Selective T-Cell Depletion to Reduce GVHD (Patients) Receiving Stem Cell Tx to Treat Leukemia, Lymphoma or MDS
Graft vs Host Disease
Leukemia, Myelomonocytic, Chronic
Drug: Isolex system
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Ex Vivo Selective Depletion of Alloreactive Donor T-Lymphocytes Using "RFT5-SMPT-dgA": Reducing GVHD Risk Associated With Matched, Nonmyeloablative, Stem Cell Transplant for Hematologic Malignancies in Older Adults|
- Treatment-related Mortality [ Time Frame: 100 days after stem cell infusion ] [ Designated as safety issue: Yes ]
Nonrelapse mortality in the first 100 days of transplant expressed as a percentage of the total subjects.
This is different from outcome measure 3 (Cumulative Nonrelapse Mortality), which is cumulative non relapse mortality till December 2011.
- Overall Survival [ Time Frame: Dec 2011. ] [ Designated as safety issue: No ]Percent overall survival (actuarial) at analysis in Dec 2011.
- Cumulative Non Relapse Mortality [ Time Frame: Dec 2011. ] [ Designated as safety issue: Yes ]Percent non relapse mortality (actuarial) at analysis in Dec 2011
- Acute GVHD (Any Grade) Using the CIBMTR Grading System. [ Time Frame: 100 days from transplant ] [ Designated as safety issue: No ]Proportion of patients with acute GVHD, grade 1 to 4
- Acute GVHD (Grade 3 or 4) Using the CIBMTR Grading System. [ Time Frame: 100 days from transplant ] [ Designated as safety issue: No ]
|Study Start Date:||May 2001|
|Study Completion Date:||February 2008|
|Primary Completion Date:||February 2008 (Final data collection date for primary outcome measure)|
Experimental: RFT5-SMPT-dgA Isolex system
RFT5-SMPT-dgA, a specific anti-interleukin-2 receptor immunotoxin used in allogeneic stem cell transplantation (SCT) in older patients with hematologic malignancies using a graft manipulation process
A specific anti-interleukin-2 receptor immunotoxin
Other Name: anti-interleukin-2 receptor immunotoxinDrug: Isolex system
CD34 selection/ T cell depletion used this system
Other Name: Nexell Isolex system
Despite improved prophylaxis and treatment, graft-versus-host disease (GVHD) remains a major complication after allogeneic stem cell transplantation. Although the most effective way to prevent GVHD is T cell depletion, this process results in poor immune function leading to increased rates of relapse, graft rejection, and post-transplant infections. Ideally, a method of removing GVHD- producing effector cells while retaining a broad T cell repertoire, including preservation of 3rd party, antiviral and anti-tumor responses would be desirable. Preclinical studies from our lab have demonstrated that alloreactive T cells can be selectively removed from the donor lymphocyte pool in vitro with the use of a specific immunotoxin directed against the interleukin-2 receptor.
To test this clinically, we will perform nonmyeloablative allogeneic stem cell transplants in older patients with hematologic malignancies. Although these patients can be cured with this approach, they have significant morbidity and mortality from GVHD. At our institution, nonmyeloablative transplantation is associated with an incidence of grade II-IV acute GVHD of approximately 50%. Although well tolerated in younger patients, patients over the age of 50 years have a transplant-related mortality (TRM) of approximately 35%, which is mostly related to GVHD. Through selective depletion of alloreactive donor lymphocytes, we hope to reduce GVHD mortality, while preserving the transplant efficacy.
Patients receive a reduced intensity preparative regimen, followed by a mobilized peripheral blood stem cell allograft from an HLA-identical sibling donor, containing "selectively-depleted" donor lymphocytes. To obtain such a graft, colony stimulating factor (G-CSF)-mobilized peripheral blood from the donor undergoes a positive cluster of differentiation (CD34) selection followed by a negative T cell selection using the "Nexell" Isolex 300i system. This stem cell-rich, T cell-depleted product will contain a CD34+ cell dose of at least 5x10(6)/kg. The unabsorbed fraction, remaining after the positive CD34 selection, is then co-cultured for 72 hours with irradiated lymphocytes from the patient. The immunotoxin, RFT5-SMPT-dgA, is added during the last 24 hours of culture to remove alloreacting cells. The washed T cell product (CD3+ cell dose of 1-4 x 10(8)/kg) is cryopreserved. Following the preparative regimen, the patient receives successive infusions of the stem cell product and selected lymphocytes. All patients receive standard post transplant immunosuppression with cyclosporine for a minimum of 30 days, followed by dose reduction depending on the degree of donor lymphocyte chimerism.
The primary end point of this study is the incidence and severity of acute GVHD. We will also examine the incidence of chronic GVHD, engraftment, degree of donor-host chimerism, transplant related morbidity and mortality, as well as disease-free and overall survival. Stopping rules will minimize the risk of untoward or unexpected side effects.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00025662
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Study Chair:||A. J Barrett, MD||NHLBI, NIH|