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

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00079391
• Collaborator: (none)
• Enrollment: 50
• Location: 1
• Arm: 1
• Duration (Months): 92
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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 For this procedure, done under local anesthetic, about a tablespoon of bone marrow is withdrawn through a needle inserted into the hipbone.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

Condition or Disease	Intervention/Treatment	Phase
Hematologic Malignancies; Bone Marrow Transplant Rejection	Device: allogeneic hematopoietic stem cell transplantation	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: Jan 1, 2004
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: allogeneic hematopoietic SCT allogeneic hematopoietic stem cell transplantation (SCT) using Nexell Isolex system	Device: 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.; Other Names: Peripheral Blood Stem Cell Transplant HSCT BMT

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

1. Overall Survival [at 5 years post transplant]

   Kaplan Meier estimate of survival

2. Non Relapse Mortality. [at 5 years post transplant]

   Non relapse mortality: death without relapse Kaplan Meier estimate

3. Cumulative Incidence of Relapse [at 5 years post transplant]

   Kaplan Meier-estimate of relapse incidence

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

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

5. Acute GVHD Overall [First 100 days]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

RECIPIENT:

• 1. Ages 10-55 years inclusive (but less than 56)
• 1. Chronic myelogenous leukemia (CML) in chronic phase
• 1. 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

• 1. 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

• 1. Myelodysplastic syndromes categories

1. refractory anemia with transfusion dependence

2. refractory anemia with excess of blasts

3. transformation to acute leukemia, chronic myelomonocytic leukemia

• 1. Myeloproliferative disorders in transformation to acute leukemia
• 1. 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
• 1. 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
• 1. No major organ dysfunction precluding transplantation
• 1. Diffusion capacity of lung for carbon monoxide (DLCO) greater than or equal to 60% predicted
• 1. Left ventricular ejection fraction: greater than or equal to 40%
• 1. Eastern Cooperative Oncology Group(ECOG) performance status of 0 or 1
• 1. Able to give informed consent
• 1. Negative pregnancy test for women of childbearing age

INCLUSION CRITERIA:

DONOR

• 1. Human leukocyte antigen (HLA) 6/6 identical family donor
• 1. Weight greater than or equal to 18 kg
• 1. Age greater than or equal to 2 or less than or equal to 80 years old
• 1. 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
• 1. Age less than 10 years and 56 years or more
• 1. Patients with CML in chronic phase who are 41 years or over in whom imatinib mesylate (STI-571)is the treatment of choice
• 1. ECOG performance status of 2 or more
• 1. Severe psychiatric illness
• 1. Major anticipated illness or organ failure incompatible with survival from BMT
• 1. DLCO less than 60% predicted
• 1. Left ventricular ejection fraction: less than 40%
• 1. Serum creatinine greater than 3mg/dl
• 1. Serum bilirubin greater than 4 mg/dl
• 1. HIV positive 12. Debilitation or age making the risk of intensive myeloablative therapy unacceptable

EXCLUSION CRITERIA:

DONOR

• 1. Pregnant or lactating
• 1. Donor unfit to receive G-CSF and undergo apheresis
• 1. HIV positive
• 1. Weight less than 18 kg
• 1. Age less than 2 or greater than 80 years
• 1. Severe psychiatric illness

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Minocher Battiwalla, MD, NIH National Heart, Lung and Blood Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

None provided.

• Responsible Party: Minoo Battiwalla, M.D., Staff Clinician, National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT00079391
• Other Study ID Numbers: 040112; 04-H-0112; NCT00076778
• First Posted: Mar 10, 2004
• Last Update Posted: Oct 26, 2015
• Last Verified: Jun 1, 2014

• Keywords provided by Minoo Battiwalla, M.D., Staff Clinician, National Heart, Lung, and Blood Institute (NHLBI): 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
• Additional relevant MeSH terms: Neoplasms; Hematologic Neoplasms

Study Results

Participant Flow

Arm/Group Title	Bone Marrow Transplantation Using "Nexell Isolex 300i"
Arm/Group Description	Bone marrow stem cell transplant program to improve the outcome of allogeneic Bone Marrow Transplant for hematologic malignancies. Immunosuppression including cyclosporine will be given six days prior to transplant up to 21 days post transplant. cluster of differentiation 34 (CD34) selection and T cell depletion using Isolex 300i immuno-magnetic cell selection and immunosuppression during peri- transplant.
Period Title: Overall Study
STARTED	50
COMPLETED	49
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Bone Marrow Transplantation Using Nexell Isolex 300i
Arm/Group Description	Bone marrow stem cell transplant program to improve the outcome of allogeneic Bone Marrow Transplant for hematologic malignancies. Immunosuppression including cyclosporine will be given six days prior to transplant up to 21 days post transplant. CD34 selection and T cell depletion using Isolex 300i immuno-magnetic cell selection and immunosuppression during peri- transplant.
Overall Participants	50
Age (Count of Participants)
<=18 years	4 8%
Between 18 and 65 years	46 92%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33 (10)
Sex: Female, Male (Count of Participants)
Female	28 56%
Male	22 44%
Region of Enrollment (participants) [Number]
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	The Proportion of Patients Who Develop Full Donor T Cell Chimerism at Day 30
Description	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).
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

Per protocol; only patients who survived to day 30 and were evaluable.

Arm/Group Title	Bone Marrow Transplantation Using Nexell Isolex 300i
Arm/Group Description	Bone marrow stem cell transplant program to improve the outcome of allogeneic Bone Marrow Transplant for hematologic malignancies. Immunosuppression including cyclosporine will be given six days prior to transplant up to 21 days post transplant. CD34 selection and T cell depletion using Isolex 300i immuno-magnetic cell selection and immunosuppression during peri- transplant.
Measure Participants	49
Number [percentage of participants]	44.9 89.8%

2. Secondary Outcome

Title	Overall Survival
Description	Kaplan Meier estimate of survival
Time Frame	at 5 years post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Transplantation Using Nexell Isolex 300i
Arm/Group Description	Bone marrow stem cell transplant program to improve the outcome of allogeneic Bone Marrow Transplant for hematologic malignancies. Immunosuppression including cyclosporine will be given six days prior to transplant up to 21 days post transplant. CD34 selection and T cell depletion using Isolex 300i immuno-magnetic cell selection and immunosuppression during peri- transplant.
Measure Participants	49
Number [percentage of participants]	47.9 95.8%

3. Secondary Outcome

Title	Non Relapse Mortality.
Description	Non relapse mortality: death without relapse Kaplan Meier estimate
Time Frame	at 5 years post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Transplantation Using Nexell Isolex 300i
Arm/Group Description	Bone marrow stem cell transplant program to improve the outcome of allogeneic Bone Marrow Transplant for hematologic malignancies. Immunosuppression including cyclosporine will be given six days prior to transplant up to 21 days post transplant. CD34 selection and T cell depletion using Isolex 300i immuno-magnetic cell selection and immunosuppression during peri- transplant.
Measure Participants	49
Number [percentage of participants]	21.1 42.2%

4. Secondary Outcome

Title	Cumulative Incidence of Relapse
Description	Kaplan Meier-estimate of relapse incidence
Time Frame	at 5 years post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Transplantation Using "Nexell Isolex 300i"
Arm/Group Description	Bone marrow stem cell transplant program to improve the outcome of allogeneic Bone Marrow Transplant for hematologic malignancies. Immunosuppression including cyclosporine will be given six days prior to transplant up to 21 days post transplant. Cluster of differentiation 34 (CD34) selection and T cell depletion using "Isolex 300i" immuno-magnetic cell selection and immunosuppression during peri- transplant.
Measure Participants	49
Number [percentage of participants]	39.8 79.6%

5. Secondary Outcome

Title	Acute Graft Versus Host Disease (Before Day 60 T Cell Add Back)
Description	Incidence of acute Graft versus host disease (GVHD) grades II-IV (before day 60 T cell add back) Modified "Glucksberg" grading
Time Frame	First 60 days

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Bone Marrow Transplantation Using "Nexell Isolex 300i"
Arm/Group Description	Bone marrow stem cell transplant program to improve the outcome of allogeneic Bone Marrow Transplant for hematologic malignancies. Immunosuppression including cyclosporine will be given six days prior to transplant up to 21 days post transplant. CD34 selection and T cell depletion using Isolex 300i immuno-magnetic cell selection and immunosuppression during peri- transplant.
Measure Participants	49
Number [participants]	20 40%

6. Secondary Outcome

Title	Acute GVHD Overall
Description	Incidence of acute GVHD grades II-IV (before and after T cell add back) Modified Glucksberg grading
Time Frame	First 100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Transplantation Using Nexell Isolex 300i
Arm/Group Description	Bone marrow stem cell transplant program to improve the outcome of allogeneic Bone Marrow Transplant for hematologic malignancies. Immunosuppression including cyclosporine will be given six days prior to transplant up to 21 days post transplant. CD34 selection and T cell depletion using Isolex 300i immuno-magnetic cell selection and immunosuppression during peri- transplant.
Measure Participants	49
Number [participants]	39 78%

Adverse Events

Time Frame	Overall study
Arm/Group Title	Bone Marrow Transplantation Using Nexell Isolex 300i
Arm/Group Description	Bone marrow stem cell transplant program to improve the outcome of allogeneic Bone Marrow Transplant for hematologic malignancies. Immunosuppression including cyclosporine will be given six days prior to transplant up to 21 days post transplant. CD34 selection and T cell depletion using Isolex 300i immuno-magnetic cell selection and immunosuppression during peri- transplant.
All Cause Mortality
	Bone Marrow Transplantation Using Nexell Isolex 300i
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bone Marrow Transplantation Using Nexell Isolex 300i
	Affected / at Risk (%)	# Events
Total	25/49 (51%)
Blood and lymphatic system disorders
Death	12/49 (24.5%)	12
Gastrointestinal disorders
Hospitalization	1/49 (2%)	1
Immune system disorders
Transplant Related Death	9/49 (18.4%)	9
Hospitalization	2/49 (4.1%)	2
Infections and infestations
Life threatening	1/49 (2%)	1
Other (Not Including Serious) Adverse Events
	Bone Marrow Transplantation Using Nexell Isolex 300i
	Affected / at Risk (%)	# Events
Total	49/49 (100%)
Blood and lymphatic system disorders
Acute GVHD before day 60	10/49 (20.4%)	10
Chronic GVHD	22/49 (44.9%)	22
Disease Relapse	18/49 (36.7%)	18
Acute GVHD after day 60	19/49 (38.8%)	19
Immune system disorders
Hemorrhagic cystitis	4/49 (8.2%)	4
Cytomegalovirus disease	37/49 (75.5%)	37

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.