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HSCT For Patients With High Risk Hemoglobinopathies Using Reduced Intensity

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ClinicalTrials.gov Identifier: NCT02435901
Recruitment Status : Recruiting
First Posted : May 6, 2015
Last Update Posted : May 16, 2017
Information provided by (Responsible Party):
Indira Sahdev, Northwell Health

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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Beta Thalassemia-Major Drug: alemtuzumab (Campath IH) Drug: Fludarabine Drug: Melphalan Drug: Cyclosporine Drug: Mycophenolate mofetil Drug: Tacrolimus Biological: Hematopoietic Stem Cell Transplantation Phase 1 Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 29 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Study Start Date : December 2008
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : January 2019

Arm Intervention/treatment
Experimental: Reduced Intensity Regimen
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.
Drug: alemtuzumab (Campath IH)
Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17
Other Name: Campath-IH
Drug: Fludarabine
Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4.
Drug: Melphalan
Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2.
Drug: Cyclosporine
Immunosuppressant to prevent graft vs host disease is given on Day -1 prior to stem cell infusion
Drug: Mycophenolate mofetil
Immunosuppresant to prevent graft vs host disease is given on Day -1.
Drug: Tacrolimus
Immunosuppresant to prevent graft vs host disease is given Day -1 prior to stem cell infusion
Biological: Hematopoietic Stem Cell Transplantation
Human Leukocyte Antigen (HLA) matched or mismatched; related or unrelated hematopoietic stem cells to be transplanted on Day 0.

Primary Outcome Measures :
  1. Assessment of Stem Cell Engraftment [ Time Frame: 1 year ]
    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 :
  1. Assessment of treatment related mortality and morbidity [ Time Frame: 2 years ]
    Patients will be evaluated for incidence and severity of graft versus host disease, infection, and cardiopulmonary complications.

  2. Event Free Survival [ Time Frame: 2 years ]
  3. Immunological Reconstitution [ Time Frame: 2 years ]
    Measure the rate of T and B cell immune reconstitution by laboratory studies at 8 weeks, 6 months, one year and two years post transplant.

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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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-occlussive 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02435901

United States, New York
Cohen Children's Medical Center of New York Recruiting
New Hyde Park, New York, United States, 11040
Contact: Indira Sahdev, MD    718-470-3611    isahdev@nshs.edu   
Contact: Nan Werther, MS, CPNP    718-470-3620    nwerther@nshs.edu   
Principal Investigator: Indira Sahdev, MD         
Sub-Investigator: Joel Brochstein, MD         
Sub-Investigator: Jonathan Fish, MD         
Sub-Investigator: Nan Werther, MS, CPNP         
Sponsors and Collaborators
Northwell Health

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Indira Sahdev, Section Head Cohen Children's Med Ctr of NY Stem Cell Transplant Program, Northwell Health
ClinicalTrials.gov Identifier: NCT02435901     History of Changes
Other Study ID Numbers: 08057
First Posted: May 6, 2015    Key Record Dates
Last Update Posted: May 16, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Outcome data to include study findings.

Keywords provided by Indira Sahdev, Northwell Health:
Reduced Intensity Conditioning Regimen

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn
Fludarabine phosphate
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents