Clinical trial NCT00408447: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Sickle Cell Disease
Beta Thalassemia
Keywords: stem cell transplant
sickle cell disease
thalassemia
moderately ablative
cord blood transplant
matched family donor
Lead sponsor: Columbia University
Sponsor class: OTHER
First posted: 2006-12-07
Enrollment: 53
Sex: ALL
Minimum age (years): 1
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: 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)
timeFrame: Day 30, Day 60, Day 100, Day 180, 1 year, 2 years, 3 years, 5 years, 10 years
Secondary outcomes:
measure: 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
timeFrame: days 60, 100, 180, 365, 730
measure: 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
timeFrame: as clinically appropriate
measure: 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
timeFrame: 6mos, 1 yr, 2 yr
measure: Quality of life (QOL) score
timeFrame: Day +180; year 1, 3, 5, 10
measure: Incidence of primary and secondary graft failure
timeFrame: Day +42, +60,
measure: Percent of mixed donor chimerism
timeFrame: Day +30, 60, 100, 180, 365, 730, and 1005
Other outcomes:
Locations:
city: New York
country: United States
facility: Morgan Stanley Children's Hospital, New York-Presbyterian, Columbia University
state: New York
Study officials:
affiliation: Columbia University
name: Monica Bhatia, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.