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

Phase 2

Completed

Conditions: Bone Marrow Transplant Rejection
Hematologic Malignancies

Interventions: Device: allogeneic hematopoietic stem cell transplantation

Registration Number: NCT00079391

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

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 For this procedure, done under local anesthetic, about a tablespoon of bone marrow is withdrawn through a needle inserted into the hipbone.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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Cumulative Incidence of Relapse	at 5 years post transplant	Kaplan Meier-estimate of relapse incidence
Overall Survival	at 5 years post transplant	Kaplan Meier estimate of survival
Non Relapse Mortality.	at 5 years post transplant	Non relapse mortality: death without relapse Kaplan Meier estimate
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
Acute GVHD Overall	First 100 days	Incidence of acute GVHD grades II-IV (before and after T cell add back) Modified Glucksberg grading