Stem Cell Transplant in Sickle Cell Disease and Thalassemia

• ClinicalTrials.gov Identifier: NCT00408447
• Recruitment Status: Active, not recruiting
• First Posted: December 7, 2006
• Last Update Posted: March 22, 2023
• Sponsor: Columbia University
• Information provided by (Responsible Party): Columbia University

Tracking Information

• First Submitted Date: December 6, 2006
• First Posted Date: December 7, 2006
• Last Update Posted Date: March 22, 2023
• Actual Study Start Date: September 2004
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 12, 2019)

Prevalence of toxicity associated with moderately ablative therapy (busulfan/fludarabine/alemtuzumab) and allogeneic stem cell transplantation in selected patients with Sickle Cell Disease (SCD) and Beta Thalassemia (BT) [ Time Frame: Day 30, Day 60, Day 100, Day 180, 1 year, 2 years, 3 years, 5 years, 10 years ]

To examine if giving lower doses of chemotherapy will result in less severe side-effects but with permanent control of the disease.

Original Primary Outcome Measures (submitted: December 6, 2006)

• 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
• 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
• 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.

Current Secondary Outcome Measures (submitted: March 12, 2019)

• Time to donor hematological reconstitution (neutrophil, red blood cell and platelet recovery) following moderately ablative therapy and allogeneic stem cell transplantation in selected patients with SCD and BT [ Time Frame: days 60, 100, 180, 365, 730 ]
  To examine if giving lower doses of chemotherapy and bone marrow replacement can result in control of the disease.
• 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 ]
  To examine if giving lower doses of chemotherapy will result in successful bone marrow replacement.
• 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 ]
  To examine if giving lower doses of chemotherapy with bone marrow replacement will result in good control of the disease.
• Quality of life (QOL) score [ Time Frame: Day +180; year 1, 3, 5, 10 ]
  To determine the impact of moderately ablative stem cell transplant on quality of life and neurocognitive functioning with SCD over time
• Incidence of primary and secondary graft failure [ Time Frame: Day +42, +60, ]
  To collect data on graft failure
• Percent of mixed donor chimerism [ Time Frame: Day +30, 60, 100, 180, 365, 730, and 1005 ]
  To collect data on donor chimerism

Original Secondary Outcome Measures (submitted: December 6, 2006)

• 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
• 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
• 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
• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Stem Cell Transplant in Sickle Cell Disease and Thalassemia
• Official Title: Allogeneic Stem Cell Transplant to Induce Mixed Donor Chimerism in Patients With Sickle Cell Disease and Thalassemia
• Brief Summary: 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.
• Detailed Description: 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).
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Sickle Cell Disease
• Beta Thalassemia

Intervention

• Drug: Busulfan
  Busulfan 4 mg/kg/d x 4d
  Other Name: Busulfex
• Drug: Fludarabine
  Fludarabine 30 mg/m2/d x 6d
  Other Name: Fludara
• Drug: Alemtuzumab
  Alemtuzumab 2mg/m2 x 1d, 6mg/m2 x 2 d, 20mg/m2 x 2d
  Other Name: Campath
• 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) or sibling cord blood donor.
  Other Names:

  • Related Bone Marrow
  • Related Cord Blood

Study Arms

• SCD group
  Sickle Cell Disease patients receiving chemotherapy (Busulfan, Fludarabine and Alemtuzumab) will undergo allogeneic stem cell transplant.
  Interventions:

  • Drug: Busulfan
  • Drug: Fludarabine
  • Drug: Alemtuzumab
  • Procedure: Allogeneic stem cell transplant
• BT group
  Beta Thalassemia patients receiving chemotherapy (Busulfan, Fludarabine and Alemtuzumab) will undergo allogeneic stem cell transplant.
  Interventions:

  • Drug: Busulfan
  • Drug: Fludarabine
  • Drug: Alemtuzumab
  • Procedure: Allogeneic stem cell transplant

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. doi: 10.1016/j.bbmt.2005.04.002.
• 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. doi: 10.1038/sj.bmt.1704399.
• Bhatia M, Jin Z, Baker C, Geyer MB, Radhakrishnan K, Morris E, Satwani P, George D, Garvin J, Del Toro G, Zuckerman W, Lee MT, Licursi M, Hawks R, Smilow E, Baxter-Lowe LA, Schwartz J, Cairo MS. Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease. Bone Marrow Transplant. 2014 Jul;49(7):913-20. doi: 10.1038/bmt.2014.84. Epub 2014 May 5.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 7, 2020): 53
• Original Enrollment (submitted: December 6, 2006): 60
• Estimated Study Completion Date: December 2023
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Sickle Cell Disease:

• Diagnosis of Homozygous Hemoglobin S Disease or Heterozygous Hemoglobin Sickle Cell (SC) or S 0/+ thalassemia, or Sickle/variant resulting in Chronic Hemolytic Anemia with hemoglobin (HgB) ≤10 mg/dL
• Age ≤30
• Matched sibling donor and asymptomatic, or 8/8 human leukocyte antigen (HLA) matched unrelated adult donor

Patient must have adequate organ function as below:

• Adequate renal function defined as serum creatinine ≤1.5 x normal, or Creatinine clearance or radioisotope glomerular filtration rate (GFR) >100 ml/min/1.73 m2 or >70ml/min/1.73m2 for patients >16 years old
• Adequate liver function defined as serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase (AST)) or serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase (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 corrected Diffusing capacity of the lungs for carbon monoxide (DLCO) ≥40% by pulmonary function test, or for children who are unable to perform DLCO maneuver ≥85% O2 saturation, no evidence of dyspnea at rest

Exclusion criteria:

General

• Karnofsky/Lansky Performance Score <60%
• Demonstrated lack of compliance with medical care
• Pregnant or nursing
• Evidence of uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms) within 1 month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen.

Histologic Exam of Liver (liver biopsy) with bridging fibrosis or cirrhosis.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Month to 30 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00408447
• Other Study ID Numbers: AAAA7701; CHNY-01-503 ( Other Identifier: CU )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Columbia University
• Original Responsible Party: Not Provided
• Current Study Sponsor: Columbia University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Monica Bhatia, MD; Columbia University

• PRS Account: Columbia University
• Verification Date: March 2023