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

• ClinicalTrials.gov Identifier: NCT00034528
• Recruitment Status: Terminated
• First Posted: May 1, 2002
• Last Update Posted: May 1, 2013
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease	Intervention/treatment	Phase
Hemoglobinopathies; Anemia, Sickle Cell; Hemoglobin SC Disease; Thalassemia; Thalassemia Major	Drug: Busulfan; Drug: Fludarabine; Drug: FK506; Drug: Prednisone	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Allogeneic Stem Cell Transplantation Following Nonmyeloablative Chemotherapy in Patients With Hemoglobinopathies
• Study Start Date: September 2001
• Actual Primary Completion Date: November 2003
• Actual Study Completion Date: November 2003

Arms and Interventions

Arm

Intervention/treatment

Experimental: Allogeneic stem cell transplantation; 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.

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.; Other Name: Busulfex; 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.; Other Names: Fludara; Oforta; Drug: FK506; 0.15 mg/kg taken orally daily for 12 to 14 weeks; Other Names: Prograf; 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.

Outcome Measures

Primary Outcome Measures :

1. Evidence of engraftment of donor hematopoietic cells following administration of low doses of busulfan and fludarabine [ Time Frame: Throughout study ]

Secondary Outcome Measures :

1. Solid organ toxicity related to the conditioning regimen [ Time Frame: Throughout study ]
2. Incidence of grade II, III, or IV acute graft versus host disease (GVHD) [ Time Frame: Throughout study ]
3. Level of disease response [ Time Frame: Throughout study ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

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

More Information

Publications of Results:

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.

Other 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. doi: 10.1038/sj.bmt.1702100.

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.

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.

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.

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00034528
• Other Study ID Numbers: DAIT DF/HCC 01-098; P01 A 129530
• First Posted: May 1, 2002
• Last Update Posted: May 1, 2013
• Last Verified: April 2013

Additional relevant MeSH terms:

Thalassemia; beta-Thalassemia; Hemoglobinopathies; Anemia, Sickle Cell; Hemoglobin SC Disease; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Genetic Diseases, Inborn; Prednisone; Fludarabine; Busulfan; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Alkylating Agents; Antineoplastic Agents, Alkylating; Myeloablative Agonists