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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

Phase 2
18 Years
75 Years
Not Enrolling
Graft vs Host Disease, Myelodysplastic Syndromes, Leukemia, Leukemia, Myeloid, Leukemia, Myelomonocytic, Chronic, Leukemia, Lymphocytic, Lymphoma, Lymphoma, Mantle-cell, Lymphoma, Non-Hodgkin, Hodgkin Disease

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Trial Information

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

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.

Inclusion Criteria


- Ages 50-75 years.

- Relapsed CML in chronic or accelerated phase after therapy with STI-571

- 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

- 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.


- 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.


- Pregnant or lactating.

- ECOG performance status of 3 or more.

- Major anticipated illness or organ failure incompatible with survival from PBSC

- 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.


- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Treatment-related Mortality

Outcome Description:

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.

Outcome Time Frame:

100 days after stem cell infusion

Safety Issue:


Principal Investigator

A. J Barrett, MD

Investigator Role:

Study Chair

Investigator Affiliation:



United States: Federal Government

Study ID:




Start Date:

May 2001

Completion Date:

February 2008

Related Keywords:

  • Graft Vs Host Disease
  • Myelodysplastic Syndromes
  • Leukemia
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Chronic
  • Leukemia, Lymphocytic
  • Lymphoma
  • Lymphoma, Mantle-cell
  • Lymphoma, Non-Hodgkin
  • Hodgkin Disease
  • 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
  • Graft vs Host Disease
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphoid
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Chronic
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Myelodysplastic Syndromes
  • Preleukemia
  • Lymphoma, Mantle-Cell



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892