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Treatment of Sickle Cell Anemia With Stem Cell Transplant

Primary Purpose

Sickle Cell Anemia, Sickle Cell-hemoglobin C Disease, Sickle Cell-β0-thalassemia

Status
Terminated
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Fludarabine
Cytarabine
Cellular Infusions
Total Body Irradiation
Cyclophosphamide
Bortezomib
Rituximab
Plasmapheresis
Sponsored by
Sidney Kimmel Cancer Center at Thomas Jefferson University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Anemia focused on measuring sickle cell, SS disease, SC disease, S-thalassemia, transplant, bone marrow transplant, stem cell transplant, matched sibling, haploidentical, hemoglobinopathy, anemia, desensitization

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patient Selection:

i) Patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, or sickle cell-β0-thalassemia) confirmed by hemoglobin electrophoresis.

ii) Patients should have one or more of the following:

  1. History of acute chest syndrome requiring recurrent hospitalization or exchange transfusion (Acute chest syndrome is defined as pulmonary infiltrate involving at least one complete lung segment, consistent with alveolar consolidation but not atelectasis, accompanied by chest pain, fever, cough, tachypnea or wheezing)
  2. History of nonhemorrhagic stroke or central nervous system event lasting longer than 24 hours
  3. Recurrent vaso-occlusive pain (≥5 episodes during the past two years) or recurrent priapism requiring hospitalization or visits to the emergency room or sickle cell day unit
  4. Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50% of normal predicted value) with progression on ACE inhibitor therapy iii) Patient must have failed therapy with hydroxyurea, as HU as evidenced by at least 6 months of maximum HU dosage for sickle cell disease, i.e. dose escalation to a level which caused some minimal hematologic toxicity in terms of CBC values. Failure to respond must also be documented by no significant increase in subjects HbF levels at this maximally tolerated dosage.AND development/ persistence of items listed in (ii) Patients who are deemed not eligible for hydroxyurea by the primary hematologist will be considered eligible without having failed hydroxyurea. Non-eligibility for hydroxyurea therapy is based on:

(1) the diagnoses of SC disease and sickle cell-β0-thalassemia in which no clear evidence supports the use of hydroxyurea therapy and thus treatment with hydroxyurea is not considered the standard of care in these entities (2) the presence of high hemoglobin F levels in patients with sickle cell anemia and documented Hereditary Persistence of Fetal Hemoglobin (HPFH) in which hydroxyurea is not considered the standard of care (3) severe adverse reactions to hydroxyurea in patients with sickle cell anemia based on, but not limited to, count suppression, GI intolerance, and dermatomyositis Patient unwillingness to be compliant with hydroxyurea therapy is not an acceptable reason for non-eligibility iv) Patients must have an acceptable related donor

  1. who is matched at the HLA-A;B; C; DR loci (8 of 8 match) or mismatched for at most one locus (7 of 8 match) (well matched related donor
  2. who is mismatched at 2-4 alleles (haplo-identical) v) Patient age greater than 18 - 45 years vi) ECOG performance status 0-2/ Karnofsky 70-100% vii) Written informed consent obtained from the patient. viii) Transaminases <3X ULN; patients with transaminases greater than the ULN but less than 3XULN will be evaluated by the hepatology service and will undergo further imaging and biopsy as deemed necessary by hepatology. They will not be considered eligible unless cleared by hepatology.

Exclusion Criteria:

Patient Selection:

i) Pregnancy/ unwillingness to use adequate contraception during study period ii) Liver disease including

  1. Acute hepatitis (transaminases >3x normal value)
  2. Chronic hepatitis C
  3. Chronic hepatitis B or history of exposure to hepatitis B iii) Cardiac ejection fraction < 50% iv) Pulmonary hypertension - as evidenced by findings on resting echocardiogram of pulmonary artery systolic pressure ≥ 40 mmHg or any evidence of right ventricular dysfunction (hypokinesis or RV dilation) v) Severe renal impairment (GFR <30% of predicted normal value) vi) Severe residual functional neurologic impairment (other than hemiplegia alone) vii) DLCO ≤50 viii) Any evidence of infection by the human immunodeficiency virus ix) Psychiatric disorder that would preclude patients from signing an informed consent x) Severe neuro-cognitive or executive function making informed consent possible

Sites / Locations

  • Thomas Jefferson University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

HSCT

Arm Description

Subjects receive the preparative regimen in 2 steps. The "first step" will be with fludarabine and cytarabine and a low dose of total body irradiation. This will be followed by the "first step" of the transplant graft - the donor lymphocytes. The "second step" of the chemotherapy will be two doses of cyclophosphamide. This will then be followed by the "second step" of the transplant graft - the stem cells. Only subjects with prior alloimmunization against donor will receive desensitization. Subjects who demonstrate alloimmunization against the HLA of the donor will receive bortezomib and rituximab in combination with plasmapheresis prior to the admission for transplant.

Outcomes

Primary Outcome Measures

Stable Engraftment
To determine if the reduced intensity preparative regimen of fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation will generate stable engraftment with donor hematopoietic stem cells in at least 80% of patients with severe sickle cell anemia.

Secondary Outcome Measures

Organ Toxicity
To assess organ toxicity related to fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation in a population with severe sickle cell anemia.
Overall Survival
To determine the overall survival at 6 months post-transplant in patients receiving a matched or partially-matched related donor transplant after reduced-intensity conditioning.
Acute Graft Versus Host Disease
To describe the incidence and severity of acute and chronic GVHD following this reduced intensity transplant from partially matched related donors using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.
Correction of Hemoglobinopathy
To evaluate the extent of correction of hemoglobinopathy following this reduced intensity transplant.
Immune Recovery
To assess the pace of lymphoid recovery and associated risk for opportunistic infections and relapse (return to recipient erythropoiesis) in this patient population.
Quality of Life
To describe the quality of life and functional status following transplantation.
Cytokine Profile
To characterize the profiles of cytokines released following administration of the lymphoid portion of the transplant (donor lymphocyte infusion [DLI]).

Full Information

First Posted
May 4, 2011
Last Updated
October 19, 2016
Sponsor
Sidney Kimmel Cancer Center at Thomas Jefferson University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT01350232
Brief Title
Treatment of Sickle Cell Anemia With Stem Cell Transplant
Official Title
Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Sickle Cell Anemia From HLA Matched or Partially-Matched Related Donors
Study Type
Interventional

2. Study Status

Record Verification Date
October 2016
Overall Recruitment Status
Terminated
Why Stopped
Poor accrual
Study Start Date
September 2009 (undefined)
Primary Completion Date
August 2011 (Actual)
Study Completion Date
August 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Cancer Center at Thomas Jefferson University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a clinical research trial in which a novel preparatory regimen was developed for bone marrow transplant (BMT) which eliminates the primary obstacle to transplant, the lack of a matched sibling donor. It is believed this regimen is sufficiently efficacious and sufficiently gentle to apply to patients with sickle cell anemia and related disorders. It is proposed to characterize the efficacy and toxicity of this regimen in high risk patients with sickle cell anemia using criteria for patient selection that have been accepted in prior BMT trials in patients with sickle cell disease, specifically only the subset of patients whose prior clinical behavior indicates that they are at high risk for serious morbidity and early mortality. In addition, it is proposed to characterize the pathophysiology of a consistent febrile response seen in the haploidentical BMT regimen the investigators have developed at Thomas Jefferson University (TJU). The primary goal of this study is to determine the response rate to a reduced intensity conditioning regimen which consists of fludarabine, cytarabine, low dose total body irradiation and cyclophosphamide in patients with severe sickle cell anemia.
Detailed Description
Hemoglobinopathies, such as sickle cell disease and thalassemia major, constitute a group of genetic diseases associated with significant morbidity and premature death. In the 1970s, the mean survival of patients with sickle cell disease was 14.3 years. With improvements in medical practice, this has improved such that estimates are now into the third decade of life. In patients with sickle cell disease, a single amino acid substitution in beta-hemoglobin causes erythrocytes to sickle in response to oxidative stress. The sequelae of this defect are vaso-occlusive crises, resulting in episodes of bony pain and infarction, acute chest syndrome, and strokes. Life long need for transfusion leads to complications including alloimmunization and iron overload. The latter condition is frequently associated with significant end-organ damage. In recent years, new strategies in supportive care, such as the use of hydroxyurea to stimulate fetal hemoglobin production in patients with sickle cell anemia, have resulted in the amelioration of some of the devastating manifestations of this disease. However, this therapy does not benefit all patients, and there have been concerns about the possible risk of latent transformation to leukemia with prolonged use of this drug. Clearly, better treatment strategies are needed for this devastating group of diseases. Patients with sickle cell anemia will be offered enrollment on a clinical trial of reduced intensity stem cell transplant. The transplant donors will be either HLA matched siblings or family members who are 50% matched for HLA. Patients will receive therapy in 2 steps. For patients who are allo-immunized against the donor (patients who have made an immune response already against the donor's HLA type), there will be a desensitization process. This will be outpatient therapy and will include therapy with bortezomib on the 1st, 4th, 8th and 11th day of a 21 day cycle. This will be repeated for a second cycle, for a total of 8 doses of bortezomib over a 6 week period. In addition, they will receive rituximab on the 1st and 8th day of each cycle. These therapies are designed to decrease the subject's chance of rejecting the transplant, as it is known that patients with sickle cell anemia are likely to be heavily immunized against donors. For patients who have high levels of antibodies against the donors, a plasmapheresis procedure will be performed prior to admission as well. All patients will undergo red cell exchange prior to admission. During the transplant admission, subjects will receive a "Two Step" chemotherapy and transplant regimen. The chemotherapy "first step" will be with fludarabine and cytarabine and a low dose of total body irradiation. This will be followed by the "first step" of the transplant graft - the donor lymphocytes. The "second step" of the chemotherapy will be two doses of cyclophosphamide. This will then be followed by the "second step" of the transplant graft - the stem cells.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Anemia, Sickle Cell-hemoglobin C Disease, Sickle Cell-β0-thalassemia
Keywords
sickle cell, SS disease, SC disease, S-thalassemia, transplant, bone marrow transplant, stem cell transplant, matched sibling, haploidentical, hemoglobinopathy, anemia, desensitization

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
HSCT
Arm Type
Experimental
Arm Description
Subjects receive the preparative regimen in 2 steps. The "first step" will be with fludarabine and cytarabine and a low dose of total body irradiation. This will be followed by the "first step" of the transplant graft - the donor lymphocytes. The "second step" of the chemotherapy will be two doses of cyclophosphamide. This will then be followed by the "second step" of the transplant graft - the stem cells. Only subjects with prior alloimmunization against donor will receive desensitization. Subjects who demonstrate alloimmunization against the HLA of the donor will receive bortezomib and rituximab in combination with plasmapheresis prior to the admission for transplant.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
Subjects will receive fludarabine at a dose of 30 mg/m2 daily for 4 days as part of the preparative regimen
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
Ara-C, Cytosar, Cytosine arabinoside
Intervention Description
Subjects will receive cytarabine at a dose of 2 g/m2 daily for 4 days, approximately 4 hours after the fludarabine
Intervention Type
Device
Intervention Name(s)
Cellular Infusions
Other Intervention Name(s)
Stem Cells, DLI, HPCT
Intervention Description
Subjects will receive the cellular product in 2 steps. The first is a lymphocyte infusion of 2 X 10e8 lymphocytes/kg on the day they receive total body irradiation. The second is a CD34 enriched stem cell product approximately 48 hours after the cyclophosphamide. The CliniMACS® Plus Instrument will be used for the selection of human CD34+ hematopoietic stem and progenitor cells in human allogeneic hematopoietic stem cell transplantation.
Intervention Type
Radiation
Intervention Name(s)
Total Body Irradiation
Other Intervention Name(s)
TBI
Intervention Description
All subjects will receive 200cGy TBI in a single fraction on the AM they receive the lymphocyte infusion
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
All subjects will receive cyclophosphamide at a dose of 60 mg/kg at approximately 72 and 96 hours after the lymphocyte infusion
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
Velcade
Intervention Description
Subjects will receive bortezomib 1.3 mg/kg on Day 1,4,8, and 11 of a 21 day cycle. This will be repeated for 2 cycles.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan
Intervention Description
Subjects will receive rituximab 375 mg/m2 on day 1 and day 8 of a 21 day cycle, on days they will also be receiving rituximab. This will be repeated for 2 cycles.
Intervention Type
Procedure
Intervention Name(s)
Plasmapheresis
Other Intervention Name(s)
Plasma exchange
Intervention Description
Subjects who continue to have detectable anti-donor antibody will receive plasmapheresis to reduce the antibody further
Primary Outcome Measure Information:
Title
Stable Engraftment
Description
To determine if the reduced intensity preparative regimen of fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation will generate stable engraftment with donor hematopoietic stem cells in at least 80% of patients with severe sickle cell anemia.
Time Frame
180 days post-infusion
Secondary Outcome Measure Information:
Title
Organ Toxicity
Description
To assess organ toxicity related to fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation in a population with severe sickle cell anemia.
Time Frame
30 days post infusion
Title
Overall Survival
Description
To determine the overall survival at 6 months post-transplant in patients receiving a matched or partially-matched related donor transplant after reduced-intensity conditioning.
Time Frame
6 months post infusion
Title
Acute Graft Versus Host Disease
Description
To describe the incidence and severity of acute and chronic GVHD following this reduced intensity transplant from partially matched related donors using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.
Time Frame
100 days post infusion
Title
Correction of Hemoglobinopathy
Description
To evaluate the extent of correction of hemoglobinopathy following this reduced intensity transplant.
Time Frame
100 days post infusion through 5 years post infusion
Title
Immune Recovery
Description
To assess the pace of lymphoid recovery and associated risk for opportunistic infections and relapse (return to recipient erythropoiesis) in this patient population.
Time Frame
100 days post infusion through 5 years post infusion
Title
Quality of Life
Description
To describe the quality of life and functional status following transplantation.
Time Frame
Through 5 years post infusion
Title
Cytokine Profile
Description
To characterize the profiles of cytokines released following administration of the lymphoid portion of the transplant (donor lymphocyte infusion [DLI]).
Time Frame
Through 5 years after infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient Selection: i) Patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, or sickle cell-β0-thalassemia) confirmed by hemoglobin electrophoresis. ii) Patients should have one or more of the following: History of acute chest syndrome requiring recurrent hospitalization or exchange transfusion (Acute chest syndrome is defined as pulmonary infiltrate involving at least one complete lung segment, consistent with alveolar consolidation but not atelectasis, accompanied by chest pain, fever, cough, tachypnea or wheezing) History of nonhemorrhagic stroke or central nervous system event lasting longer than 24 hours Recurrent vaso-occlusive pain (≥5 episodes during the past two years) or recurrent priapism requiring hospitalization or visits to the emergency room or sickle cell day unit Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50% of normal predicted value) with progression on ACE inhibitor therapy iii) Patient must have failed therapy with hydroxyurea, as HU as evidenced by at least 6 months of maximum HU dosage for sickle cell disease, i.e. dose escalation to a level which caused some minimal hematologic toxicity in terms of CBC values. Failure to respond must also be documented by no significant increase in subjects HbF levels at this maximally tolerated dosage.AND development/ persistence of items listed in (ii) Patients who are deemed not eligible for hydroxyurea by the primary hematologist will be considered eligible without having failed hydroxyurea. Non-eligibility for hydroxyurea therapy is based on: (1) the diagnoses of SC disease and sickle cell-β0-thalassemia in which no clear evidence supports the use of hydroxyurea therapy and thus treatment with hydroxyurea is not considered the standard of care in these entities (2) the presence of high hemoglobin F levels in patients with sickle cell anemia and documented Hereditary Persistence of Fetal Hemoglobin (HPFH) in which hydroxyurea is not considered the standard of care (3) severe adverse reactions to hydroxyurea in patients with sickle cell anemia based on, but not limited to, count suppression, GI intolerance, and dermatomyositis Patient unwillingness to be compliant with hydroxyurea therapy is not an acceptable reason for non-eligibility iv) Patients must have an acceptable related donor who is matched at the HLA-A;B; C; DR loci (8 of 8 match) or mismatched for at most one locus (7 of 8 match) (well matched related donor who is mismatched at 2-4 alleles (haplo-identical) v) Patient age greater than 18 - 45 years vi) ECOG performance status 0-2/ Karnofsky 70-100% vii) Written informed consent obtained from the patient. viii) Transaminases <3X ULN; patients with transaminases greater than the ULN but less than 3XULN will be evaluated by the hepatology service and will undergo further imaging and biopsy as deemed necessary by hepatology. They will not be considered eligible unless cleared by hepatology. Exclusion Criteria: Patient Selection: i) Pregnancy/ unwillingness to use adequate contraception during study period ii) Liver disease including Acute hepatitis (transaminases >3x normal value) Chronic hepatitis C Chronic hepatitis B or history of exposure to hepatitis B iii) Cardiac ejection fraction < 50% iv) Pulmonary hypertension - as evidenced by findings on resting echocardiogram of pulmonary artery systolic pressure ≥ 40 mmHg or any evidence of right ventricular dysfunction (hypokinesis or RV dilation) v) Severe renal impairment (GFR <30% of predicted normal value) vi) Severe residual functional neurologic impairment (other than hemiplegia alone) vii) DLCO ≤50 viii) Any evidence of infection by the human immunodeficiency virus ix) Psychiatric disorder that would preclude patients from signing an informed consent x) Severe neuro-cognitive or executive function making informed consent possible
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joanne Filicko-O'Hara, MD
Organizational Affiliation
Thomas Jefferson University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.JeffersonHospital.org
Description
Thomas Jefferson University Hospitals

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Treatment of Sickle Cell Anemia With Stem Cell Transplant

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