Sickle Cell Disease
Conditions
Brief summary
The purpose of this study is to develop a safe and curative stem cell transplant approach to treating sickle cell disease by assessing the safety of haploidentical hematopoietic stem cell transplantation using αβ+ T-cell depletion for children and adolescents with severe sickle cell disease (SCD).
Interventions
DEVICEαβ+ T-cell depletion with Miltenyi CliniMACS system
Haploidentical CD34+ megadose hematopoietic stem cell transplant in which cells are purified using the Miltenyi CliniMACS system designed for αβ+ T-cell receptor selection using immunomagnetic beads.
Sponsors
University of Chicago
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
* Hemoglobin SS, SC, S-β0 Thalassemia, or SO-Arab Sickle Cell Disease * Between the ages of 2 and 25 years (Stage 1: 10-25 years; Stage II: 2-25 years) * Lack a fully matched family donor or fully matched unrelated donor register in the National Marrow Donor Program * Partially-matched family member with hemoglobin AA (normal) or hemoglobin AS (sickle trait) phenotype * SCD with Severe Phenotype, defined by the following criteria: Neurologic manifestations of sickle disease including cerebral vascular accident (CVA), transient ischemic event (TIA) or abnormal MRI findings suggestive of silent infarct; Two or more episodes of acute chest syndrome (ACS) requiring admission for transfusional or respiratory support including supplemental oxygen within \[two years\] of enrollment in study despite hydroxyurea therapy. Patients who cannot tolerate hydroxyurea and who experience multiple episodes of ACS will also be eligible; History of severe vaso-occlusive (VOC) disease requiring hospitalization and intravenous narcotics on 3 or more occasions per year over the two years prior to enrollment despite hydroxyurea therapy. Patients who cannot tolerate hydroxyurea and who experience multiple episodes of VOC will also be eligible; Other severe phenotype as evidenced by end organ dysfunction related to sickle cell disease.
Exclusion criteria
* Karnofsky or Lansky score \< 60% * Acute hepatitis or evidence of moderate or severe portal fibrosis on biopsy. (Biopsy will be obtained if patient has been on chronic transfusion therapy \> 6 months or has a ferritin \> 1000 ng/ml) or AST or ALT \>5 times the upper limit of normal * Severe renal impairment (as evidenced by creatinine clearance of \<50ml/minute glomerular filtration rate (GFR) \< 50% predicted normal) * Cardiac function that demonstrates shortening fraction less than 26% by cardiac echocardiogram or pulmonary hypertension. * Pregnant Female. * Lactating female. * Pulmonary function with baseline O2 saturation \<85% or Diffusing Capacity for Carbon Monoxide (DLCO) on pulmonary function testing (PFT) with a DLCO \<40%.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety, as Measured by Incidence of Graft Failure, Grade III/IV Irreversible End Organ Toxicity, Grade III/IV aGvHD, or Death Within 100 Days Post-Hap-HSCT | 100 days post-Hap-HSCT | Graft Function: efficacy is defined as stable donor engraftment (\>5% total nucleated cell DNA) and donor erythropoiesis that corrects the SCD hematologic phenotype (\<50% HbS in the peripheral blood). Organ Toxicity: grade III/IV irreversible end organ toxicity based on NCI grading Graft Versus Host disease: grade III/IV aGvHD or death within 100 days post- Hap-HSCT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estimate 1-year Overall and Event-free Survival After Hap-HSCT | 1 year post transplant | Proportion of patients at 1 year who have not died or had graft failure |
| Observe the Incidence of Grades I Through IV Acute GvHD | 100 days post transplant | Proportion of subjects with grades I through IV acute GvHD |
| Observe Incidence of Severe Acute GvHD as Defined by Grades III Through IV | 100 days post transplant | Proportion of subjects with grades III through IV acute GvHD |
| Observe the Incidence of Grades I Through IV Chronic GvHD | 1 year post transplant | Proportion of subjects with grades I through IV chronic GvHD |
| Observe Incidence of Severe Chronic GvHD as Defined by Grades III and IV | 1 year post transplant | Proportion of subjects with grades III through IV chronic GvHD |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Stage I Stage I will include eligible subjects between the ages of 10-25 years.
αβ+ T-cell depletion with Miltenyi CliniMACS system: Haploidentical CD34+ megadose hematopoietic stem cell transplant in which cells are purified using the Miltenyi CliniMACS system designed for αβ+ T-cell receptor selection using immunomagnetic beads. | 3 |
| Stage II Stage II will include eligible subjects between the ages of 2-25 years.
αβ+ T-cell depletion with Miltenyi CliniMACS system: Haploidentical CD34+ megadose hematopoietic stem cell transplant in which cells are purified using the Miltenyi CliniMACS system designed for αβ+ T-cell receptor selection using immunomagnetic beads. | 0 |
| Total | 3 |
Baseline characteristics
| Characteristic | Stage II | Total | Stage I |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Continuous | — | 20 years | 20 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | — | 3 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Safety, as Measured by Incidence of Graft Failure, Grade III/IV Irreversible End Organ Toxicity, Grade III/IV aGvHD, or Death Within 100 Days Post-Hap-HSCT
Graft Function: efficacy is defined as stable donor engraftment (\>5% total nucleated cell DNA) and donor erythropoiesis that corrects the SCD hematologic phenotype (\<50% HbS in the peripheral blood). Organ Toxicity: grade III/IV irreversible end organ toxicity based on NCI grading Graft Versus Host disease: grade III/IV aGvHD or death within 100 days post- Hap-HSCT
Time frame: 100 days post-Hap-HSCT
Population: No subjects underwent transplant while on study. All subjects withdrawn and study closed prior to any study procedures/outcome measures performed.
Secondary
Estimate 1-year Overall and Event-free Survival After Hap-HSCT
Proportion of patients at 1 year who have not died or had graft failure
Time frame: 1 year post transplant
Population: No subjects underwent transplant while on study. All subjects withdrawn and study closed prior to any study procedures/outcome measures performed.
Secondary
Observe Incidence of Severe Acute GvHD as Defined by Grades III Through IV
Proportion of subjects with grades III through IV acute GvHD
Time frame: 100 days post transplant
Population: No subjects underwent transplant while on study. All subjects withdrawn and study closed prior to any study procedures/outcome measures performed.
Secondary
Observe Incidence of Severe Chronic GvHD as Defined by Grades III and IV
Proportion of subjects with grades III through IV chronic GvHD
Time frame: 1 year post transplant
Population: No subjects underwent transplant while on study. All subjects withdrawn and study closed prior to any study procedures/outcome measures performed.
Secondary
Observe the Incidence of Grades I Through IV Acute GvHD
Proportion of subjects with grades I through IV acute GvHD
Time frame: 100 days post transplant
Population: No subjects underwent transplant while on study. All subjects withdrawn and study closed prior to any study procedures/outcome measures performed.
Secondary
Observe the Incidence of Grades I Through IV Chronic GvHD
Proportion of subjects with grades I through IV chronic GvHD
Time frame: 1 year post transplant
Population: No subjects underwent transplant while on study. All subjects withdrawn and study closed prior to any study procedures/outcome measures performed.