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

NCT ID: NCT00079391

Last Updated: 2015-10-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-01-31
• Study Completion Date: 2011-09-30

Brief 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. 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 For this procedure, done under local anesthetic, about a tablespoon of bone marrow is withdrawn through a needle inserted into the hipbone.

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.

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.

Conditions

Hematologic Malignancies; Bone Marrow Transplant Rejection

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

allogeneic hematopoietic SCT

allogeneic hematopoietic stem cell transplantation (SCT) using Nexell Isolex system

Group Type: EXPERIMENTAL

allogeneic hematopoietic stem cell transplantation

Intervention Type: DEVICE

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.

Interventions

allogeneic hematopoietic stem cell transplantation

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.

Intervention Type: DEVICE

Other Intervention Names

Peripheral Blood Stem Cell Transplant; HSCT; BMT

Eligibility Criteria

Inclusion Criteria

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

1. Adults in first remission with high-risk features

2. All second or subsequent remissions, primary induction failure, partially responding or untreated relapse

• 4. Acute myelogenous leukemia (AML)

1. AML in first remission Except AML with good risk karyotypes

2. All AML in second or subsequent remission, primary induction failure and resistant relapse

• 5. Myelodysplastic syndromes categories

1. refractory anemia with transfusion dependence

2. refractory anemia with excess of blasts

3. 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)

Exclusion Criteria

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
• 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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: lead

Responsible Party

Minoo Battiwalla, M.D.

Staff Clinician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Minocher Battiwalla, MD

Role: PRINCIPAL_INVESTIGATOR

NIH National Heart, Lung and Blood Institute

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 17162214 (View on PubMed)

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.

Reference Type: RESULT

PMID: 16115130 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23524640 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23065508 (View on PubMed)

Related Links

http://clinicalstudies.info.nih.gov/detail/B_2004-H-0112.html

NIH Clinical Center Detailed Web Page

Other Identifiers

04-H-0112

Identifier Type: OTHER

Identifier Source: secondary_id

040112

Identifier Type: -

Identifier Source: org_study_id

NCT00076778

Identifier Type: -

Identifier Source: nct_alias