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Peripheral Blood Stem Cell Allotransplantation for Hematological Malignancies Using a Positive Stem Cell Selection Technique for T Cell Depletion, Followed by Delayed T Cell Add-Back


Phase 2
10 Years
75 Years
Open (Enrolling)
Both
Chronic Myelogenous Leukemia, Acute Myelogenous Leukemia, Chronic Lymphocytic Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome

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Trial Information

Peripheral Blood Stem Cell Allotransplantation for Hematological Malignancies Using a Positive Stem Cell Selection Technique for T Cell Depletion, Followed by Delayed T Cell Add-Back


Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on
transplant techniques designed to decrease graft versus host disease (GVHD), increase the
graft-versus-leukemia (GVL) effect and reduce the risk of post-transplant graft rejection.

We have found that by controlling the stem cell (CD34+ cell) and T lymphocyte (CD3+ cell)
dose severe GVHD can be reduced whilst beneficial GVL effects can be preserved by postponed
donor lymphocyte infusion (DLI). We found that T cell depleted transplants using the
Nexell/Baxter Isolex 300i system to obtain high CD34+ doses depleted of lymphocytes were
safe to administer and associated with less severe acute GVHD and promising response rates
and overall survival, when combined with a delayed T cell add-back (DLI). This protocol is
designed to evaluate safety and efficacy of an improved T cell depletion procedure using the
Miltenyi CliniMACs system (CD34 reagent system) with a delayed T cell add back in the
HLA-matched peripheral blood stem cell transplant setting.

The protocol will accrue up to 68 subjects ages 10-75 with a hematological malignancy, in
whom allogeneic stem cell transplantation from an HLA-matched sibling would be routinely
indicated. 68 sibling donors will also be recruited. Diagnostic categories will include
acute and chronic leukemia, myelodysplastic syndrome, lymphoma, multiple myeloma and
myeloproliferative syndromes.

Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine
and total body irradiation, followed by an infusion of a stem cell product prepared using
the Miltenyi CliniMacs system for CD34 selection, and a delayed T-cell add back as donor
lymphocyte infusion (DLI) at day 90. Older subjects will receive a lower dose of
irradiation to reduce the regimen intensity.

Primary endpoint will be overall survival at day +200. Non-relapse mortality at day +200
will be monitored for safety. Secondary endpoints will be standard transplant outcome
variables such as non-hematologic toxicity, incidence and severity of acute and chronic GVHD
and relapse of disease.

Inclusion Criteria


- INCLUSION CRITERIA - RECIPIENT:

Ages 10-75 years inclusive

Chronic myelogenous leukemia (CML):

- Subjects under the age of 21 in chronic phase

- Subjects ages 10-75 in chronic phase who have failed treatment with imatinib, have
intolerance to imatinib, or who did not receive imatinib at therapeutic doses within
the first 12 months from diagnosis.

- Subjects ages 10-75 in accelerated phase or blast transformation.

Acute lymphoblastic leukemia (ALL): any of these categories: ALL 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 (MDS): any of these categories - refractory anemia with
transfusion dependence, refractory anemia with excess of blasts, transformation to acute
leukemia, chronic myelomonocytic leukemia, atypical MDS/myeloproliferative syndromes

Myeloproliferative disorders including atypical (Ph negative) chronic myeloid and
neutrophilic leukemias, progressing myelofibrosis, and polycythemia vera, essential
thrombocythemia in transformation to acute leukemia or with progressive transfusion
requirements or pancytopenia.

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

Non-Hodgkin's lymphoma including Mantle cell lymphoma relapsing or refractory to standard
of care treatments

Multiple myeloma, Waldenstroms macroglobulinemia, unresponsive or relapsed following
standard of care treatments.

HLA identical (6/6) related donor

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.

EXCLUSION CRITERIA - RECIPIENT: (ANY OF THE FOLLOWING)

Estimated probability of surviving less than three months

Major anticipated illness or organ failure incompatible with survival from transplant

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

Positive pregnancy test for women of childbearing age.

HIV positive

DLCO adjusted for ventilation and hemoglobin less than 65 percent predicted

Left ventricular ejection fraction less than 40 percent

AST/SGOT greater than 10 times ULN (CTCAE grade IV v3.0)

Bilirubin greater than 5 times ULN (CTCAE grade IV v3.0)

Creatinine greater than 4.5 times ULN (CTCAE grade IV v 3.0)

Prior allogeneic stem cell transplantation.

INCLUSION CRITERIA - DONOR:

Related donor, HLA identical (6/6) with recipient

Weight greater than or equal to 18 kg

Age greater than or equal to 2 or less than or equal to 80 years old

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 - DONOR: (ANY OF THE FOLLOWING)

Pregnant. Lactating donors permitted provide breast milk is discarded during the days that
G-CSF is given

Unfit to receive filgrastim (G-CSF) and undergo apheresis (abnormal blood counts, history
of stroke, uncontrolled hypertension)

Sickling hemoglobinopathies including HbSS, HbAS, HbSC

HIV positive donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or human
T-cell lymphotropic virus (HTLV-I/II) will be used at the discretion of the investigator
following counseling and approval from the recipient

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:

Increased rate of survival at day +200. Non-relapse mortality at day +200 will be monitored for safety.

Outcome Time Frame:

Day 200

Safety Issue:

Yes

Principal Investigator

Minocher M Battiwalla, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Heart, Lung, and Blood Institute (NHLBI)

Authority:

United States: Federal Government

Study ID:

060248

NCT ID:

NCT00378534

Start Date:

September 2006

Completion Date:

August 2014

Related Keywords:

  • Chronic Myelogenous Leukemia
  • Acute Myelogenous Leukemia
  • Chronic Lymphocytic Leukemia
  • Acute Lymphoblastic Leukemia
  • Myelodysplastic Syndrome
  • Chronic Myelogenous Leukemia (CML)
  • Acute Myelogenous Leukemia (AML)
  • Chronic Lymphocytic Leukemia (CLL)
  • Acute Lymphoblastic Leukemia (ALL)
  • Myelodysplastic Syndrome (MDS)
  • Leukemia
  • Chronic Myelogenous Leukemia
  • CML
  • Acute Myeloid Leukemia
  • AML
  • Chronic Lymphocytic Leukemia
  • CLL
  • Acute Lymphoblastic Leukemia
  • ALL
  • Myelodysplasia Syndrome
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

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