Selective T-Cell Depletion to Reduce GVHD (Patients) Receiving Stem Cell Tx to Treat Leukemia, Lymphoma or MDS

Phase 2

Completed

Conditions: Graft vs Host Disease
Myelodysplastic Syndromes
Leukemia
Leukemia, Myeloid
Leukemia, Myelomonocytic, Chronic
Leukemia, Lymphocytic
Lymphoma
Lymphoma, Mantle-cell
Lymphoma, Non-Hodgkin
Hodgkin Disease

Interventions: Drug: RFT5-SMPT-dgA
Drug: Isolex system

Registration Number: NCT00025662

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 donors T lymphocytes have undergone "selective depletion." Certain patients with cancers of the blood undergo transplantation of donated stem cells to generate new and normally functioning bone marrow. In addition to producing the new bone marrow, the donor's T-lymphocytes also fight any tumor cells that might have remained in the body. This attack on tumor cells is called a "graft-versus-leukemia" (GVL) effect. However, another type of T-lymphocyte from the donor may cause what is called "graft-versus-host-disease" (GVHD), in which the donor cells recognize the patient's cells as foreign and mount an immune response to reject them. Selective depletion is a technique that was developed to remove the T-lymphocytes that cause harmful GVHD, while keeping those that produce the desirable GVL effect.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
RFT5-SMPT-dgA Isolex system	RFT5-SMPT-dgA	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
RFT5-SMPT-dgA Isolex system	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

Primary Outcome Measures

Name	Time	Method
Treatment-related Mortality	100 days after stem cell infusion	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Dec 2011.	Percent overall survival (actuarial) at analysis in Dec 2011.
Cumulative Non Relapse Mortality	Dec 2011.	Percent non relapse mortality (actuarial) at analysis in Dec 2011