Stem Cell Transplant in Sickle Cell Disease and Thalassemia

• 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.

• 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 ]

• 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.

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.

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.

• Sickle Cell Disease
• Beta Thalassemia

• 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

• SCD group
  Sickle Cell Disease
  Interventions:

  • Drug: Busulfan
  • Drug: Fludarabine
  • Drug: Alemtuzumab
  • Procedure: Allogeneic stem cell transplant
• BT group
  Beta Thalassemia
  Interventions:

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

• 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.

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 or equal to 10 mg/dL
• Age < or equal to 21
• Matched sibling donor and asymptomatic

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

Additionally,

Patient must have adequate organ function as below:

• Adequate renal function defined as serum creatinine < or equal to 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 uncorrected DLCO≥35% by pulmonary function test; for children who are uncooperative, no evidence of dyspnea at rest

Exclusion Criteria

• Karnofsky/Lansky Performance Score <60%
• Demonstrated lack of compliance with medical care
• Pregnant or nursing
• Sickle Cell Disease: Grade III-IV* residual non-motor neurologic; Grade IV* Hematuria
• Thalassemia: Lucarelli Stage 3