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Haploidentical PBMC Transplant for Severe Congenital Anemias
Phase 1, PHASE2 trial testing PBSC Transplant in Sickle Cell Anemia in 23 participants. Participants enrolled and being followed up; not accepting new ones.
| Lead sponsor | National Heart, Lung, and Blood Institute (NHLBI) |
|---|---|
| Phase | Phase 1, PHASE2 |
| Status | Active, enrolled |
| Study type | INTERVENTIONAL |
| Allocation | non randomized |
| Design | sequential |
| Masking | none |
| Primary purpose | treatment |
| Enrollment | 23 |
| Start date | 14 December 2009 |
| Primary completion | 1 August 2018 |
| Estimated completion | 10 September 2026 |
| Sites | 1 location across United States |
National Heart, Lung, and Blood Institute (NHLBI)
Adults 2 to 80, any sex, with Sickle Cell Anemia. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
Percentage of patients post transplant with sustained donor type hemoglobin on hemoglobin electrophoresis
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 3 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 6 |
Define the level of chimerism required to maintain graft survival and hematologic normalcy. Hematologic normalcy may be defined as: being free from sickle cell disease. The chimeric status of patients will be measured on days +14 (or when subject starts to engraft), +30, +60 and +100, and periodically after day +100, by microsatellite analysis of the peripheral blood. Engraftment of donor cells was assessed with the use of methods that detect informative polymorphisms in regions known to contain short tandem repeats. Peripheral-blood CD3+ T cells and CD14+CD15+ myeloid cells were selected fo
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 2 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 6 |
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 3 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 6 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 6 |
Number of participants who developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV as defined by CIMBTR criteria for Organ Stages of Acute GVHD. Grades are defined as: Grade I: Skin = Maculopapular rash\< 25% of body surface area (BSA); Liver = Total Bilirubin 2-3 mg/dL; Lower GI = stool output/day is 500-999 mL/day. Grade II: Skin = rash on 25-50 percent body surface area; Liver = Total Bilirubin 3.1-6.0 mg/dL; Lower GI = Diarrhea 1001-1500 mL/day. Grade III: Skin = Rash on \>50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea \> 1500 mL/day. Gra
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 1 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 1 |
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 |
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 |
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 |
Number of incidences of participants who developed Limited Chronic Graft vs Host Disease (GVHD). Limited disease is characterized by localized skin involvement and/or evidence of hepatic dysfunction. Limited disease is associated with a favorable outcome without systemic therapy, while extensive disease patients have an unfavorable outcome.
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 1 |
Number of participants with extensive, Chronic Graft vs Host Disease (GVHD). Extensive chronic GVHD is defined as GVHD occurring after day 100 that did not meet the definition of limited chronic GVHD. Extensive disease presents either with generalized skin involvement, or with localized skin involvement or hepatic dysfunction plus at least one of the following: * Liver histology showing chronic progressive hepatitis, bridging necrosis, or cirrhosis * Involvement of the eye (Schirmer's test with less than 5 mm wetting) (see "Diagnosis and classification of Sjögren's syndrome") * Involvement o
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 |
Number of participants with disease-free survival, as defined by: alive and free acute complications related to sickle cell disease.
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 2 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 6 |
Number of participants overall survival by year 5
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 1 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 7 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 11 | |
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 2 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 1 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 1 |
Number of participants with graft failure by year 5. Graft failure is defined by return of sickle cell disease.
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 3 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 6 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 6 |
Number of participants that experienced a transplant related mortality, as defined as death from causes other than relapse (GVHD, toxicity, infection, other and unknown causes).
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 1 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 |
Number of stem cell transplant participants that experienced rejection at each dose of post-transplant cyclophosphamide. Determine whether post-transplant cyclophosphamide is required and will reduce the incidence and severity of regimen failure.
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 3 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 |
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 6 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 |
| Group | Value | 95% CI |
|---|---|---|
| PBSC Transplant With no Post-transplant Cyclophosphamide (PT-Cy) | 0 | |
| PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 0 | |
| PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy) | 6 |
Determine whether specific haploidentical donors (i.e. parent versus sibling versus child) will decrease the incidence of regimen failure
| Group | Value | 95% CI |
|---|---|---|
| Participants Who Engrafted Following Stem Cell Transplant | 0 | |
| Participants Who Rejected Engraftment Following Stem Cell Transplant | 1 |
| Group | Value | 95% CI |
|---|---|---|
| Participants Who Engrafted Following Stem Cell Transplant | 3 | |
| Participants Who Rejected Engraftment Following Stem Cell Transplant | 6 |
| Group | Value | 95% CI |
|---|---|---|
| Participants Who Engrafted Following Stem Cell Transplant | 2 | |
| Participants Who Rejected Engraftment Following Stem Cell Transplant | 1 |
| Group | Value | 95% CI |
|---|---|---|
| Participants Who Engrafted Following Stem Cell Transplant | 3 | |
| Participants Who Rejected Engraftment Following Stem Cell Transplant | 3 |
| Group | Value | 95% CI |
|---|---|---|
| Participants Who Engrafted Following Stem Cell Transplant | 0 | |
| Participants Who Rejected Engraftment Following Stem Cell Transplant | 1 |
Time frame: 5 year. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | PBSC Transplant With no Po… | PBSC Transplant With 50 mg… | PBSC Transplant With 100 m… |
|---|---|---|---|---|
| Infection | Infections and infestations | — | — | — |
| Pain | General disorders | — | — | — |
| Sepsis | Infections and infestations | — | — | — |
| Sickle cell anemia with crisis | Blood and lymphatic system disorders | — | — | — |
| Syncope | Cardiac disorders | — | — | — |
| Lung infection | Infections and infestations | — | — | — |
| Upper respiratory tract infection | Infections and infestations | — | — | — |
| Pulmonary Embolism | Respiratory, thoracic and mediastinal disorders | — | — | — |
| Anemia | Blood and lymphatic system disorders | — | — | — |
| Myelodysplastic syndrome | Blood and lymphatic system disorders | — | — | — |
| Cardiovascular disorder | Cardiac disorders | — | — | — |
| Ventricular tachycardia | Cardiac disorders | — | — | — |
| Abdominal pain | Gastrointestinal disorders | — | — | — |
| Colitis | Gastrointestinal disorders | — | — | — |
| Upper gastrointestinal Hemorrhage | Gastrointestinal disorders | — | — | — |
| Device related infection | General disorders | — | — | — |
| Device related thrombosis | General disorders | — | — | — |
| Extravasation | General disorders | — | — | — |
| Inflammation | General disorders | — | — | — |
| Hepatic hemorrhage | Hepatobiliary disorders | — | — | — |
| Portal hypertension | Hepatobiliary disorders | — | — | — |
| Hypersensitivity | Immune system disorders | — | — | — |
| Cytomegalovirus infection | Infections and infestations | — | — | — |
| Infective Myositis | Infections and infestations | — | — | — |
| Fall | Injury, poisoning and procedural complications | — | — | — |
Most-reported serious reactions: Infection, Pain, Sepsis, Sickle cell anemia with crisis, Syncope, Lung infection, Upper respiratory tract infection, Pulmonary Embolism.
Data from ClinicalTrials.gov NCT00977691 adverse events section.
Background: Bone marrow transplantation (BMT), which involves transplanting a donor's marrow stem cells, is capable of curing some congenital anemias. BMT usually involves high-intensity treatment with chemotherapy and radiation to kill abnormal cells, which affects all systems of the body. People with anemias often have damage to other organs such as the kidneys, which can be further damaged by the chemotherapy. Only approximately 20 percent of patients have a full-matched donor, making treatment for many people with anemias unavailable. However, 90 percent of patients may have a half-matched donor, but using a half-matched donor increases the toxicity of BMT. Objectives: To determine if a research BMT with half-matched donor cells, low-intensity radiation, immunosuppressant drugs, and no chemotherapy will be effective in patients with sickle cell disease and Beta-thalassemia. To determine the effectiveness of cyclophosphamide, an immunosuppressant drug, in preventing rejection of the donor cells. Eligibility: Recipients are individuals at least 18 years of age who have been diagnosed with sickle cell disease and Beta-thalassemia, and who have a family member who is a haploidentical (i.e., half match) tissue match. Donors are healthy individuals between the ages of 2 and 80 who are found to be suitable donors. Design: Donors will undergo apheresis, which involves withdrawing blood from one arm vein, passing it through a machine that removes bone marrow stem cells, and returning the remaining blood through the vein in the other arm. Donors will receive a drug that causes the stem cells to be released into the bloodstream prior to the apheresis procedure. Recipients will undergo routine physical and laboratory examinations, including bone marrow sampling at the beginning of the study. After transplantation, physical and laboratory examinations will occur on a weekly or twice weekly basis at the outpatient clinic. Recipients will be examined every 6 months starting 100 days posttransplant for 5 years. Recipients will receive low-dose radiation in two treatments 1 and 2 days before the transplant. They will also be given immunosuppressant therapy with alemtuzumab and sirolimus. Another immunosuppressant drug, cyclophosphamide, will be given in the future as needed to subsets of the recipients to prevent rejection of donor cells. Recipients will receive the donor stem cells through a previously inserted central line. The process takes up to 8 hours. Recipients will receive blood transfusions as necessary to prevent anemia and bleeding during the posttransplant period. They may also receive intravenous antibiotics to prevent infection.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing