Cell Transplantation Following Nonmyeloablative Chemotherapy in Patients With Hemoglobinopathies

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00034528
• Other study ID #: DAIT DF/HCC 01-098
• Secondary ID: P01 A 129530
• Status: Terminated
• Phase: Phase 2
• First received: April 30, 2002
• Last updated: April 30, 2013
• Start date: September 2001
• Est. completion date: November 2003

Study information

• Verified date: April 2013
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: November 2003
• Est. primary completion date: November 2003
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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)

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Beta-Thalassemia
• Hemoglobin SC Disease
• Hemoglobinopathies
• Thalassemia
• Thalassemia Major

Intervention

Drug:
• Busulfan
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.
• 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.
• FK506
0.15 mg/kg taken orally daily for 12 to 14 weeks
• 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.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

References & Publications (7)

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. — View Citation

Gómez-Almaguer D, Ruiz-Argüelles GJ, Ruiz-Argüelles A, González-Llano O, Cantú OE, Hernández 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. — View 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. — View 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. — View 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. — View 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. — View 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. Epub 2005 Aug 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evidence of engraftment of donor hematopoietic cells following administration of low doses of busulfan and fludarabine		Throughout study	No
Secondary	Solid organ toxicity related to the conditioning regimen		Throughout study	No
Secondary	Incidence of grade II, III, or IV acute graft versus host disease (GVHD)		Throughout study	Yes
Secondary	Level of disease response		Throughout study	No