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

Primary Purpose

Hematologic Malignancies, Bone Marrow Transplant Rejection

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

allogeneic hematopoietic stem cell transplantation

About this trial

This is an interventional treatment trial for Hematologic Malignancies focused on measuring 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

Eligibility Criteria

2 Years - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 Adults in first remission with high-risk features All second or subsequent remissions, primary induction failure, partially responding or untreated relapse 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 INCLUSION CRITERIA: 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 EXCLUSION CRITERIA: 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

Sites / Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

allogeneic hematopoietic SCT

Arm Description

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Overall Survival

Kaplan Meier estimate of survival

Non Relapse Mortality.

Non relapse mortality: death without relapse Kaplan Meier estimate

Cumulative Incidence of Relapse

Kaplan Meier-estimate of relapse incidence

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

Acute GVHD Overall

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

Full Information

NCT ID

NCT00079391

First Posted

March 8, 2004

Last Updated

October 5, 2015

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT00079391

Brief Title

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

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 Type

Interventional

2. Study Status

Record Verification Date

June 2014

Overall Recruitment Status

Completed

Study Start Date

January 2004 (undefined)

Primary Completion Date

December 2008 (Actual)

Study Completion Date

September 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hematologic Malignancies, Bone Marrow Transplant Rejection

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Actual)

8. Arms, Groups, and Interventions

Arm Title

allogeneic hematopoietic SCT

Arm Type

Experimental

Arm Description

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

Intervention Type

Device

Intervention Name(s)

allogeneic hematopoietic stem cell transplantation

Other Intervention Name(s)

Peripheral Blood Stem Cell Transplant, HSCT, BMT

Intervention Description

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.

Primary Outcome Measure Information:

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

Secondary Outcome Measure Information:

Title

Overall Survival

Description

Kaplan Meier estimate of survival

Time Frame

at 5 years post transplant

Title

Non Relapse Mortality.

Description

Non relapse mortality: death without relapse Kaplan Meier estimate

Time Frame

at 5 years post transplant

Title

Cumulative Incidence of Relapse

Description

Kaplan Meier-estimate of relapse incidence

Time Frame

at 5 years post transplant

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

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Minocher Battiwalla, MD

Organizational Affiliation

NIH National Heart, Lung and Blood Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

17162214

Citation

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.

Results Reference

result

PubMed Identifier

16115130

Citation

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.

Results Reference

result

PubMed Identifier

23524640

Citation

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.

Results Reference

derived

PubMed Identifier

23065508

Citation

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.

Results Reference

derived

Links:

URL

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

Description

NIH Clinical Center Detailed Web Page

Learn more about this trial

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

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