Sickle Cell Disease, Thalassemia Major
Conditions
Brief summary
This is a single arm pilot study of peripheral stem cell transplantation (PSCT) with ex vivo t-cell receptor alpha beta+(TCRαβ+) T cell and cluster of differentiation 19+ beta (CD19+ B) cell depletion of unrelated donor (URD) grafts using the CliniMACS device in patients with sickle cell disease (SCD) and beta thalassemia major (BTM).
Detailed description
This is a single arm pilot study of peripheral stem cell transplantation (PSCT) with ex vivo TCRαβ+ T cell and CD19+ B cell depletion of URD grafts using the CliniMACS device in patients with SCD and BTM. Apart from CliniMACS-based cell processing, PSCT will be performed according to current standards of care in the Children's Hospital of Philadelphia (CHOP) Cell Therapy and Transplant Section, including the use of a standard chemotherapy conditioning regimen and standard follow-up laboratory assessments. The study will determine efficacy of this strategy in terms of engraftment, rates of acute and chronic Graft versus Host Disease (GvHD), and one-year overall and event-free survival.
Interventions
DEVICECliniMACS
Peripheral blood stem cells from closely matched unrelated donors will be processed using the CliniMACS device to remove TCRalpha/beta T cells and B cells, in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique
Sponsors
Timothy Olson
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
Severe Sickle Cell Disease * Genotype: Hemoglobin SS, Hemoglobin SC, Hemoglobin SD, SOArab, or Hemoglobin SBeta thalassemia * Must have at least one of the following disease manifestations * Clinically symptomatic neurologic event (stroke) or any neurologic deficit lasting greater than 24 hours at any time prior to enrollment * History of two or more episodes of vaso-occlusive events (VOE) per year in the 2 years preceding enrolment. Patients must be refractory to hydroxyurea, defined as developing VOE despite receiving hydroxyurea for at least 6 months. Patients who are intolerant of hydroxyurea may also be enrolled. Vaso-occlusive events include: * Acute chest syndrome * Pain episodes requiring intravenous pain management and/or hospitalization * Priapism * Splenic sequestration (defined as a 2 g/dL drop in hemoglobin in the setting of an acutely enlarging spleen. This will be determined as part of clinical care and prior to the research) * Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving ≥ 8 RBC transfusions in the year preceding enrollment to prevent sickle cell-related complications of any kind per treating hematologist's judgment. Beta Thalassemia Major * Genotype: Confirmed Beta Thalassemia genotype by molecular genetic testing (May include E/Beta0 and Beta0/Beta+ genotypes) * Must meet clinical diagnosis of transfusion-dependent thalassemia, defined as need for ≥ 8 RBC transfusions per year in the two years preceding study enrollment.
Exclusion criteria
* Patients who do not meet disease, organ or infectious criteria. * Previous Hematopoietic stem cell transplant (HSCT) * Patients with no suitable unrelated donor available. Patients with suitable fully matched related donor are also not eligible. * Pregnant females. All females of childbearing potential must have negative pregnancy test. * Participation in a clinical trial in which the patient receives an investigational drug must be discontinued prior to the time of initiation of transplant therapy. Specifically transplant chemotherapy should not begin until at least 3 half-lives after last use of the investigational drug. * Severe RBC alloimmunization, defined as inability to receive packed RBC transfusion therapy due to anti-RBC antibodies. Patients with high titer anti-donor human leukocyte antigen (HLA) antibodies detected on screening may be enrolled if they are willing to undergo HLA antibody desensitization therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Graft Failure | Up to 1 year post-transplantation | Number of patients with primary graft failure (defined as no evidence of neutrophil engraftment by day +30 after stem cell infusion) and secondary graft failure (defined as ANC \<500 for at least 7-10 days after initial engraftment occurs in the absence of known infection or drug-mediated suppression, and confirmed by hypocellular bone marrow biopsy and/or total donor chimerism percentage from blood or bone marrow \< 10 percent) |
| Time to Neutrophil Engraftment | Up to 60 days post-transplantation | Number of days to neutrophil engraftment (first day of ANC \>500/µl for the first of 3 consecutive days) |
| Incidence of Acute Graft vs. Host Disease (GVHD) | Up to 100 days post-transplantation | Acute GvHD was assessed by the number of patients who developed acute graft-versus-host disease, graded according to current Center for International Bone Marrow Transplant Registry (CIBMTR) reporting guidelines. Grading follows established criteria based on the severity of skin, liver, and gastrointestinal involvement, including extent of rash, bilirubin elevation, and gastrointestinal symptoms (e.g., diarrhea volume). Evaluation was performed by clinical assessment and laboratory data consistent with standard transplant-related acute GvHD grading practices. |
| Incidence of Chronic Graft vs. Host Disease (GVHD) | Up to two years post-transplantation | Number of patients with Grade II-IV acute GVHD, Severe Grade III-IV acute GVHD, and Chronic Extensive GVHD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Deaths Due to Treatment | Up to 100 days post-transplantation | Number of subjects deaths that were related to study treatment |
| Probability of Event-free Survival (EFS) | Up to 1 year post-transplantation | Number of patients without complications or events |
| Probability of Overall Survival (OS) | 1 year post-transplantation | Number of patients with the following survival outcome: one-year overall survival (OS) |
| Incidence of Viral Reactivation and Symptomatic Viral Infection | Up to 1 year post-transplantation | Number of patients experiencing viral reactivation requiring therapy and symptomatic viral infections, including CMV, adenovirus, and EBV |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTimothy Olson, MD, PhD
Children's Hospital of Philadelphia
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 7 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 10.7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| HLA Donor Match Category (10/10 Matched vs 9/10 Mismatched) Matched Donor (10/10) | 4 participants |
| HLA Donor Match Category (10/10 Matched vs 9/10 Mismatched) Mismatched Donor (9/10) | 1 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 7 | 0 / 1 |
| other Total, other adverse events | 7 / 7 | 1 / 1 |
| serious Total, serious adverse events | 2 / 7 | 0 / 1 |
Outcome results
None listed