Beta Thalassemia-Major, Sickle Cell Disease
Conditions
Keywords
Reduced Intensity Conditioning Regimen
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.
Interventions
DRUGalemtuzumab (Campath IH)
Alemtuzumab (Campath IH) is given daily over first 4 days, Day -20 to Day -17
DRUGFludarabine
Fludarabine 35/m2 is given daily over 4 days on Day -7 to Day -4.
DRUGMelphalan
Melphalan 70mg/m2 is given daily over 2 days on Day -3 to Day -2.
DRUGCyclosporine
Immunosuppressant to prevent graft vs host disease is given on Day -1 prior to stem cell infusion
DRUGMycophenolate mofetil
Immunosuppressant to prevent graft vs host disease is given on Day -1.
DRUGTacrolimus
Immunosuppressant to prevent graft vs host disease is given Day -1 prior to stem cell infusion
BIOLOGICALHematopoietic Stem Cell Transplantation
Human Leukocyte Antigen (HLA) matched or mismatched; related or unrelated hematopoietic stem cells to be transplanted on Day 0.
Sponsors
Northwell Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
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-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
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
There were no significant events in the study which prevented participant enrollment.
Participants by arm
| Arm | Count |
|---|---|
| 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.
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 | 29 |
| Total | 29 |
Baseline characteristics
| Characteristic | Reduced Intensity Regimen | — |
|---|---|---|
| Age, Categorical <=18 years | 28 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 1 Participants | — |
| Hemoglobinopathies | 29 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 9 Participants | — |
| Sex: Female, Male Male | 20 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 29 |
| other Total, other adverse events | 13 / 29 |
| serious Total, serious adverse events | 3 / 29 |
Outcome results
Primary
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.
Time frame: 1 year
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Reduced Intensity Regimen | Number of Participants With Sustained Cell Engraftment of Donor Cells | 29 Participants |
Secondary
Assessment of Treatment Related Mortality and Morbidity
Patients will be evaluated for incidence and severity of graft versus host disease, infection, and cardiopulmonary complications.
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Reduced Intensity Regimen | Assessment of Treatment Related Mortality and Morbidity | Grade I-Grade III GVHD | 13 Participants |
| Reduced Intensity Regimen | Assessment of Treatment Related Mortality and Morbidity | Chronic GVHD | 9 Participants |
| Reduced Intensity Regimen | Assessment of Treatment Related Mortality and Morbidity | No complications | 7 Participants |
Secondary
Event Free Survival; Number of Participants Who Survived at 2 Years
29 participants will be evaluated for Event Free Survival.
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Reduced Intensity Regimen | Event Free Survival; Number of Participants Who Survived at 2 Years | Expired Secondary to Sepsis | 1 Participants |
| Reduced Intensity Regimen | Event Free Survival; Number of Participants Who Survived at 2 Years | Expired Secondary to GVHD | 2 Participants |
| Reduced Intensity Regimen | Event Free Survival; Number of Participants Who Survived at 2 Years | Survived Participants | 26 Participants |