Sickle Cell Disease
Conditions
Keywords
Stem cell transplant, Sickle cell, Stem cell transplantation, Related, Unrelated
Brief summary
This protocol will be investigating the use of stem cell transplantation, in related donors, to cure sickle cell disease. Sickle cell disease is a recessive disorder caused by a point mutation that results in the substitution of valine for glutamic acid at the sixth position in the B-chain of hemoglobin. This leads to sickling of the red blood cells under many conditions, such as hypoxia, dehydration, and hyperthermia. The sickling leads to vaso-occlusion, which causes irreversible damage in almost all systems in the body, including the central nervous system (CNS), lungs, heart, bones, eyes, liver, and kidneys.
Detailed description
Primary objective: 1\) To determine disease free survival (DFS) at two years after matched sibling transplant using bone marrow (BM) after a conditioning regimen consisting of distal timed Alemtuzumab, Fludarabine, and Melphalan for patients 2-30 y/o Secondary objectives: 1. Overall survival 2. Rate of neutrophil and platelet engraftment for BM 3. Incidence of graft failure 4. Incidence of grade II-IV and grade III-IV acute graft vs host disease (GVHD) 5. Incidence of chronic GVHD 6. Incidence of other transplant complications, such as veno-occlusive disease, central nervous system (CNS) toxicity, and idiopathic pneumonia syndrome (IPS) 7. Incidence of reactivation of CMV, EBV, adenovirus, BK/JC virus 8. Incidence of invasive fungal disease 9. Time to immune reconstitution via monitoring of lymphocyte subpopulations and immunoglobulin levels
Interventions
DRUGAlemtuzumab
Adjusted Ideal Body Weight Formula: AIBW = IBW + \[(0.4) x (ABW - IBW)\] b) Medications i.) Alemtuzumab I. Hb S% must be \< or = 45% within 7 days prior to initiation of Alemtuzumab II. Iron chelation and hydroxyurea must be discontinued \>48 hours before initiating therapy III. Alemtuzumab will be diluted in 100mL of 0.9% NS and infused at a rate as below
DRUGFludarabine
I. Fludarabine should be diluted in 100 ml 0.9%NS and given over 30 minutes. II. A daily dose of an antiemetic should be given 30 minutes prior to administration of the Fludarabine
DRUGMelphalan
I. Melphalan should be diluted in 0.9%NS to a concentration of 0.1 -0.45 mg/mL and given over 45 minutes. \*Entire dose must be infused within 60 minutes of reconstitution in Pharmacy. II. A daily dose of an antiemetic should be given 30 minutes prior to administration of the Melphalan III. Patients should be encouraged to suck on a popsicle or something similar during the Melphalan infusion.
PROCEDUREStem Cells
Infusion of Hematopoietic Stem Cells
Sponsors
Hackensack Meridian Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
* Patient Eligibility 1\) Matched sibling donors (9-10/10 marrow/PBSC or 5-6/6 UCB (single or double) with a total TNC dose of greater than 5 x 107/kg recipient weight) 1. Age 2-30 2. Hb SS, S-thal0, S-thal+, SC 3. Evidence of ongoing hemolysis: Hb\<10, retic \>5%, LDH \> 500, TB\>2 4. Karnofsky/Lansky score \>50 5. LVSF\>26% or LVEF\>40% 6. DLCO \>40% or O2 sat \>85% for those patients that can't perform PFTs 7. GFR \>70 and serum creatinine \< 1.5 \* ULN for age 8. ALT and AST \< 5 x ULN, direct bilirubin \<2 x ULN 9. If the patient has been on chronic transfusion or has a ferritin \>1000, liver biopsy should be done and show no evidence of bridging fibrosis or cirrhosis *
Exclusion criteria
1. Evidence of uncontrolled bacterial, viral, or fungal infection within one month prior to initiation of the conditioning regimen 2. Pregnant or breastfeeding 3. HIV positive 4. Written informed consent not obtained
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Graft Failure | 2 years | Primary endpoint: In each group, the Number of participants with Graft Failure at the 2 years endpoint will be estimated using the Kaplan Meier product limit estimator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 2 years | Secondary endpoints: Overall survival: The distribution of time to death from any cause will be estimated by Kaplan- Meier product limit function and plotted. The overall survival will be measured from the time of transplant to any death and patients will be followed for 2 years. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients With Sickle Cell Anemia Patients with sickle cell anemia, age 2-30, that received transplant after after conditioning regimen Alemtuzumab, Fludarabine, and Melphalan. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Ineligible | 4 |
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Patients With Sickle Cell Anemia |
|---|---|
| Age, Categorical <=18 years | 22 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 11.68 years |
| Race/Ethnicity, Customized Race/Ethnicity | 0 Participants |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 25 |
| other Total, other adverse events | 0 / 25 |
| serious Total, serious adverse events | 13 / 25 |
Outcome results
Primary
Number of Participants With Graft Failure
Primary endpoint: In each group, the Number of participants with Graft Failure at the 2 years endpoint will be estimated using the Kaplan Meier product limit estimator.
Time frame: 2 years
Population: Patients that were followed at 2 years post transplant for graft failure
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patients With Sickle Cell Anemia | Number of Participants With Graft Failure | 3 Participants |
Secondary
Overall Survival
Secondary endpoints: Overall survival: The distribution of time to death from any cause will be estimated by Kaplan- Meier product limit function and plotted. The overall survival will be measured from the time of transplant to any death and patients will be followed for 2 years.
Time frame: 2 years
Population: Patients surviving at 2 years post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patients With Sickle Cell Anemia | Overall Survival | 23 Participants |