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Hematologic MalignanciesPhase 2NCT00079391

Stem Cell Transplantation and T-Cell Add-Back to Treat Bone Marrow Malignancies

A Phase 2 study testing allogeneic hematopoietic stem cell transplantation in people with Hematologic Malignancies and Bone Marrow Transplant Rejection, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study will evaluate the safety and effectiveness of stem cell transplantation in which the donor's T cells (a type of lymphocyte, or white blood cell) are removed and then added back. Read more about this study

Who is it for?
Ages 2 to 80 years
What is being tested?
allogeneic hematopoietic stem cell transplantation
Type of treatment
Medical device
Could I receive a placebo?
No, everyone receives an active treatment
How many people
50 participants
Where
1 siteUnited States
Study dates
Jan 2004to Sep 2011
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 2 to 80 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • RECIPIENT:
  • 1. Ages 10-55 years inclusive (but less than 56)
  • 2. Chronic myelogenous leukemia (CML) in chronic phase
  • 3. Acute lymphoblastic leukemia (ALL) categories
  • Adults in first remission with high-risk features
  • All second or subsequent remissions, primary induction failure, partially responding or untreated relapse
Show all 27Show fewer
  • 4. Acute myelogenous leukemia (AML)
  • AML in first remission Except AML with good risk karyotypes
  • All AML in second or subsequent remission, primary induction failure and resistant relapse
  • 5. Myelodysplastic syndromes categories
  • refractory anemia with transfusion dependence
  • refractory anemia with excess of blasts
  • transformation to acute leukemia, chronic myelomonocytic leukemia
  • 6. Myeloproliferative disorders in transformation to acute leukemia
  • 7. Chronic lymphocytic leukemia refractory to fludarabine treatment and with bulky progressive disease or with thrombocytopenia (less than or equal to 100,000 /micro L) or anemia (less than or equal to 10g/dl) not due to recent chemotherapy
  • 8. Non-Hodgkin's lymphoma including Mantle cell lymphoma relapsing or refractory to current chemotherapy and monoclonal antibody treatment and unsuitable for autologous stem cell transplantation
  • 9. No major organ dysfunction precluding transplantation
  • 10. Diffusion capacity of lung for carbon monoxide (DLCO) greater than or equal to 60% predicted
  • 11. Left ventricular ejection fraction: greater than or equal to 40%
  • 12. Eastern Cooperative Oncology Group(ECOG) performance status of 0 or 1
  • 13. Able to give informed consent
  • 14. Negative pregnancy test for women of childbearing age
  • DONOR
  • 1. Human leukocyte antigen (HLA) 6/6 identical family donor
  • 2. Weight greater than or equal to 18 kg
  • 3. Age greater than or equal to 2 or less than or equal to 80 years old
  • 4. Fit to receive granulocyte colony -stimulating factor(G-CSF) and give peripheral blood stem cells (normal blood count, normotensive, no history of stroke)

Who cannot join

  • RECIPIENT
  • 1. Patient pregnant
  • 2. Age less than 10 years and 56 years or more
  • 3. Patients with CML in chronic phase who are 41 years or over in whom imatinib mesylate (STI-571)is the treatment of choice
  • 4. ECOG performance status of 2 or more
  • 5. Severe psychiatric illness
Show all 19Show fewer
  • 6. Major anticipated illness or organ failure incompatible with survival from BMT
  • 7. DLCO less than 60% predicted
  • 8. Left ventricular ejection fraction: less than 40%
  • 9. Serum creatinine greater than 3mg/dl
  • 10. Serum bilirubin greater than 4 mg/dl
  • 11. HIV positive 12. Debilitation or age making the risk of intensive myeloablative therapy unacceptable
  • DONOR
  • 1. Pregnant or lactating
  • 2. Donor unfit to receive G-CSF and undergo apheresis
  • 3. HIV positive
  • 4. Weight less than 18 kg
  • 5. Age less than 2 or greater than 80 years
  • 6. Severe psychiatric illness

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Effect of Peri-transplant Cyclosporine on Chimerism

This study will evaluate the safety and effectiveness of stem cell transplantation in which the donor's T cells (a type of lymphocyte, or white blood cell) are removed and then added back. Certain patients with bone marrow malignancies undergo transplantation of donated stem cells to generate new and normally functioning bone marrow. However, T-cells from the donor may see the patient's cells as foreign and mount an immune response to reject them, causing what is called "graft-versus-host-disease" (GVHD). Therefore, in this protocol, T-cells are removed from the donor cells to prevent this complication. However, because T-cells are important in fighting viral infections as well as any remaining malignant cells (called graft-versus-leukemia effect), the donor T-cells are given to the patient (added back) at a later time after the transplant when they can provide needed immunity with less risk of causing GVHD.

Patients between 10 and 55 years of age with acute or chronic leukemia, myelodysplastic syndrome, or myeloproliferative syndrome may be eligible for this study. Prospective participants and their donors are screened with a medical history and physical examination, blood tests (including a test to match for genetic compatibility), breathing tests, chest and sinus x-rays, and tests of heart function. They also undergo a bone marrow biopsy and aspiration. For this procedure, done under local anesthetic, about a tablespoon of bone marrow is withdrawn through a needle inserted into the hipbone.

Read more

They undergo apheresis to collect lymphocytes for research studies. This procedure involves collecting blood through a needle in the arm, similar to donating a unit of blood. The lymphocytes are then separated and removed by a cell separator machine, and the rest of the blood is returned through a needle in the other arm.

Before treatment begins, patients have a central intravenous line (flexible plastic tube) placed in a vein in the chest. This line remains in place during the stem cell transplant and recovery period for drawing and transfusing blood, giving medications, and infusing the donated cells. Preparation for the transfusion includes high-dose radiation and chemotherapy. Patients undergo total body irradiation in 8 doses given in two 30-minute sessions a day for 4 days. Eight days before the transplant, they begin taking fludarabine, and 3 days before the procedure they start cyclophosphamide.

Read the detailed description

Bone marrow stem cell transplant studies carried out by the National Heart Lung \& Blood Institute (NHLBI) Bone Marrow Transplantation (BMT) Unit have focused on approaches to optimize the stem cell and lymphocyte dose in order to improve transplant survival and increase the graft-versus-leukemia effect. The aim is to create the transplant conditions that permit rapid donor immune recovery without causing graft-versus-host disease (GVHD) by using reduced post-transplant immunosuppression in conjunction with a transplant depleted of T cells to a fixed low dose, below the threshold known to be associated with GVHD.

We have found that the outcome from transplant is improved by controlling the stem cell (CD34+ cell) and T lymphocyte (CD3+ cell) dose. We use the "Nexell Isolex 300i" system to obtain high CD34+ doses depleted of lymphocytes to a fixed CD3+ T cell dose of 2 x 104/kg. The use of the cell separator and the monoclonal antibodies is covered by an Investigational Device Exemption. A persisting problem with these T cell depleted transplants has been the slow acquisition of full donor T cell engraftment (T cell chimerism). Two previous protocols have failed to increase the speed of donor T cell chimerism. Patients with mixed donor-recipient T cell populations are known to be at higher risk for late graft rejection and leukemic relapse after transplant. Therefore, the achievement of full donor chimerism remains an important therapeutic goal. In this study we will test whether cyclosporine given between day -6 and +21 after transplant can significantly improve day 30 T cell chimerism (the principle end-point). The study also will measure the incidence of acute and chronic GVHD, day 100 transplant related mortality, cytomegalovirus reactivation, relapse, and disease-free survival with appropriate safety stopping rules.

This protocol follows closely previous studies in this series. Three additional modifications will be made however: 1) The first T cell add-back will be delayed until day 60 (instead of day 45) so as to continue to allow a 45 day period without cyclosporine immunosuppression. 2) No day 100 T cell add-back will be given. (In previous studies many patients have, for protocol-defined reasons, not received the second transfusion and there is no evidence that it is required). 3) Patients with high-risk leukemias with a high relapse probability will receive an additional chemotherapy agent prior to transplant using etoposide (VP16) 60mg/kg to improve the chance of remaining in remission.

Keywords
Chronic Myelogenous Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Myelodysplastic Syndromes (MDS), Peripheral Blood Stem Cells, Graft-Versus Leukemia/Myeloma, Graft-Versus-Host Disease (GVHD), Cyclosporine, Fludarabine, Leukemia, Myelodysplastic Syndrome, Myeloproliferative Syndrome, Non-Hodgkin Lymphoma
Medical subject headings
Hematologic Neoplasms, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myeloid, Acute, Leukemia, Lymphocytic, Chronic, B-Cell, Myelodysplastic Syndromes, Neoplasms, Plasma Cell, Graft vs Host Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • allogeneic hematopoietic stem cell transplantationDevice

    Also called Peripheral Blood Stem Cell Transplant, HSCT, BMT

    Manipulated Peripheral Blood Stem Cell graft on Day 0. Target CD34+ dose 6 x10e6/kg, (range 3 to 8x10e6/kg) CD3+ dose fixed to 2 x 10e4/kg.

Study groups in NCT00079391
Study groupRoleWhat they receive
allogeneic hematopoietic SCTExperimentalallogeneic hematopoietic stem cell transplantation (SCT) using Nexell Isolex system
Receives: Device: allogeneic hematopoietic stem cell transplantation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The Proportion of Patients Who Develop Full Donor T Cell Chimerism at Day 30

    The proportion of patients who develop full donor CD3+ lymphocyte chimerism by day 30.

    Full chimerism is defined as >95% donor alleles by molecular profiling (Short Tandem Repeat analysis).

    Measured: Day 30

Secondary outcomes (5)

  1. Overall Survival

    Kaplan Meier estimate of survival

    Measured: at 5 years post transplant

  2. Non Relapse Mortality.

    Non relapse mortality: death without relapse

    Kaplan Meier estimate

    Measured: at 5 years post transplant

  3. Cumulative Incidence of Relapse

    Kaplan Meier-estimate of relapse incidence

    Measured: at 5 years post transplant

  4. Acute Graft Versus Host Disease (Before Day 60 T Cell Add Back)

    Incidence of acute Graft versus host disease (GVHD) grades II-IV (before day 60 T cell add back)

    Modified "Glucksberg" grading

    Measured: First 60 days

  5. Acute GVHD Overall

    Incidence of acute GVHD grades II-IV (before and after T cell add back) Modified Glucksberg grading

    Measured: First 100 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Mar 2004 (estimated)
  2. Study startJan 2004
  3. Primary completionDec 2008
  4. Study completionSep 2011

Resources

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 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
50 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00079391
Sponsor's protocol ID
040112
Other IDs
04-H-0112
Status last verified
Jun 2014
First submitted
8 Mar 2004
Last updated
26 Oct 2015
Data monitoring committee
Yes

Publications

  • Montero A, Savani BN, Shenoy A, Read EJ, Carter CS, Leitman SF, Mielke S, Rezvani K, Childs R, Barrett AJ. T-cell depleted peripheral blood stem cell allotransplantation with T-cell add-back for patients with hematological malignancies: effect of chronic GVHD on outcome. Biol Blood Marrow Transplant. 2006 Dec;12(12):1318-25. doi: 10.1016/j.bbmt.2006.08.034.

    PubMed 17162214

  • Montero A, Savani BN, Kurlander R, Read EJ, Leitman SF, Childs R, Solomon SR, Barrett AJ. Lineage-specific engraftment and outcomes after T-cell-depleted peripheral blood stem cell transplant with Flu/Cy/TBI conditioning. Br J Haematol. 2005 Sep;130(5):733-9. doi: 10.1111/j.1365-2141.2005.05665.x.

    PubMed 16115130

  • McIver ZA, Yin F, Hughes T, Battiwalla M, Ito S, Koklanaris E, Haggerty J, Hensel NF, Barrett AJ. Second hematopoietic SCT for leukemia relapsing after myeloablative T cell-depleted transplants does not prolong survival. Bone Marrow Transplant. 2013 Sep;48(9):1192-7. doi: 10.1038/bmt.2013.39. Epub 2013 Mar 25.

    PubMed 23524640

  • McIver Z, Melenhorst JJ, Wu C, Grim A, Ito S, Cho I, Hensel N, Battiwalla M, Barrett AJ. Donor lymphocyte count and thymic activity predict lymphocyte recovery and outcomes after matched-sibling hematopoietic stem cell transplant. Haematologica. 2013 Mar;98(3):346-52. doi: 10.3324/haematol.2012.072991. Epub 2012 Oct 12.

    PubMed 23065508

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing allogeneic hematopoietic stem cell transplantation in people with Hematologic Malignancies and Bone Marrow Transplant Rejection, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 19 exclusion criteria. 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 26 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 May 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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.

What does the primary outcome measure?

The Proportion of Patients Who Develop Full Donor T Cell Chimerism at Day 30 (time frame: Day 30). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00079391, which also lists 4 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 26 Oct 2015.

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