Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes Using G-CSF Mobilized CD34+ Selected Hematopoietic Precursor Cells Co-Infused With a Reduced Dose of Non-Mobilized Donor T-cells
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT01174108|
Recruitment Status : Recruiting
First Posted : August 3, 2010
Last Update Posted : May 9, 2018
- Stem cell transplants from related donors (allogenic stem cell transplants) can be used to treat individuals with certain kinds of severe blood diseases or cancers, such as severe anemia. Allogenic stem cell transplants encourage the growth of new bone marrow to replace that of the recipient. Because stem cell transplants can have serious complications, researchers are interested in developing new approaches to stem cell transplants that will reduce the likelihood of these complications.
- By reducing the number of white blood cells included in the blood taken during the stem cell collection process, and replacing them with a smaller amount of white blood cells collected prior to stem cell donation, the stem cell transplant may be less likely to cause severe complications for the recipient. Researchers are investigating whether altering the stem cell transplant donation procedure in this manner will improve the likelihood of a successful stem cell transplant with fewer complications.
- To evaluate a new method of stem cell transplantation that may reduce the possibly of severe side effects or transplant rejection in the recipient.
- Recipient: Individuals between 4 and 80 years of age who have been diagnosed with a blood disease that can be treated with allogenic stem cell transplants, and who have a related donor to provide the stem cells.
- Donor: Individuals between 4 and 80 years of age who are related to the recipient and are eligible to donate blood.
- All participants will be screened with a physical examination and medical history.
- Donors will undergo an initial apheresis procedure to donate white blood cells.
- After the initial donation, donors will receive injections of filgrastim to release bone marrow cells into the blood.
- After 5 days of filgrastim injections, donors will have apheresis again to donate stem cells that are present in the blood.
- Recipients will provide an initial donation of white blood cells to be used for research purposes only.
- From 7 days before the stem cell transplant, participants will be admitted to the inpatient unit of the National Institutes of Health Clinical Center and will receive regular doses of cyclophosphamide, fludarabine, and anti-thymocyte globulin to suppress their immune system and prepare for the transplant.
- After the initial chemotherapy, participants will receive the donated white blood cells and stem cells as a single infusion.
- After the stem cell and white blood cell transplant, participants will have regular doses of cyclosporine and methotrexate to prevent rejection of the donor cells. Participants will have three doses of methotrexate within the week after the transplant, but will continue to take cyclosporine for up to 4 months after the transplant.
- Participants will remain in inpatient care for up to 1 month after the transplant, and will be followed with regular visits for up to 3 years with periodic visits thereafter to evaluate the success of the transplant and any side effects.
|Condition or disease||Intervention/treatment||Phase|
|Severe Aplastic Anemia MDS (Myelodysplastic Syndrome)||Device: Miltenyi CD34 Reagent System Other: Donor derived G-CSF mobilized PBC||Phase 2|
Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with a variety of bone marrow failure syndromes (BMFS) including severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH) or myelodysplastic syndrome (MDS) associated with cytopenias. Patients with BMFS have traditionally been transplanted with bone marrow (BM) as a stem cell source. Although chronic graft versus host disease (cGVHD) occurs less commonly with BM compared to filgrastim (G-CSF) mobilized peripheral blood stem cell (PBSC) transplants, BM allografts have lower CD34+ progenitor cell numbers, which increases the risk of graft rejection in heavily transfused BMFS patients to 15-20 percent. To overcome this risk, our group developed a novel transplant approach for patients at high risk for graft rejection that utilized cyclophosphamide, fludarabine and anti-thymocyte globulin (ATG) conditioning followed by infusion of a CD34+ cell rich, T-cell replete G-CSF mobilized PBSC allograft. Remarkably, in 56 consecutive BMFS patients who had multiple risk factors for graft rejection who underwent this transplant approach graft rejection did not occur, with all patients achieving complete donor lymphohematopoietic chimerism. Unfortunately, recipients of G-CSF mobilized PBSC had a higher incidence of chronic GVHD than has historically been observed with BM transplantation (72 percent vs. 50 percent cumulative incidence of cGVHD at 1 year respectively). G-CSF mobilized PBSC transplants contained approximately a 20 fold higher dose of T-cells that had undergone a TH- 2 type cytokine polarization, a factor which likely contributed to this high incidence of cGVHD. In this protocol, we attempt to prevent graft failure and to reduce the incidence of cGVHD by transplanting high numbers of CD34+ selected PBSC co-infused with a reduced dose of non-mobilized donor T-cells that have not undergone a TH-2 cytokine polarization.
Subjects with BMFS at high risk for graft rejection will undergo allogeneic stem cell transplantation from an HLA identical sibling or match unrelated donor using the identical conditioning regimen utilized in protocol 99-H-0050. Using the Miltenyi CliniMACs system, recipients will receive an allograft on day 0 containing donor CD34+ cells that have been positively selected and T-cell depleted following G-CSF mobilization (goal CD34+ cell dose of 5 times 10(6) CD34+ cells /kg recipient) combined with 2 times 10(7) cells/kg of non-mobilized CD3+ T-cells previously collected and cryopreserved from the same donor by apheresis prior to G-CSF mobilization.
Primary objective: To evaluate whether administering a CD34+ selected, T-cell depleted peripheral blood stem cell graft with a concomitant infusion of non-mobilized donor T-cells at a dose that matches the T-cell dose that is infused in historical bone marrow transplant cohorts will reduce the incidence of cGVHD at 1 year to that observed with a conventional bone marrow transplant (50 percent) without increasing the risk of graft failure. This trial design will allow the trial to stop early if it is unlikely that we have reduced the proportion of one year cGVHD to 50 percent or if the combined event rate for failed donor engraftment or treatment related mortality (TRM) at day 100 exceeds 20 percent.
The primary endpoint of this study will be cGVHD at day 365.
Secondary end points include transplant related mortality, engraftment, degree of donor-host chimerism, incidence of acute and chronic graft versus host disease (GVHD), transplant related morbidity and overall survival. Health related quality of life will also be assessed as a secondary outcome measure pre-transplant, 30 and 100 days post transplant and every 6 months until 5 years post transplant.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||117 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes Using G-CSF Mobilized CD34+ Selected Hematopoietic Precursor Cells Co-Infused With a Reduced Dose of Non-Mobilized Donor T-Cells|
|Study Start Date :||July 30, 2010|
|Estimated Primary Completion Date :||June 30, 2019|
|Estimated Study Completion Date :||June 30, 2020|
- Primary endpoint of this study is chronic GVHD by one year. [ Time Frame: 1 year ]
- Transplant related mortality, engraftment, degree of donor-host chimerism, incidence of acute and chronic graft versus host disease (GVHD), transplant related morbidity and overall survival. [ Time Frame: Cumulative ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01174108
|Contact: Tatyana Worthy, R.N.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 email@example.com|
|University of Maryland at Baltimore/MPRC||Recruiting|
|Catonsville, Maryland, United States, 21228|
|Contact: Nancy Hardy, M.D. 410-328-1230 firstname.lastname@example.org|
|Principal Investigator:||Richard W Childs, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|