HSCT For Patients With High Risk Hemoglobinopathies Using Reduced Intensity
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
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 Design
Arms and Interventions
| 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 Names:
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
Immunosuppressant to prevent graft vs host disease is given on Day -1.
Drug: Tacrolimus
Immunosuppressant 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.
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Sustained Cell Engraftment of Donor Cells [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
- Assessment of Treatment Related Mortality and Morbidity [2 years]
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 [2 years]
29 participants will be evaluated for Event Free Survival.
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Cohen Children's Medical Center of New York | New Hyde Park | New York | United States | 11040 |
Sponsors and Collaborators
- Northwell Health
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.- 08057
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | There were no significant events in the study which prevented participant enrollment. |
| Arm/Group Title | Reduced Intensity Regimen |
|---|---|
| Arm/Group 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 alemtuzumab (Campath IH): Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17 Fludarabine: Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4. Melphalan: Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2. Cyclosporine: Immunosuppressant to prevent graft vs host disease is given on Day -1 prior to s |
| Period Title: Overall Study | |
| STARTED | 29 |
| COMPLETED | 29 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Reduced Intensity Regimen |
|---|---|
| Arm/Group 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. alemtuzumab (Campath IH): Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17 Fludarabine: Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4. Melphalan: Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2. Cyclosporine: Immunosuppressant to prevent graft vs host disease is given on Day -1 |
| Overall Participants | 29 |
| Age (Count of Participants) | |
| <=18 years |
28
96.6%
|
| Between 18 and 65 years |
1
3.4%
|
| >=65 years |
0
0%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
9
31%
|
| Male |
20
69%
|
| Race and Ethnicity Not Collected (Count of Participants) | |
| Hemoglobinopathies (Count of Participants) | |
| Count of Participants [Participants] |
29
100%
|
Outcome Measures
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All 29 participants were analyzed at time-points of 30 days, 100 days, 6 month and 1 year for sustained stem cell engraftment of donor cells. |
| Arm/Group Title | Reduced Intensity Regimen |
|---|---|
| Arm/Group Description | Alemtuzumab (Campath-IH) IV 3mg test dose on Day -20 followed by 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. Day -1 Cyclosporine OR Tacrolimus along with Mycophenolate Mofetil as a graft vs host disease prophylaxis. On Day 0 the HLA matched or mismatched Hematopoietic Stem Cells from either the related or unrelated donor will be infused. alemtuzumab (Campath IH): Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17 Fludarabine: Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4. Melphalan: Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2. Cyclosporine: Immunosuppressant to prevent graft vs host disease is given on Day -1 prior to s |
| Measure Participants | 29 |
| Count of Participants [Participants] |
29
100%
|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Reduced Intensity Regimen |
|---|---|
| Arm/Group Description | 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. Day -1 Cyclosporine OR Tacrolimus along with Mycophenolate Mofetil as a graft vs host disease prophylaxis. On Day 0 the HLA matched or mismatched Hematopoietic Stem Cells from either the related or unrelated donor will be infused. alemtuzumab (Campath IH): Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17 Fludarabine: Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4. Melphalan: Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2. Cyclosporine: Immunosuppressant to prevent graft vs host disease is given on Day -1 prior to s |
| Measure Participants | 29 |
| Grade I-Grade III GVHD |
13
44.8%
|
| Chronic GVHD |
9
31%
|
| No complications |
7
24.1%
|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Reduced Intensity Regimen |
|---|---|
| Arm/Group Description | 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. Day -1 Cyclosporine OR Tacrolimus along with Mycophenolate Mofetil as a graft vs host disease prophylaxis. On Day 0 the HLA matched or mismatched Hematopoietic Stem Cells from either the related or unrelated donor will be infused. alemtuzumab (Campath IH): Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17 Fludarabine: Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4. Melphalan: Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2. Cyclosporine: Immunosuppressant to prevent graft vs host disease is given on Day -1 prior to s |
| Measure Participants | 29 |
| Expired Secondary to Sepsis |
1
3.4%
|
| Expired Secondary to GVHD |
2
6.9%
|
| Survived Participants |
26
89.7%
|
Adverse Events
| Time Frame | Adverse event data was collected up to the end of the first year post transplant. | |
|---|---|---|
| Adverse Event Reporting Description | Serious adverse events included 3 participants who expired within the first year post transplant. One participant expired secondary to sepsis episode. Two participants expired secondary to complications of Grade III-IV graft vs. host disease. Adverse event included13 patients experienced adverse event of Grade I-II graft vs host disease, and responded to oral and/or topical treatment. | |
| Arm/Group Title | Reduced Intensity Regimen | |
| Arm/Group Description | 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. Day -1 Cyclosporine OR Tacrolimus along with Mycophenolate Mofetil as a graft vs host disease prophylaxis. Day 0 the HLA matched or mismatched Hematopoietic Stem Cells from either the related or unrelated donor will be infused. alemtuzumab (Campath IH): Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17 Fludarabine: Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4. Melphalan: Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2. Cyclosporine: Immunosuppressant to prevent graft vs host disease is given on Day -1 Mycophenolate mofetil: Immunosuppressant to prevent graft vs host | |
All Cause Mortality |
||
| Reduced Intensity Regimen | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/29 (10.3%) | |
Serious Adverse Events |
||
| Reduced Intensity Regimen | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/29 (10.3%) | |
| Gastrointestinal disorders | ||
| Graft vs Host Disease | 2/29 (6.9%) | 2 |
| Infections and infestations | ||
| Sepsis | 1/29 (3.4%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Reduced Intensity Regimen | ||
| Affected / at Risk (%) | # Events | |
| Total | 13/29 (44.8%) | |
| Immune system disorders | ||
| Grade I-II Graft vs Host Disease | 13/29 (44.8%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Indira Sahdev, MD |
|---|---|
| Organization | Northwell Health System Cohen Children's Medical Center of NY |
| Phone | 7184703460 |
| isahdev@northwell.edu |
- 08057