Improving the Results of Bone Marrow Transplantation for Patients With Severe Congenital Anemias

Phase 1

Active, not recruiting

Conditions: Congenital Hemolytic Anemia
Sickle Cell Disease

Interventions: Procedure: Peripheral blood hematopoietic progenitor cell (PBPC) transplant
Procedure: Peripheral blood hematopoietic progenitor cell Apheresis
Drug: Alemtuzumab
Drug: Sirolimus

Registration Number: NCT00061568

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Brief Summary: People with severe congenital anemias, such as sickle cell anemia and beta-thalassemia, have been cured with bone marrow transplantation (BMT). The procedure, however, is limited to children younger than the age of 16 because the risks are lower for children than for adults.

The purpose of this study is to explore the use of a BMT regimen that, instead of chemotherapy, uses a low dose of radiation, combined with two immunosuppressive drugs. This type BMT procedure is described as nonmyeloablative, meaning that it does not destroy the patient s bone marrow. It is hoped that this type of BMT will be safe for patients normally excluded from the procedure because of their age and other reasons.

To participate in this study, patients must be between the ages of 18 and 65 and have a sibling who is a well-matched stem-cell donor. Beyond the standard BMT protocol, study participants will undergo additional procedures. The donor will receive G-CSF by injection for five days; then his or her stem cells will be collected and frozen one month prior to BMT. Approximately one month later, the patient will be given two immune-suppressing drugs, Campath 1-H and Sirolimus, as well as a single low dose of total body irradiation and then the cells from the donor will be infused.

Prior to their participation in this study, patients will undergo the following evaluations: a physical exam, blood work, breathing tests, heart-function tests, chest and sinus x-rays, and bone-marrow sampling.

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Detailed Description: Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number of transplant centers. Preliminary data have shown a high rate of complete donor engraftment with a relatively low toxicity profile. The decreased risk of transplant-related complications associated with nonmyeloablative transplants expands eligibility to patients with nonmalignant hematological disorders curable by allogeneic transplantation; however, significant toxicity with current regimens persists including severe graft versus host disease (GVHD) leading to significant morbidity and mortality. Moreover, mixed chimerism has been shown to be sufficient to induce clinical remissions in children with nonmalignant hematologic disorders undergoing conventional allogeneic transplantation. Therefore, newer regimens need to be developed that are more applicable to patients with non-malignant disorders in whom no graft vs. leukemia effect is needed, and where mixed chimerism is sufficient for disease amelioration.

In this protocol, we propose transplantation in patients with severe beta-globin disorders including sickle cell disease (SCD), and beta-thalassemia, considered at high risk for complications from or ineligible for standard BMT, with allogeneic PBSCs from an HLA identical sibling using a novel immunosuppressive regimen without myeloablation in an attempt to further decrease the transplant related morbidity/mortality. The low intensity nonmyeloablative conditioning regimen will consist of low dose radiation, Alemtuzumab (Campath) and Sirolimus (Rapamune) as a strategy to provide adequate immunosuppression to allow sufficient engraftment for clinical remission with a lower risk of GVHD development. T-cell replete, donor-derived, granulocyte colony stimulating factor (filgrastim, G-CSF) mobilized PBSCs will be used to establish hematopoietic and lymphoid reconstitution.

The primary endpoint of this study is treatment success at one year, defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with SCD and transfusion-independence for patients with beta-thalassemia. Other end points include degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic graft-vs-host disease (GVHD), incidence of graft rejection, transplant related morbidity, as well as disease-free and overall survival.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 130

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Participants with Severe Beta-globin Disorders in Allogeneic Peripheral Blood Stem Cell Transplants	Peripheral blood hematopoietic progenitor cell (PBPC) transplant	Nonmyeloablative transplant regiment, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells from human leukocyte antigen-matched siblings.
Human Leukocyte Antigens (HLA) Matched Related Stem Cell Donor	Peripheral blood hematopoietic progenitor cell Apheresis	Participants received Filgrastim to mobilize peripheral blood stem cells for apheresis collection. Collected stem cells of donor will then be infused to HLA matched sibling.
Participants with Severe Beta-globin Disorders in Allogeneic Peripheral Blood Stem Cell Transplants	Alemtuzumab	Nonmyeloablative transplant regiment, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells from human leukocyte antigen-matched siblings.
Participants with Severe Beta-globin Disorders in Allogeneic Peripheral Blood Stem Cell Transplants	Sirolimus	Nonmyeloablative transplant regiment, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells from human leukocyte antigen-matched siblings.

Primary Outcome Measures

Name	Time	Method
Number of Participants That Experience Treatment Success Following Stem Cell Transplant	Up to 1 year	Number of participants that experience treatment success at one year following stem cell transplant. Treatment success is defined as full donor type hemoglobin on hemoglobin electrophoresis for patients with sickle cell disease and transfusion-independence for patients with beta-thalassemia.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Disease-free Survival	Up to 2 year	Number of participants with disease-free survival, as defined by: alive and free of acute complications related to sickle cell disease or beta-thalassemia.
Number of Participants With Regimen Failure	Up to 1 year	Number of participants with regimen failure. Regimen failure is defined as those participants that experienced graft verses host disease or relapse of sickle cell disease or beta-thalassemia.
Number of Participants Who Developed Limited or Extensive Chronic GVHD	Day 100 up to 3 Years	Number of participants who developed Limited or Extensive Chronic Graft vs Host Disease (GVHD). Limited disease is characterized by localized skin involvement and/or evidence of hepatic dysfunction. Limited disease is associated with a favorable outcome without systemic therapy, while extensive disease patients have an unfavorable outcome. Extensive chronic GVHD is defined as GVHD occurring after day 100 that did not meet the definition of limited chronic GVHD. Extensive disease presents either with generalized skin involvement, or with localized skin involvement or hepatic dysfunction plus at least one of the following: Liver histology showing chronic progressive hepatitis, bridging necrosis, or cirrhosis Involvement of the eye (Schirmer's test with less than 5 mm wetting) (see "Diagnosis and classification of Sjögren's syndrome") Involvement of minor salivary glands or oral mucosa (as demonstrated on labial or mucosal biopsy specimen) Involvement of any other target organ
Number of Participants That Experienced a Transplant-related Mortality	Up to 2 year	Number of participants that experienced a transplant related mortality, as defined as death from causes other than relapse (such as: GVHD, toxicity, infection, other and unknown causes).
Mean Myeloid Chimerism Level	up to 2 years	Mean Myeloid Chimerism Level in participants following stem cell transplant.
Number of Participants Who Developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV as Defined by CIMBTR Criteria for Organ Stages of Acute GVHD.	Up to 1 year	Number of participants who developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV as defined by CIMBTR criteria for Organ Stages of Acute GVHD. Grades are defined as: Grade I: Skin = Maculopapular rash\< 25% of body surface area (BSA); Liver = Total Bilirubin 2-3 mg/dL; Lower GI = stool output/day is 500-999 mL/day. Grade II: Skin = rash on 25-50 percent body surface area; Liver = Total Bilirubin 3.1-6.0 mg/dL; Lower GI = Diarrhea 1001-1500 mL/day. Grade III: Skin = Rash on \>50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea \> 1500 mL/day. Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin \>15 mg/dL; Lower GI = Severe abdominal pain with or without ileus. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
Number of Participants Overall Survival	1 year and 2 year	Number of participants overall survival at year 1 and year 2. Overall survival is defined as participants alive at 1 and 2 years following stem cell transplant.