Bone Marrow TransplantationPhase 3NCT00000591
T-Cell Depletion in Unrelated Donor Marrow Transplantation
A Phase 3 study testing lymphocyte depletion in people with Bone Marrow Transplantation and Graft vs Host Disease, run by National Heart, Lung, and Blood Institute (NHLBI).
Trial summary
To determine if a reduction in morbidity and mortality from acute and chronic graft versus host disease (GvHD) can be achieved through use of T-cell depletion techniques without a counterbalancing increase in relapse of leukemia in patients receiving an unrelated donor marrow transplant. Read more about this study
- Who is it for?
- Ages 1 year to 55 years
- Conditions the study is for
- Bone Marrow Transplantation, Graft vs Host Disease, Immunologic Diseases
- What is being tested?
- lymphocyte depletion
- Type of treatment
- Surgery or procedure
- How many people
- Not given
- Where
- No sites listed yet
- Study dates
- Nov 1993to Feb 2005
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 55 years
- All sexes
- No healthy volunteers
- Child, Adult
No eligibility criteria
About this study
To determine if a reduction in morbidity and mortality from acute and chronic graft versus host disease (GvHD) can be achieved through use of T-cell depletion techniques without a counterbalancing increase in relapse of leukemia in patients receiving an unrelated donor marrow transplant.
Read the detailed description
BACKGROUND:
Allogeneic bone marrow transplantation is an accepted therapeutic option for many hematologic, immunologic, and malignant diseases, including chronic myelocytic leukemia and acute leukemia during or after first relapse (second remission). In order to maximize the chance for a successful transplant, it is desirable that the donor and the recipient share the same Human Leukocyte Antigen (HLA) histocompatibility antigens. Because of the Mendelian inheritance of HLA antigens, the chances of finding a match are much greater among relatives than in the general population. However, only about 30 percent of patients needing a transplant have a matched sibling. Thus a transplant from an HLA-matched unrelated donor may be an important alternative for these patients.
Graft versus host disease is a frequent and severe complication of marrow transplantation. Acute GvHD typically occurs within three months after transplantation and is characterized by skin rash, liver dysfunction, and diarrhea. Although the pathophysiology of this disease is not fully defined in humans, data from animal studies suggest that it is mediated by mature donor T cells that react against disparate recipient histocompatibility antigens.
One treatment modality that ameliorates or prevents GvHD following allogeneic marrow transplantation is T cell-depletion of donor marrow before infusion into the recipient. T cell-depletion can be divided into physical methods such as separation by elutriation or sheep cell rosetting, and immunologic methods which use a T cell-specific antibody(ies) plus complement or toxin to kill the cells. These different techniques may remove a subpopulation of T cells, all T cells, or T cells plus other cell types such as B cells or natural killer (NK) cells. The number of stem cells transferred may also be affected.
Unfortunately, in many of the published studies conducted in patients receiving transplants from HLA-matched siblings, T cell-depletion used to prevent or treat GvHD increased the chances of other complications, namely graft failure and leukemia relapse. This is not surprising in light of studies of patients with both early and advanced leukemias that demonstrated a decreased risk of relapse associated with acute and/or chronic GvHD. Because the net effect of these opposing consequences of T cell-depletion on leukemia-free survival in related donor transplants is generally unfavorable, T cell-depletion for related donor marrow transplantation is controversial. The utility of T-cell depletion in unrelated-donor transplants needs to be determined.
The initiative grew out of increasing concern on the part of Institute staff, the bone marrow transplantation community, and members of Congress that graft versus host disease is so frequent and severe a complication of unrelated donor transplants that it has become a limiting factor in their outcome. The initiative was given concept clearance by the May 1992 National Heart, Lung, and Blood Advisory Council and released in January 1993.
DESIGN NARRATIVE:
The primary endpoint of this trial was disease free survival at three years post transplant. Secondary endpoints included overall survival, incidence of GvHD, graft failure, infections and other complications, and time to disease relapse. The covariates considered included age of recipient, disease risk status, interval between diagnosis and transplant, disease type, age and gender of donor, post-transplant chimerism, pre-transplant Karnofsky score, and other measures of performance status. An economic analysis was performed.
Patients were randomly assigned to receive either a T-cell depleted or a non-depleted transplant. Two methods of T-cell depletion were in use: an anti-CD3 monoclonal antibody, T10B9, plus complement, or counterflow elutriation plus the Ceprate column. Each method of T-depletion was part of a package that included a specific pre-transplant conditioning regimen and additional GvHD prophylaxis. Patients randomized to the non-T-cell depleted arm received a conditioning regimen containing cyclophosphamide and total body irradiation, and a GvHD prophylaxis regimen of cyclosporin and methotrexate. A total of 410 patients were enrolled. Enrollment ended October 31, 2000.
A total of 14 transplant centers participated in the study, Follow-up ended in April 2002.
- Conditions
- Bone Marrow Transplantation, Graft vs Host Disease, Immunologic Diseases, Leukemia, Myelodysplastic Syndromes
- Being tested
- lymphocyte depletion
- Medical subject headings
- Graft vs Host Disease, Immune System Diseases, Leukemia, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
lymphocyte depletionProcedure or surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Oct 1999 (estimated)
- Study startNov 1993
- Study completionFeb 2005
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Bone Marrow TransplantationStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Investigators
- Shelly Carter, The Emmes Company, LLCJohn Wagner, University of Minnesota
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00000591
- Sponsor's protocol ID
- 311
- Status last verified
- Nov 2005
- First submitted
- 27 Oct 1999
- Last updated
- 15 Apr 2016
- Results posted
- No
Publications
Howe C, Wagner J, Kerman N, et al. 1995. T-cell Depletion in Unrelated-donor Marrow Transplantation. Blood 391a (abstract).
Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood. 2003 Jun 1;101(11):4233-44. doi: 10.1182/blood-2002-08-2510. Epub 2003 Jan 9. No abstract available.
PubMed 12522002Davies SM, Radloff GA, Wagner JE, McGlennen R, Kersey JH, Ramsay NK. Polyclonal engraftment after unrelated donor bone marrow and cord blood transplantation. Biol Blood Marrow Transplant. 1997 Dec;3(6):304-9.
PubMed 9502297Davies SM, Wagner JE, Defor T, Blazar BR, Katsanis E, Kersey JH, Orchard PJ, McGlave PB, Weisdorf DJ, Ramsay NK. Unrelated donor bone marrow transplantation for children and adolescents with aplastic anaemia or myelodysplasia. Br J Haematol. 1997 Mar;96(4):749-56. doi: 10.1046/j.1365-2141.1997.d01-2087.x.
PubMed 9074418Davies SM, Wagner JE, Weisdorf DJ, Shu XO, Blazar BR, Enright H, McGlave PB, Ramsay NK. Unrelated donor bone marrow transplantation for hematological malignancies-current status. Leuk Lymphoma. 1996 Oct;23(3-4):221-6. doi: 10.3109/10428199609054824.
PubMed 9031102Pawlowska AB, Davies SM, Orchard PJ, Wagner JE, Ramsay NK. Unrelated donor bone marrow transplantation for acute leukemia in patients with Down's syndrome. Bone Marrow Transplant. 1996 Aug;18(2):453-5.
PubMed 8864463Davies SM, Szabo E, Wagner JE, Ramsay NK, Weisdorf DJ. Idiopathic hyperammonemia: a frequently lethal complication of bone marrow transplantation. Bone Marrow Transplant. 1996 Jun;17(6):1119-25.
PubMed 8807124Davies SM, Khan S, Wagner JE, Arthur DC, Auerbach AD, Ramsay NK, Weisdorf DJ. Unrelated donor bone marrow transplantation for Fanconi anemia. Bone Marrow Transplant. 1996 Jan;17(1):43-7.
PubMed 8673053Pavletic SZ, Carter SL, Kernan NA, Henslee-Downey J, Mendizabal AM, Papadopoulos E, Gingrich R, Casper J, Yanovich S, Weisdorf D; National Heart, Lung, and Blood Institute Unrelated Donor Marrow Transplantation Trial. Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation. Blood. 2005 Nov 1;106(9):3308-13. doi: 10.1182/blood-2005-04-1614. Epub 2005 Jul 26.
PubMed 16046530de Lissovoy G, Hurd D, Carter S, Beatty P, Ewell M, Henslee-Downey J, Kernan N, Yanovich S, Weisdorf D. Economic analysis of unrelated allogeneic bone marrow transplantation: results from the randomized clinical trial of T-cell depletion vs unmanipulated grafts for the prevention of graft-versus-host disease. Bone Marrow Transplant. 2005 Sep;36(6):539-46. doi: 10.1038/sj.bmt.1705078.
PubMed 16044144McCullough J, McKenna D, Kadidlo D, Schierman T, Wagner J. Issues in the quality of umbilical cord blood stem cells for transplantation. Transfusion. 2005 Jun;45(6):832-41. doi: 10.1111/j.1537-2995.2005.04265.x.
PubMed 15934980Wagner JE, Thompson JS, Carter SL, Kernan NA; Unrelated Donor Marrow Transplantation Trial. Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial. Lancet. 2005 Aug 27-Sep 2;366(9487):733-41. doi: 10.1016/S0140-6736(05)66996-6.
PubMed 16125590
Study at a glance
From the registry record, last updated by the sponsor on 15 Apr 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- T-Cell Depletion in Unrelated Donor Marrow Transplantation
- ClinicalTrials.gov ID
- NCT00000591
- Acronym / sponsor ID
- 311
- Conditions
- Bone Marrow Transplantation, Graft vs Host Disease, Immunologic Diseases, Leukemia, Myelodysplastic Syndromes
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- Nov 1993
- Study completion
- Feb 2005
- First posted
- 28 Oct 1999 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To determine if a reduction in morbidity and mortality from acute and chronic graft versus host disease (GvHD) can be achieved through use of T-cell depletion techniques without a counterbalancing increase in relapse of leukemia in patients receiving an unrelated donor marrow transplant.
Detailed description
BACKGROUND:
Allogeneic bone marrow transplantation is an accepted therapeutic option for many hematologic, immunologic, and malignant diseases, including chronic myelocytic leukemia and acute leukemia during or after first relapse (second remission). In order to maximize the chance for a successful transplant, it is desirable that the donor and the recipient share the same Human Leukocyte Antigen (HLA) histocompatibility antigens. Because of the Mendelian inheritance of HLA antigens, the chances of finding a match are much greater among relatives than in the general population. However, only about 30 percent of patients needing a transplant have a matched sibling. Thus a transplant from an HLA-matched unrelated donor may be an important alternative for these patients.
Graft versus host disease is a frequent and severe complication of marrow transplantation. Acute GvHD typically occurs within three months after transplantation and is characterized by skin rash, liver dysfunction, and diarrhea. Although the pathophysiology of this disease is not fully defined in humans, data from animal studies suggest that it is mediated by mature donor T cells that react against disparate recipient histocompatibility antigens.
One treatment modality that ameliorates or prevents GvHD following allogeneic marrow transplantation is T cell-depletion of donor marrow before infusion into the recipient. T cell-depletion can be divided into physical methods such as separation by elutriation or sheep cell rosetting, and immunologic methods which use a T cell-specific antibody(ies) plus complement or toxin to kill the cells. These different techniques may remove a subpopulation of T cells, all T cells, or T cells plus other cell types such as B cells or natural killer (NK) cells. The number of stem cells transferred may also be affected.
Unfortunately, in many of the published studies conducted in patients receiving transplants from HLA-matched siblings, T cell-depletion used to prevent or treat GvHD increased the chances of other complications, namely graft failure and leukemia relapse. This is not surprising in light of studies of patients with both early and advanced leukemias that demonstrated a decreased risk of relapse associated with acute and/or chronic GvHD. Because the net effect of these opposing consequences of T cell-depletion on leukemia-free survival in related donor transplants is generally unfavorable, T cell-depletion for related donor marrow transplantation is controversial. The utility of T-cell depletion in unrelated-donor transplants needs to be determined.
The initiative grew out of increasing concern on the part of Institute staff, the bone marrow transplantation community, and members of Congress that graft versus host disease is so frequent and severe a complication of unrelated donor transplants that it has become a limiting factor in their outcome. The initiative was given concept clearance by the May 1992 National Heart, Lung, and Blood Advisory Council and released in January 1993.
DESIGN NARRATIVE:
The primary endpoint of this trial was disease free survival at three years post transplant. Secondary endpoints included overall survival, incidence of GvHD, graft failure, infections and other complications, and time to disease relapse. The covariates considered included age of recipient, disease risk status, interval between diagnosis and transplant, disease type, age and gender of donor, post-transplant chimerism, pre-transplant Karnofsky score, and other measures of performance status. An economic analysis was performed.
Patients were randomly assigned to receive either a T-cell depleted or a non-depleted transplant. Two methods of T-cell depletion were in use: an anti-CD3 monoclonal antibody, T10B9, plus complement, or counterflow elutriation plus the Ceprate column. Each method of T-depletion was part of a package that included a specific pre-transplant conditioning regimen and additional GvHD prophylaxis. Patients randomized to the non-T-cell depleted arm received a conditioning regimen containing cyclophosphamide and total body irradiation, and a GvHD prophylaxis regimen of cyclosporin and methotrexate. A total of 410 patients were enrolled. Enrollment ended October 31, 2000.
A total of 14 transplant centers participated in the study, Follow-up ended in April 2002.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
Who may qualify
- Ages
- 1 year to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| lymphocyte depletion | Procedure or surgery | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Apr 2016.
- BackgroundHowe C, Wagner J, Kerman N, et al. 1995. T-cell Depletion in Unrelated-donor Marrow Transplantation. Blood 391a (abstract).
- Background: PubMed 12522002Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood. 2003 Jun 1;101(11):4233-44. doi: 10.1182/blood-2002-08-2510. Epub 2003 Jan 9. No abstract available.
- Background: PubMed 9502297Davies SM, Radloff GA, Wagner JE, McGlennen R, Kersey JH, Ramsay NK. Polyclonal engraftment after unrelated donor bone marrow and cord blood transplantation. Biol Blood Marrow Transplant. 1997 Dec;3(6):304-9.
- Background: PubMed 9074418Davies SM, Wagner JE, Defor T, Blazar BR, Katsanis E, Kersey JH, Orchard PJ, McGlave PB, Weisdorf DJ, Ramsay NK. Unrelated donor bone marrow transplantation for children and adolescents with aplastic anaemia or myelodysplasia. Br J Haematol. 1997 Mar;96(4):749-56. doi: 10.1046/j.1365-2141.1997.d01-2087.x.
- Background: PubMed 9031102Davies SM, Wagner JE, Weisdorf DJ, Shu XO, Blazar BR, Enright H, McGlave PB, Ramsay NK. Unrelated donor bone marrow transplantation for hematological malignancies-current status. Leuk Lymphoma. 1996 Oct;23(3-4):221-6. doi: 10.3109/10428199609054824.
- Background: PubMed 8864463Pawlowska AB, Davies SM, Orchard PJ, Wagner JE, Ramsay NK. Unrelated donor bone marrow transplantation for acute leukemia in patients with Down's syndrome. Bone Marrow Transplant. 1996 Aug;18(2):453-5.
- Background: PubMed 8807124Davies SM, Szabo E, Wagner JE, Ramsay NK, Weisdorf DJ. Idiopathic hyperammonemia: a frequently lethal complication of bone marrow transplantation. Bone Marrow Transplant. 1996 Jun;17(6):1119-25.
- Background: PubMed 8673053Davies SM, Khan S, Wagner JE, Arthur DC, Auerbach AD, Ramsay NK, Weisdorf DJ. Unrelated donor bone marrow transplantation for Fanconi anemia. Bone Marrow Transplant. 1996 Jan;17(1):43-7.
- Background: PubMed 16046530Pavletic SZ, Carter SL, Kernan NA, Henslee-Downey J, Mendizabal AM, Papadopoulos E, Gingrich R, Casper J, Yanovich S, Weisdorf D; National Heart, Lung, and Blood Institute Unrelated Donor Marrow Transplantation Trial. Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation. Blood. 2005 Nov 1;106(9):3308-13. doi: 10.1182/blood-2005-04-1614. Epub 2005 Jul 26.
- Background: PubMed 16044144de Lissovoy G, Hurd D, Carter S, Beatty P, Ewell M, Henslee-Downey J, Kernan N, Yanovich S, Weisdorf D. Economic analysis of unrelated allogeneic bone marrow transplantation: results from the randomized clinical trial of T-cell depletion vs unmanipulated grafts for the prevention of graft-versus-host disease. Bone Marrow Transplant. 2005 Sep;36(6):539-46. doi: 10.1038/sj.bmt.1705078.
- Background: PubMed 15934980McCullough J, McKenna D, Kadidlo D, Schierman T, Wagner J. Issues in the quality of umbilical cord blood stem cells for transplantation. Transfusion. 2005 Jun;45(6):832-41. doi: 10.1111/j.1537-2995.2005.04265.x.
- Background: PubMed 16125590Wagner JE, Thompson JS, Carter SL, Kernan NA; Unrelated Donor Marrow Transplantation Trial. Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial. Lancet. 2005 Aug 27-Sep 2;366(9487):733-41. doi: 10.1016/S0140-6736(05)66996-6.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Shelly Carter
The Emmes Company, LLC
John Wagner
University of Minnesota
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing lymphocyte depletion in people with Bone Marrow Transplantation and Graft vs Host Disease, run by National Heart, Lung, and Blood Institute (NHLBI).
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Apr 2016. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00000591, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Apr 2016.