HSCT For Patients With High Risk Hemoglobinopathies Using Reduced Intensity

NCT ID: NCT02435901

Last Updated: 2021-08-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 29 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-12-31
• Study Completion Date: 2019-12-31

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.

Conditions

Sickle Cell Disease; Beta Thalassemia-Major

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

alemtuzumab (Campath IH)

Intervention Type: DRUG

Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17

Fludarabine

Intervention Type: DRUG

Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4.

Melphalan

Intervention Type: DRUG

Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2.

Cyclosporine

Intervention Type: DRUG

Immunosuppressant to prevent graft vs host disease is given on Day -1 prior to stem cell infusion

Mycophenolate mofetil

Intervention Type: DRUG

Immunosuppressant to prevent graft vs host disease is given on Day -1.

Tacrolimus

Intervention Type: DRUG

Immunosuppressant to prevent graft vs host disease is given Day -1 prior to stem cell infusion

Hematopoietic Stem Cell Transplantation

Intervention Type: BIOLOGICAL

Human Leukocyte Antigen (HLA) matched or mismatched; related or unrelated hematopoietic stem cells to be transplanted on Day 0.

Interventions

alemtuzumab (Campath IH)

Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17

Intervention Type: DRUG

Fludarabine

Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4.

Intervention Type: DRUG

Melphalan

Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2.

Intervention Type: DRUG

Cyclosporine

Immunosuppressant to prevent graft vs host disease is given on Day -1 prior to stem cell infusion

Intervention Type: DRUG

Mycophenolate mofetil

Immunosuppressant to prevent graft vs host disease is given on Day -1.

Intervention Type: DRUG

Tacrolimus

Immunosuppressant to prevent graft vs host disease is given Day -1 prior to stem cell infusion

Intervention Type: DRUG

Hematopoietic Stem Cell Transplantation

Human Leukocyte Antigen (HLA) matched or mismatched; related or unrelated hematopoietic stem cells to be transplanted on Day 0.

Intervention Type: BIOLOGICAL

Other Intervention Names

Campath-IH

Eligibility Criteria

Inclusion Criteria

• 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

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

• 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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Northwell Health

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Cohen Children's Medical Center of New York

New Hyde Park, New York, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 26348869 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

08057

Identifier Type: -

Identifier Source: org_study_id