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Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Role of Preparative Regimen and T Cell Dose in Graft Rejection and GVHD


Phase 2
10 Years
80 Years
Not Enrolling
Both
Immunosuppression, Leukemia

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Trial Information

Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Role of Preparative Regimen and T Cell Dose in Graft Rejection and GVHD


Bone marrow stem cell transplant studies carried out by the NHLBI BMT Unit have focused on
approaches to optimize the stem cell and lymphocyte dose in order to improve transplant
survival and increase the graft-vs.-leukemia effect. The aim is to create the transplant
conditions that permit rapid donor immune recovery without causing graft-versus-host disease
(GVHD) by using no post-transplant immunosuppression in conjunction with a transplant
depleted of T cells to a fixed low dose, below the threshold known to be associated with
GVHD. A primary objective of the protocol is therefore to test whether the low dose of T
cells chosen minimizes the risk and severity of GVHD.

We have found that the outcome from transplant is improved by using high stem cell doses,
and in successive protocols we have achieved progressive improvement in transplant-related
mortality from 35% in the first protocol in 1993 to 22% for the latest study. In the last
study, in this series, we used the Nexell Isolex 300i system to obtain high CD34+ doses
depleted of lymphocytes to a fixed CD3+ T cell dose of 5 x 10(4)/kg. The use of the cell
separator and the monoclonal antibodies is covered by IDE 8139. The study focused on the
role of cyclosporine in preventing GVHD after T cell depletion. We found that CSA appears
to protect against both GVHD and graft failure, with a higher incidence of both
complications occurring in patients not receiving CSA.

To address the results and shortcomings of the previous protocol, while continuing to avoid
immunosuppression post-transplant, we will now test two hypotheses: (1) GVHD incidence and
severity can be reduced by transfusing a T cell dose of 2 x 10(4)/CD3 cell/kg. (2) Graft
rejection can be prevented by increasing the immunosuppressive intensity of the
pre-transplant preparative regimen using fludarabine and cyclophosphamide and a reduced dose
of total body irradiation (12 Gy instead of 13.6 Gy). We will use the same in vitro cell
separation system namely the Isolex 300i and monoclonal antibodies provided by CTEP (anti CD
6, anti CD2, anti CD7). This is covered by a continuing IND for the selection of CD34+ and
CD3+ cells for T cell depleted peripheral blood stem cell transplantation.

Inclusion Criteria


- INCLUSION CRITERIA - PATIENT:

Ages 10-55 years inclusive (but less than 56).

Chronic myelogenous leukemia in chronic phase

A) Patients not treated with STI 571 under the age of 41 (subject to regular DSMB review);

B) Age 10-55 in chronic phase who have failed treatment with STI-571;

C) Age 10-55 in accelerated phase or 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/cu mm, karyotypes t9; 22, t4, t19, t11, biphenotypic leukemia). All second or
subsequent 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 transfusion
dependence, refractory anemia with excess of blasts, transformation to acute leukemia,
chronic myelomonocytic leukemia.

Myeloproliferative disorders (myelofibrosis, polycythemia vera, essential thrombocythemia)
in transformation to acute leukemia.

Chronic lymphocytic leukemia refractory to fludarabine treatment and with bulky
progressive disease or with thrombocytopenia (less than or equal to 100,000/microliters)
or anemia (less than or equal to 10 g/dl) not due to recent chemotherapy.

No major organ dysfunction precluding transplantation.

DLCO greater than or equal to 60% predicted.

Left ventricular ejection fraction: greater than or equal to 40% predicted.

ECOG performance status of 0 or 1.

For adults: Ability to comprehend the investigational nature of the study and provide
informed consent. For minors: Written informed consent from one parent or guardian.
Informed oral consent from minors: The process will be explained to the minor on a level
of complexity appropriate for their age and ability to comprehend.

Negative pregnancy test for women of childbearing age.

INCLUSION CRITERIA - DONORS:

HLA 6/6 identical family donor.

Weight greater than or equal to 18 kg.

Age less than or equal to 80 years old.

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

For adults: Ability to comprehend the investigational nature of the study and provide
informed consent. For minors: Written informed consent from one parent or guardian and
informed assent: The process will be explained to the minor on a level of complexity
appropriate for their age and ability to comprehend.

EXCLUSION CRITERIA - RECIPIENT:

Patient pregnant.

Age less than 10 years and 56 years or more.

Patients with CML in chronic phase who are 41 years or over in whom STI 571 is the
treatment of choice.

ECOG performance status of 2 or more.

Severe psychiatric illness. 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 60% 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 3x 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.

Individuals with diseases listed in the inclusion criteria but where debility or age makes
the risk of intensive myeloablative therapy unacceptable. This includes patients who have
received busulfan treatment for more than 6 months continuously. These patients will be
considered for non-myeloablative allogeneic transplantation protocols.

EXCLUSION CRITERIA - DONOR

Pregnant or lactating.

Donor unfit to receive G-CSF and undergo apheresis. (uncontrolled hypertension, history
of congestive heart failure, or unstable angina, thrombocytopenia).

HIV positive. Donors who are positive for HBV, HCV or HTLV-1 may be used if the
risk-benefit ratio is considered acceptable by the patient and investigator.

Weight less than 18 kg.

Age greater than 80 years.

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

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:

The proportion of patients with clinically significant acute GHVD (Grade II or higher) following the T depleted PBPC transplant.

Outcome Time Frame:

Before day 45.

Safety Issue:

Yes

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:

020111

NCT ID:

NCT00353860

Start Date:

January 2002

Completion Date:

November 2007

Related Keywords:

  • Immunosuppression
  • Leukemia
  • Leukemia
  • Transplant - Mortality
  • Immunosuppression
  • Radiation
  • Cure
  • Peripheral Blood Stem Cells
  • Graft-versus Leukemia/Myeloma
  • Graft-versus-host Disease
  • Cyclosporine
  • Fludarabine
  • Leukemia

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892