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HSCT For Patients With High Risk Hemoglobinopathies Using Reduced Intensity

Primary Purpose

Sickle Cell Disease, Beta Thalassemia-Major

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
alemtuzumab (Campath IH)
Fludarabine
Melphalan
Cyclosporine
Mycophenolate mofetil
Tacrolimus
Hematopoietic Stem Cell Transplantation
Sponsored by
Northwell Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring Reduced Intensity Conditioning Regimen

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patient Inclusion Criteria for Sickle Cell Disease
  • Patients at least one year of age to less than or equal to 21 years of age with (Sickle Cell Disease-SS or Sickle Cell-S-β-Thalassemia and with one or more of the following disease complications:
  • Development of stroke on chronic transfusion protocol.
  • Allosensitization on chronic transfusion therapy
  • Impaired neuropsychological function and abnormal MRI scan
  • Abnormal Transcranial Doppler studies
  • Acute chest syndrome (2 to 3 episodes of acute chest syndrome in last 3 to 4 years).
  • Ferritin level < 1500 mg/ml
  • Recurrent painful priapism; 3-4 episodes/year requiring intervention.
  • Recurrent vaso-occlusive crisis of at least 3 to 4 episodes/year.
  • Osteonecrosis of multiple bones with documented destructive changes.
  • Signed informed consent
  • Patients physically and psychologically capable of undergoing transplantation and a period of strict isolation.
  • Ferritin < 1500
  • Liver Iron Concentration < 6mg/g

Patient Inclusion Criteria for β Thalassemia major Patients less than or equal to 21 years of age with B- Thalassemia major on routine monthly transfusion protocol or with one or more of the following complications;

  1. Hepatomegaly.
  2. Liver biopsy revealing evidence of portal fibrosis as A) Mild B) Moderate
  3. Ferritin level≤ 1500ng/ml
  4. Liver Iron Concentration (LIC) < 6mg/g

Exclusion Criteria:

  • Exclusion Criteria for Both Sickle Cell and β Thalassemia Major Patient
  • HIV positive result confirmed by Western Blot.
  • Pregnancy (Pregnancy testing for females of child-bearing age will be performed and those with a positive serum β-Human Chorionic Gonadotropin will be excluded) and lactating females.
  • Creatinine greater than two times the upper limit of normal for the laboratory,
  • Pulmonary disease with FVC, FEV1 or DLCO parameters < 50% predicted (corrected for hemoglobin) or stage 3 or 4 sickle lung disease.
  • Cardiac insufficiency or coronary artery disease requiring treatment
  • Active infection requiring systemic antibiotic therapy with antibacterial, antifungal or antiviral agents
  • Lansky performance score <70%- (Appendix B)
  • Acute hepatitis/biopsy evidence of cirrhosis.
  • Pulmonary Hypertension

Sites / Locations

  • Cohen Children's Medical Center of New York

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Reduced Intensity Regimen

Arm Description

Administration of reduced doses of alemtuzumab (Campath-IH) IV 3mg test dose on Day -20 followed by daily dose of 10mg/dose on Day -19 to Day -17 for patients <10yrs or a daily dose of 15mg/dose on Day -19 to Day -17 for patients > 10yrs. Fludarabine 35mg/m2 daily for 4 days on Day -7 to Day -4. Melphalan 70mg/m2 daily for 2 days on Day -3 and Day -2. On Day -1 Cyclosporine OR Tacrolimus will be initiated along with Mycophenolate Mofetil as a graft vs host disease prophylaxis. On Day 0 the Human Leukocyte Antigen (HLA) matched or mismatched Hematopoietic Stem Cells from either the related or unrelated donor will be infused.

Outcomes

Primary Outcome Measures

Number of Participants With Sustained Cell Engraftment of Donor Cells
Sustained stem cell engraftment of donor cells will be evaluated by chimerism (FISH fluorescence in situ hybridization OR VNTR (Variable Number of Tandem Repeats), based on recipient/donor gender, at 30 days, 100 days, 6 months and 1 year following the use of reduced intensity conditioning.

Secondary Outcome Measures

Assessment of Treatment Related Mortality and Morbidity
Patients will be evaluated for incidence and severity of graft versus host disease, infection, and cardiopulmonary complications.
Event Free Survival; Number of Participants Who Survived at 2 Years
29 participants will be evaluated for Event Free Survival.

Full Information

First Posted
April 24, 2015
Last Updated
July 30, 2021
Sponsor
Northwell Health
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1. Study Identification

Unique Protocol Identification Number
NCT02435901
Brief Title
HSCT For Patients With High Risk Hemoglobinopathies Using Reduced Intensity
Official Title
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN PATIENTS WITH HIGH RISK HEMOGLOBINOPATHIES LIKE SICKLE CELL DISEASE AND β-THALESSEMIA-MAJOR USING REDUCED INTENSITY CONDITIONING REGIMEN
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
December 2008 (undefined)
Primary Completion Date
March 2019 (Actual)
Study Completion Date
December 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Northwell Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will evaluate the use of reduced intensity conditioning regimen in patients with high risk hemoglobinopathy Sickle Cell and B-Thalassemia Major in combination with standard immunosuppressive medications, followed by a routine stem cell transplant in order to assess whether or not it is as effective as myeloablative high dose chemotherapy and transplant.
Detailed Description
Standard myeloablative regimens are toxic to non-hematopoietic tissue and are associated with treatment related mortality and morbidity (TRM). Preparative regimens that are not myeloablative are associated with a greatly decreased incidence of TRM. In addition to providing a less toxic regimen, the reduced intensity chemotherapy preparative regimen also remains immunosuppressive enough to allow donor engraftment. Recent report of non-myeloablative regimens which resulted in engraftment of allogeneic stem cell in hematological malignancies raises the possibility that this conditioning regimen might be useful in achieving engraftment in non hematological disorder. In an effort to achieve stable engraftment with any suitable donor stem cell source and to minimize toxicity the investigators have developed a new reduced intensity conditioning regimen for high risk hemoglobinopathies with the main aim of significantly suppressing the recipient's immune system and facilitate engraftment. Non-myeloablative or reduced-intensity immunosuppressive preparative regimens have achieved a stable, mixed chimerism engraftment and successful allogeneic bone marrow transplants.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease, Beta Thalassemia-Major
Keywords
Reduced Intensity Conditioning Regimen

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
29 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Reduced Intensity Regimen
Arm Type
Experimental
Arm Description
Administration of reduced doses of alemtuzumab (Campath-IH) IV 3mg test dose on Day -20 followed by daily dose of 10mg/dose on Day -19 to Day -17 for patients <10yrs or a daily dose of 15mg/dose on Day -19 to Day -17 for patients > 10yrs. Fludarabine 35mg/m2 daily for 4 days on Day -7 to Day -4. Melphalan 70mg/m2 daily for 2 days on Day -3 and Day -2. On Day -1 Cyclosporine OR Tacrolimus will be initiated along with Mycophenolate Mofetil as a graft vs host disease prophylaxis. On Day 0 the Human Leukocyte Antigen (HLA) matched or mismatched Hematopoietic Stem Cells from either the related or unrelated donor will be infused.
Intervention Type
Drug
Intervention Name(s)
alemtuzumab (Campath IH)
Other Intervention Name(s)
Campath-IH
Intervention Description
Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4.
Intervention Type
Drug
Intervention Name(s)
Melphalan
Intervention Description
Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2.
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Intervention Description
Immunosuppressant to prevent graft vs host disease is given on Day -1 prior to stem cell infusion
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil
Intervention Description
Immunosuppressant to prevent graft vs host disease is given on Day -1.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Intervention Description
Immunosuppressant to prevent graft vs host disease is given Day -1 prior to stem cell infusion
Intervention Type
Biological
Intervention Name(s)
Hematopoietic Stem Cell Transplantation
Intervention Description
Human Leukocyte Antigen (HLA) matched or mismatched; related or unrelated hematopoietic stem cells to be transplanted on Day 0.
Primary Outcome Measure Information:
Title
Number of Participants With Sustained Cell Engraftment of Donor Cells
Description
Sustained stem cell engraftment of donor cells will be evaluated by chimerism (FISH fluorescence in situ hybridization OR VNTR (Variable Number of Tandem Repeats), based on recipient/donor gender, at 30 days, 100 days, 6 months and 1 year following the use of reduced intensity conditioning.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Assessment of Treatment Related Mortality and Morbidity
Description
Patients will be evaluated for incidence and severity of graft versus host disease, infection, and cardiopulmonary complications.
Time Frame
2 years
Title
Event Free Survival; Number of Participants Who Survived at 2 Years
Description
29 participants will be evaluated for Event Free Survival.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient Inclusion Criteria for Sickle Cell Disease Patients at least one year of age to less than or equal to 21 years of age with (Sickle Cell Disease-SS or Sickle Cell-S-β-Thalassemia and with one or more of the following disease complications: Development of stroke on chronic transfusion protocol. Allosensitization on chronic transfusion therapy Impaired neuropsychological function and abnormal MRI scan Abnormal Transcranial Doppler studies Acute chest syndrome (2 to 3 episodes of acute chest syndrome in last 3 to 4 years). Ferritin level < 1500 mg/ml Recurrent painful priapism; 3-4 episodes/year requiring intervention. Recurrent vaso-occlusive crisis of at least 3 to 4 episodes/year. Osteonecrosis of multiple bones with documented destructive changes. Signed informed consent Patients physically and psychologically capable of undergoing transplantation and a period of strict isolation. Ferritin < 1500 Liver Iron Concentration < 6mg/g Patient Inclusion Criteria for β Thalassemia major Patients less than or equal to 21 years of age with B- Thalassemia major on routine monthly transfusion protocol or with one or more of the following complications; Hepatomegaly. Liver biopsy revealing evidence of portal fibrosis as A) Mild B) Moderate Ferritin level≤ 1500ng/ml Liver Iron Concentration (LIC) < 6mg/g Exclusion Criteria: Exclusion Criteria for Both Sickle Cell and β Thalassemia Major Patient HIV positive result confirmed by Western Blot. Pregnancy (Pregnancy testing for females of child-bearing age will be performed and those with a positive serum β-Human Chorionic Gonadotropin will be excluded) and lactating females. Creatinine greater than two times the upper limit of normal for the laboratory, Pulmonary disease with FVC, FEV1 or DLCO parameters < 50% predicted (corrected for hemoglobin) or stage 3 or 4 sickle lung disease. Cardiac insufficiency or coronary artery disease requiring treatment Active infection requiring systemic antibiotic therapy with antibacterial, antifungal or antiviral agents Lansky performance score <70%- (Appendix B) Acute hepatitis/biopsy evidence of cirrhosis. Pulmonary Hypertension
Facility Information:
Facility Name
Cohen Children's Medical Center of New York
City
New Hyde Park
State/Province
New York
ZIP/Postal Code
11040
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Outcome data to include study findings.
Citations:
PubMed Identifier
26348869
Citation
King AA, Kamani N, Bunin N, Sahdev I, Brochstein J, Hayashi RJ, Grimley M, Abraham A, Dioguardi J, Chan KW, Douglas D, Adams R, Andreansky M, Anderson E, Gilman A, Chaudhury S, Yu L, Dalal J, Hale G, Cuvelier G, Jain A, Krajewski J, Gillio A, Kasow KA, Delgado D, Hanson E, Murray L, Shenoy S. Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies. Am J Hematol. 2015 Dec;90(12):1093-8. doi: 10.1002/ajh.24183. Epub 2015 Oct 6.
Results Reference
derived

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HSCT For Patients With High Risk Hemoglobinopathies Using Reduced Intensity

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