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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

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;

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

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

NCT ID

NCT02435901

First Posted

April 24, 2015

Last Updated

July 30, 2021

Sponsor

Northwell Health

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

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

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

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

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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