Stem Cell Transplant in Sickle Cell Disease and Thalassemia - Full Text View

Sponsored by:	Columbia University
Information provided by:	Columbia University
ClinicalTrials.gov Identifier:	NCT00408447

Purpose

Sickle cell disease is a genetic disorder in which a mutation in the beta chain of human hemoglobin results in abnormal blood hemoglobin, causing red blood cells to sickle under stress with resulting symptoms including severe pains and strokes. Beta thalassemia is another genetic disorder in which there are abnormal beta hemoglobin chains, causing anemia. In both disorders, frequent red blood cell transfusions may be required to sustain life, but these often result in complications including multiple hospitalizations, iron overload, or bacterial or viral infections such as hepatitis. Standard drugs and therapies used in the treatment of sickle cell disease and/or beta thalassemia provide only supportive care, and may result in long-term side effects, and inadequate control of the disease process. Bone marrow transplant has been increasingly used for the long-term treatment and cure of sickle cell disease and beta thalassemia. Although, not without acute and potential long term side effects, this alternative offers long term control and potential cure of the disease. Most of the side effects seen with bone marrow transplant are directly related to the high intensity of chemotherapy used (ablative).

The primary purpose of this study is to see if giving lower doses of chemotherapy (moderately ablative) will result in successful bone marrow replacement without as severe side-effects but with permanent control of the disease. Patients will receive a chemotherapy regimen with busulfan, fludarabine, and alemtuzumab followed by an infusion of stem cells, either from a family-related or cord-blood matched donor.

Condition	Intervention	Phase
Sickle Cell Disease Beta Thalassemia	Drug: Busulfan Drug: Fludarabine Drug: Alemtuzumab Procedure: Allogeneic stem cell transplant	Phase II

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Parallel Assignment, Safety/Efficacy Study
Official Title:	Allogeneic Stem Cell Transplant to Induce Mixed Donor Chimerism in Patients With Sickle Cell Disease and Thalassemia

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: Busulfan Fludarabine Fludarabine monophosphate Campath Alemtuzumab

U.S. FDA Resources

Further study details as provided by Columbia University:

Primary Outcome Measures:

To determine the toxicity associated with moderately ablative therapy (busulfan/fludarabine/alemtuzumab) and allogeneic stem cell transplantation in selected patients with sickle cell disease and Beta thalassemia [ Time Frame: day 1-100: weekly, day 101-365 clinic visit, day +180, day +365 ] [ Designated as safety issue: Yes ]
to determine the incidence of primary and secondary graft failure after moderately ablative therapy and allogeneic stem cell transplantation in selected patient with SCD and BT [ Time Frame: days +14, 30, 60, 100, 180, 365 ] [ Designated as safety issue: No ]
to determine the percent of mixed donor chimerism following moderately ablative therapy and allogeneic stem cell transplantation in selected patients with SCD and BT. Stable Mixed Chimerism (SMC) is defined as > 50% donor chimerism by day 180. [ Time Frame: days +14, 30, 60, 100, 180, 365, 2yrs ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To determine the time to donor hematological reconstitution (neutrophil, RBC and platelet recovery) following moderately ablative therapy and allogeneic stem cell transplantation in selected patients with SCD and BT [ Time Frame: days 30, 60, 100, 180, 365 ] [ Designated as safety issue: No ]
to estimate the incidence of acute and chronic graft versus host disease (GVHD) following moderately ablative therapy and allogeneic stem cell transplantation in selected patients with SCD and BT [ Time Frame: as clinically appropriate ] [ Designated as safety issue: No ]
to determine the percent of patients who have either a complete, very good partial, partial or no response (clinical/laboratory) following moderately ablative therapy and allogeneic stem cell transplantation in selected patients with SCD and BT [ Time Frame: 6mos, 1 yr, 2 yr ] [ Designated as safety issue: No ]
to determine the impact of moderately ablative stem cell transplant on quality of life (QOL) and on neurocognitive functioning of patients with SCD and BT over time. [ Time Frame: Day +180; year 1, 3, 5, 10 ] [ Designated as safety issue: No ]

Estimated Enrollment:	60
Study Start Date:	December 2001
Estimated Study Completion Date:	January 2012
Estimated Primary Completion Date:	January 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1 Sickle Cell Disease	Drug: Busulfan Busulfan 4 mg/kg/d x 4d Drug: Fludarabine Fludarabine 30 mg/m2/d x 6d Drug: Alemtuzumab Alemtuzumab 2mg/m2 x 1d, 6mg/m2 x 2 d, 20mg/m2 x 2d Procedure: Allogeneic stem cell transplant Allogeneic stem cells will be given on day 0 (after chemotherapy conditioning)obtained either from a family donor (first degree relative), sibling cord blood donor or cryopreserved unrelated cord blood unit.
2 Beta Thalassemia	Drug: Busulfan Busulfan 4 mg/kg/d x 4d Drug: Fludarabine Fludarabine 30 mg/m2/d x 6d Drug: Alemtuzumab Alemtuzumab 2mg/m2 x 1d, 6mg/m2 x 2 d, 20mg/m2 x 2d Procedure: Allogeneic stem cell transplant Allogeneic stem cells will be given on day 0 (after chemotherapy conditioning)obtained either from a family donor (first degree relative), sibling cord blood donor or cryopreserved unrelated cord blood unit.

Arms

Assigned Interventions

1

Sickle Cell Disease

Drug: Busulfan

Busulfan 4 mg/kg/d x 4d

Drug: Fludarabine

Fludarabine 30 mg/m2/d x 6d

Drug: Alemtuzumab

Alemtuzumab 2mg/m2 x 1d, 6mg/m2 x 2 d, 20mg/m2 x 2d

Procedure: Allogeneic stem cell transplant

Allogeneic stem cells will be given on day 0 (after chemotherapy conditioning)obtained either from a family donor (first degree relative), sibling cord blood donor or cryopreserved unrelated cord blood unit.

2

Beta Thalassemia

Drug: Busulfan

Busulfan 4 mg/kg/d x 4d

Drug: Fludarabine

Fludarabine 30 mg/m2/d x 6d

Drug: Alemtuzumab

Alemtuzumab 2mg/m2 x 1d, 6mg/m2 x 2 d, 20mg/m2 x 2d

Procedure: Allogeneic stem cell transplant

Allogeneic stem cells will be given on day 0 (after chemotherapy conditioning)obtained either from a family donor (first degree relative), sibling cord blood donor or cryopreserved unrelated cord blood unit.

Detailed Description:

Further study details will be provided by Columbia University, Division of Pediatric Blood & Marrow Transplantation.

STUDY DESIGN:

Patients will receive busulfan, fludarabine and alemtuzumab prior to the stem cell transplant to help the stem cells take and grow. The stem cells will be infused on day 0 through an intravenous catheter. Patients will receive immunosuppressive therapy such as tacrolimus and MMF to prevent graft-versus-disease.

Patients will be followed up after transplant to look for special cells in the blood that show that the new bone marrow is taking hold (engrafting). Response shall be documented at 6 months, 1 year, 2 years and 3 years post-SCT.

Eligibility

Ages Eligible for Study:	1 Month to 21 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Sickle Cell Disease:

Diagnosis of Homozygous Hemoglobin S Disease or Heterozygous Hemoglobin SC or SB/+ thalassemia, or Sickle/variant resulting in Chronic Hemolytic Anemia with HgB < 10 mg/dL
Age < or equal to 21
Highly symptomatic with a

MINIMUM OF ONE OF THE FOLLOWING CRITERIA:

Vaso-occlusive crisis: 2 or more episodes per year requiring oral or parenteral narcotic therapy
Priapism: one episode
Acute Chest Syndrome: one episode
Cerebrovascular accident: one episode
Splenic sequestration: one episode
Transient neurological event: greater than 24 hours
Transient ischemic attack (TIA): >2 in < 12 months, or > 3 TIAs total
Transcranial doppler: past and/or present abnormality
Sickle Nephropathy:
- Grade 1-4* proteinuria or hematuria (without other cause) OR
- Hyposthenuria with grade 2-4* urinary electrolyte wasting
Aplastic crisis: one episode requiring packed red blood cell transfusion
Red blood cell alloimmunization
Severe Anemia Hgb < 7 and Early Dactylitis (< 1 year of age)
Severe Anemia Hgb < 7 and WBC >20 x 109/L (without infection)
Early Dactylitis and WBC >20 x 109/L (without infection)
Retinopathy with grade 2-3* vision changes in 1 eye
Osteonecrosis: one episode
Septicemia: one or more episodes

Thalassemia Homozygous B-thalassemia Clinical syndrome of B-thalassemia intermedia (including double heterozygotes, e.g. Hgb E-Beta thalassemia) who either:

Require regular transfusions, or
Have evidence of severe ineffective erythropoiesis - marked marrow hyperplasia and the resultant cosmetic abnormalities and/or retardation of growth and development as a result of severe anemia.

and

Lucarelli Stage 1 or 2
Age < or equal to 21

Patient must have adequate organ function as below:

Adequate renal function defined as:

Serum creatinine <1.5 x normal, or
Creatinine clearance or radioisotope GFR =40 ml/min/m2 or >60 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range

Adequate liver function defined as:

SGOT (AST) or SGPT (ALT) < 5.0 x normal

Adequate cardiac function defined as:

Shortening fraction of >28% by echocardiogram, or
Ejection fraction of >48% by radionuclide angiogram or echocardiogram

Adequate pulmonary function defined as:

DLCO >35% by pulmonary function test
For children who are uncooperative, no evidence of dyspnea at rest

Exclusion Criteria:

General

Karnofsky/Lansky Performance Score < 60%
Demonstrated lack of compliance with medical care
Pregnant or nursing women

Sickle Cell Disease

Grade III-IV residual non-motor neurologic
Grade IV Hematuria

Thalassemia

Lucarelli Stage 3

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00408447

Contacts

Contact: Monica Bhatia, MD	212 305 9138	mb2476@columbia.edu
Contact: William A Kim, Ph.D.	212-305-7213	billkim@columbia.edu

Locations

United States, New York
Morgan Stanley Children's Hospital, New York-Presbyterian, Columbia University	Recruiting
New York, New York, United States, 10032
Contact: Monica Bhatia, MD 212-305-9138 mb2476@columbia.edu
Contact: William A Kim, Ph.D. 212-305-7213 billkim@columbia.edu
Principal Investigator: Monica Bhatia, MD
Sub-Investigator: Mitchell S. Cairo, MD

Sponsors and Collaborators

Columbia University

Investigators

Study Chair:

Mitchell S. Cairo, MD

Columbia University

More Information

Additional Information:

Click on "Morgan Stanley Children's Hospital" and then "Clinical Services" and then "Blood & Marrow Transplantation" This link exits the ClinicalTrials.gov site

This link exits the ClinicalTrials.gov site

Publications:

Satwani P, Harrison L, Morris E, Del Toro G, Cairo MS. Reduced-intensity allogeneic stem cell transplantation in adults and children with malignant and nonmalignant diseases: end of the beginning and future challenges. Biol Blood Marrow Transplant. 2005 Jun;11(6):403-22. Review.

Del Toro G, Satwani P, Harrison L, Cheung YK, Brigid Bradley M, George D, Yamashiro DJ, Garvin J, Skerrett D, Bessmertny O, Wolownik K, Wischhover C, van de Ven C, Cairo MS. A pilot study of reduced intensity conditioning and allogeneic stem cell transplantation from unrelated cord blood and matched family donors in children and adolescent recipients. Bone Marrow Transplant. 2004 Mar;33(6):613-22.

Responsible Party:	Columbia University ( Monica Bhatia, MD )
Study ID Numbers:	CHNY-01-503, IRB#AAAA7701
Study First Received:	December 6, 2006
Last Updated:	August 28, 2009
ClinicalTrials.gov Identifier:	NCT00408447 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by Columbia University:

stem cell transplant
sickle cell disease
thalassemia

moderately ablative
cord blood transplant
matched family donor

Study placed in the following topic categories:

Antimetabolites
Immunologic Factors
Hematologic Diseases
Beta-thalassemia
Anemia
Anemia, Hemolytic
Fludarabine monophosphate
Immunosuppressive Agents
Thalassemia
Anemia, Hemolytic, Congenital
Thalassemia Minor

Genetic Diseases, Inborn
Busulfan
Alemtuzumab
Beta-Thalassemia
Hemoglobinopathies
Sickle Cell Anemia
Antineoplastic Agents, Alkylating
Fludarabine
Hemoglobinopathy
Alkylating Agents
Anemia, Sickle Cell

Additional relevant MeSH terms:

Antimetabolites
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Alemtuzumab
Therapeutic Uses
Anemia, Sickle Cell
Alkylating Agents
Hematologic Diseases
Anemia
Anemia, Hemolytic

Fludarabine monophosphate
Thalassemia
Immunosuppressive Agents
Pharmacologic Actions
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Busulfan
Hemoglobinopathies
Beta-Thalassemia
Myeloablative Agonists
Fludarabine
Antineoplastic Agents, Alkylating

ClinicalTrials.gov processed this record on September 01, 2009