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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier:
NCT00025662
First received: October 11, 2001
Last updated: December 9, 2011
Last verified: December 2011
  Purpose

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.


Condition Intervention Phase
Graft vs Host Disease
Myelodysplastic Syndromes
Leukemia
Leukemia, Myeloid
Leukemia, Myelomonocytic, Chronic
Leukemia, Lymphocytic
Lymphoma
Lymphoma, Mantle-cell
Lymphoma, Non-Hodgkin
Hodgkin Disease
Drug: RFT5-SMPT-dgA
Drug: Nexell Isolex system
Phase 2

Study Type: Interventional
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,Specific Anti-IL-2 Receptor Immunotoxin: Reducing GVHD Risk Associated With HLA-Matched, Nonmyeloablative, Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies in Older Adults

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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.



Secondary Outcome Measures:
  • 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


Enrollment: 23
Study Start Date: May 2001
Study Completion Date: February 2008
Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Allogeneic Stem Cell Transplantation
Allogeneic Stem Cell Transplantation in older patients with hematologic malignancies using a graft manipulation process
Drug: RFT5-SMPT-dgA
A specific anti-interleukin-2 receptor immunotoxin
Drug: Nexell Isolex system
CD34 selection/ T cell depletion used this system

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, G-CSF-mobilized peripheral blood from the donor undergoes a positive 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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA - PATIENT

    • Ages 50-75 years.
    • Relapsed CML in chronic or accelerated phase after therapy with STI-571 (Gleevec).
    • Acute lymphoblastic leukemia (ALL), all patients in complete or partial remission. Exceptions: T cell ALL.
    • Acute myelogenous leukemia (AML): AML in first complete or partial remission including AML secondary to chemotherapy or prior hematological disease such as myelodysplastic syndrome, and myeloproliferative disorder. Exceptions: AML with good risk karyotypes: AML M3 t(5;17), AML M4Eo (inv. 16), AML t(8;21). All AML in second or subsequent complete remission.
    • Myelodysplastic syndromes: (1) refractory anemia with excess of blasts (RAEB), (2) refractory anemia with excess blasts in transformation (RAEBT), (3) MDS with poor risk cytogenetics defined by a complex karyotype (greater than or equal to three anomalies) or chromosome 7 abnormalities, (4) secondary MDS after prior cytotoxic or radiation therapy, or (5) chronic myelomonocytic leukemia (CMML).
    • Chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia, refractory to nucleoside analog therapy, with either progressive bulky disease or anemia (less than 10 g/dl) or thrombocytopenia (less than 100,000/microliter) not due to recent chemotherapy.
    • Mantle cell lymphoma;
    • Relapsed intermediate- or high-grade non-Hodgkin's lymphoma: (1) post autologous marrow or PBSC transplant, or (2) chemorefractory relapse. Exceptions: T cell NHL.
    • Relapse Hodgkin's disease: (1) post autologous marrow or PBSC transplant, or (2) chemorefractory relapse.
    • Low-grade follicular or small lymphocytic lymphoma: (1) relapsed following conventional chemotherapy, (2) relapsed following autologous marrow or PBSC transplant, or (3) chemoresistant disease.
    • Life expectancy greater than 3 months.
    • Ability to comprehend the investigational nature of the study and provide informed consent.
    • Availability of an HLA-identical family donor, 18 to 75 years old.
  • INCLUSION CRITERIA - DONOR:

    • HLA identical family donor, 18 to 75 years old.
    • Fit to receive G-CSF and give peripheral blood stem cells (normal blood count, normotensive, no history of stroke, no history of severe heart disease).
    • Ability to comprehend the investigational nature of the study and provide informed consent.
  • EXCLUSION CRITERIA RECIPIENT:

    • Pregnant or lactating.
    • ECOG performance status of 3 or more.
    • Major anticipated illness or organ failure incompatible with survival from PBSC transplant.
    • DLCO less than 60% predicted.
    • Left ventricular ejection fraction less than 40%, or any angina.
    • Absolute lymphocyte count less than 300/mm(3).
    • Serum creatinine greater than 2.5 mg/dl.
    • Serum bilirubin greater than 4 mg/dl, transaminases greater than 5x upper limit of normal.
    • HIV positive.
    • Other malignant diseases liable to relapse or progress within 2 years.
  • EXCLUSION CRITERIA DONOR:

    • Pregnant or lactating.
    • HIV positive. Donors who are positive for HBV, HCV or HTLV will be used at the discretion of the investigator and with appropriate consent of the recipient.
    • Donor unfit to receive G-CSF and undergo apheresis (uncontrolled hypertension, history of heart failure or unstable angina, platelet count less than 90,000/cu mm).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00025662

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Study Chair: A. J Barrett, MD NHLBI, NIH
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier: NCT00025662     History of Changes
Obsolete Identifiers: NCT00016484
Other Study ID Numbers: 010162, 01-H-0162
Study First Received: October 11, 2001
Results First Received: April 20, 2011
Last Updated: December 9, 2011
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Peripheral Blood Stem Cell
Melphalan
Fludarabine
Donor Apheresis
Non-Myeloablative
MDS
Chronic Myeloid Leukemia
CML
Chronic Lymphocytic Leukemia
CLL
Lymphoma
Non-Hodgkin's Lymphoma
Hodgkin's Disease
Mantle Cell Lymphoma
Acute Myelogenous Leukemia (AML)
Chronic Myeloid Leukemia (CML)
Chronic Lymphocytic Leukemia (CLL)
Myelodysplasia (MDS)
Acute Lymphoblastic Leukemia (ALL)
Bone Marrow Transplant

Additional relevant MeSH terms:
Graft vs Host Disease
Hodgkin Disease
Leukemia
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myelomonocytic, Chronic
Lymphoma
Lymphoma, Non-Hodgkin
Myelodysplastic Syndromes
Preleukemia
Lymphoma, Mantle-Cell
Immune System Diseases
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Immunotoxins
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 26, 2014