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HLA-Matched Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies


N/A
10 Years
55 Years
Not Enrolling
Both
Graft vs Host Disease, Hematologic Neoplasm, Leukemia, Multiple Myeloma, Myelodysplastic Syndrome

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Trial Information

HLA-Matched Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies


One of the most effective ways of preventing lethal graft-versus-host disease (GVHD) after
allogeneic bone marrow transplantation (BMT) for leukemia is to remove T-lymphocytes from
the transplanted marrow. The reduced early mortality from T cell depletion is however
offset by an increased risk of leukemic relapse and infection. We have shown that bone
marrow transplants for leukemia depleted of T cells by elutriation and followed by delayed
add-back of donor T cells reduces GVHD while preserving an immune response to the
hematologic malignancy (the so-called graft-versus-leukemia (GVL) or graft-versus-myeloma
effect). The study highlighted a possible benefit of large doses of marrow progenitor cells
on transplant outcome. GVHD was reduced but not prevented by T cell depletion of the
marrow. The first objective of our BMT studies is to prevent GVHD from the transplant while
conserving GVL reactivity. This is a prerequisite to our second objective of determining
the risk of GVHD and the benefit from GVL from add-back of donor lymphocytes. These studies
will provide the basis for a planned trial adding back donor lymphocytes selected in vitro
to confer immunity against infectious agents and residual leukemia without causing GVHD.

In this study we will evaluate the use of T cell depleted peripheral blood progenitor cells
(PBPC) (instead of bone marrow) to optimize the stem cell and lymphocyte dose. Donors will
be given G-CSF and their mobilized PBPC harvested by leukapheresis. To minimize acute GVHD,
the transplant will be T cell depleted, using a new technique developed in normal volunteers
which improves T cell depletion and reduces stem cell loss (protocol 96-H-0049). The study
has two phases: The first phase evaluates engraftment and GVHD following T cell depleted
PBPC transplants. Stopping rules will be used to make modifications to the protocol in the
event of graft failure. Cyclosporine will be withdrawn from the protocol if the incidence
of acute GVHD is low or absent. In the second phase patients will receive add-back of donor
lymphocytes on day 45 and day 100 post transplant to prevent relapse and confer donor-immune
function. The risk of acute GVHD following this procedure will be determined. It is
planned to treat up to 55 patients aged between 10 and 60 years. The end points of the
study are graft take; acute and chronic GVHD, leukemic relapse, transplant-related and all
causes of mortality, cytomegalovirus reactivation and leukemia-free survival. Patients will
be followed for 5 years.

Inclusion Criteria


- INCLUSION CRITERIA-PATIENT:

Ages 10 to 55 years.

Chronic myelogenous leukemia, any of these categories: chronic phase, accelerated phase
of blast transformation.

Acute lymphoblastic leukemia, any of these categories: Adults (greater than 18 years) in
first remission with high risk features (presenting leukocyte count greater than 100,000
per cu mm, Karyotypes t9;22, t4, t19, t11, biphenotypic leukemia). All second remissions,
primary induction failure, partially responding or untreated relapse.

Acute myelogenous leukemia (AML): AML in first remission Except AML with good risk
karyotypes: AML M3 (t15;17), AML M4Eo (inv 16), AML t(8;21). All AML in second or
subsequent remission, primary induction failure and resistant relapse.

Myelodysplastic syndromes, any of these categories: refractory anemia with excess of
blasts, transformation to acute leukemia, chronic myelomonocytic leukemia.

Multiple myeloma following initial disease control with chemotherapy.

Chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia, in remission or partial
remission following fludarabine treatment. Richter transformation of CLL.

No major organ dysfunction precluding transplantation.

DLCO greater than 65 percent predicted.

Left ventricular ejection fraction: greater than 40 percent predicted.

ECOG performance status of 0 or 1.

Informed consent given. Informed consent from both parents for minors.

Women of childbearing age with a negative pregnancy test may participate.

EXCLUSION CRITERIA - PATIENT:

Pregnant.

Age greater than 55 or less than 10.

ECOG performance of 2 or more.

Severe psychiatric illness in patient or donor. Mental deficiency sufficiently severe as
to make compliance with the BMT treatment unlikely, and making informed consent
impossible.

Major anticipated illness or organ failure incompatible with survival from BMT.

DLCO less than 65% predicted.

Left ventricular ejection fraction: less than 40% predicted.

Serum creatinine greater than 3 mg/dl.

Serum bilirubin greater than 4 mg/dl.

Transaminases greater than 3 x upper limit of normal.

HIV positive.

History of other malignancies except basal cell or squamous carcinoma of the skin,
positive PAP smear and subsequent

negative follow up (patient).

INCLUSION CRITERIA-DONOR:

HLA 6/6 or 5/6 matched sibling donor.

Fit to receive G-CSF and give peripheral blood stem cells (normal blood count,
normotensive, no history of stroke).

Informed consent given.

EXCLUSION CRITERIA - DONOR:

Pregnant.

Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance
with the BMT treatment unlikely, and making informed consent impossible.

Donor unfit to receive G-CSF and undergo apheresis. (Uncontrolled hypertension, history
of stroke, thrombocytopenia).

HIV positive.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To evaluate the feasibility of using G-CSF mobilized donor blood to transplant a predetermined dose of stem cells and T lymphocytes to recipients with hematologic malignacies.

Principal Investigator

A. John Barrett, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Heart, Lung, and Blood Institute (NHLBI)

Authority:

United States: Federal Government

Study ID:

970099

NCT ID:

NCT00001623

Start Date:

March 1997

Completion Date:

January 2008

Related Keywords:

  • Graft Vs Host Disease
  • Hematologic Neoplasm
  • Leukemia
  • Multiple Myeloma
  • Myelodysplastic Syndrome
  • Peripheral Blood Stem Cells
  • Graft-Versus-Leukemia
  • Graft vs. Host Disease
  • Whole Body Irradiation
  • Donor Apheresis
  • Cyclophosphamide
  • Graft-Versus-Myeloma
  • Leukemic Relapse
  • Multiple Myeloma
  • Acute Myelogenous Leukemia (AML)
  • Chronic Myelogenous Leukemia (CML)
  • Acute Lymphoblastic Leukemia (ALL)
  • Myelodysplastic Syndromes
  • Chronic Lymphocytic Leukemia (CLL)
  • Neoplasms
  • Graft vs Host Disease
  • Leukemia
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Myelodysplastic Syndromes
  • Preleukemia
  • Hematologic Neoplasms

Name

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