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Pilot Study of Donor Th2 Cells for the Prevention of Graft-Versus-Host Disease in the Setting of Non-Myeloablative, HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation


Phase 1
12 Years
75 Years
Open (Enrolling)
Both
Chronic Lymphocytic Leukemia, Graft vs Host Disease, Hodgkin's Disease, Multiple Myeloma, Non Hodgkin's Lymphoma

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Trial Information

Pilot Study of Donor Th2 Cells for the Prevention of Graft-Versus-Host Disease in the Setting of Non-Myeloablative, HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation


Allogeneic peripheral blood stem cell transplantation (PBSCT) is primarily limited by
graft-versus-host disease (GVHD). In murine models, we found that donor CD4+ Th1 cells
(secretion of IL-2 and IFN-Gamma) mediate GVHD. In contrast, donor Th2 cells (secretion of
IL-4 and IL-10) do not generate GVHD, and abrogate Th1-mediated GVHD. We also found that
murine allografts enriched with Th2 cells reduced GVHD without impairing the ability of
donor T cells to prevent graft rejection. These studies indicate that donor Th2 cells may
be a new approach to reducing GVHD.

In addition to GVHD, allogeneic PBSCT has been limited by toxicity associated with
conventional myeloablative preparative regimens. Although non-myeloablative regimens may
reduce regimen-related toxicity, such transplants have been associated with a 30 to 40%
incidence of severe acute GVHD (similar to rates observed with myeloablative regimens).
Because non-myeloablative regimens appear to have reduced regimen-related toxicity, we have
conducted this pilot study of Th2 cells in the setting of an immunoablative
(non-myeloablative) preparative regimen.

In this protocol, patients with lymphoid or hematologic malignancy receive induction therapy
(fludarabine and EPOCH) and transplant chemotherapy (fludarabine and cytoxan) to deplete
host T cells that mediate graft rejection. In our initial NCI cohort receiving HLA-matched
sibling, G-CSF mobilized PBSCT on this protocol (n=19), graft rejection was prevented in
all cases, with most recipients having 100% donor chimerism by day 28 post-SCT. With this
reduced intensity regimen, GVHD remained a significant complication, with 6/19 recipients
having grade II and 6/19 recipients having grade III acute GVHD. Importantly, potent
graft-versus-tumor responses were observed, with 9/19 patients remaining in complete
remission at a median of 17 months post-SCT.

Given that this allogeneic SCT regimen achieves engraftment and durable anti-tumor
responses, yet is associated with GVHD, this protocol represents an appropriate setting for
evaluation of donor Th2 cells. Initial patients will receive Th2 cells in a phase I manner.
Three patients will receive 5 x 10(6) Th2/kg, six patients will receive 2.5 x 10(7) Th2/kg,
and six patients will receive 1.25 x 10(8) Th2/kg. The highest dose of Th2 cells that
results in an acceptable toxicity profile (not more than 1/6 serious adverse events) and a
favorable rate of acute GVHD (not more than 2/6 cases of grade II or greater acute GVHD)
will be selected for the phase II study arm. Eighteen patients will be treated with
allogeneic SCT and Th2 cells on this phase II study arm. In the event that Th2 recipients
have reduced GVHD, further clinical trials involving Th2 cells will be warranted.

Inclusion Criteria


- INCLUSION CRITERIA - Patient:

Patients with lymphoid malignancy and leukemia (including myelodysplasia) are candidates
for this study. The following diagnoses and ages will be considered:

Chronic Lymphocytic Leukemia, Age 18-75

1. Relapse Post-fludarabine, or

2. Non-CR after Salvage Regimen

Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma), Age
18-75

1. Primary Treatment Failure, or

2. Relapse after AutoSCT, or

3. Non-CR after Salvage Regimen

Multiple Myeloma, Age 18-75

1. Primary Treatment Failure, or

2. Relapse after AutoSCT, or

3. Non-CR after Salvage Regimen

Acute Myelogenous Leukemia, Age 18-75

1. In CR #1, 2, or 3

2. Any Relapse with less than 10% blasts (marrow and blood)

Acute Lymphocytic Leukemia, Age 18-75

1. In Complete Remission #2

2. In Complete Remission #3

3. Any Relapse with less than 10% blast (marrow and blood).

Myelodysplastic Syndrome, Age 18-75

1. RAEB

2. RAEB-T (if blasts are less than 10% in marrow and blood after induction chemotherapy)

Chronic Myelogenous Leukemia, Age 18-75

1. Chronic Phase CML

2. Accelerated Phase CML

Patient age of at least 18 and not greater than 75 years of age.

Availability of 6/6 antigen (A, B, and DR) HLA-matched sibling donor.

Karnofsky performance status of greater than or equal to 70%.

Life expectancy greater than 3 months.

Serum bilirubin less than 2.5 mg/dL, and serum ALT and AST values less than or equal
to 2.5 times the upper limit of normal. Values above these levels may be accepted,
at the discretion of the PI or study chairman, if such elevations are thought to be
due to tumor involvement by the lymphoid malignancy. If these values do not
normalize during the induction chemotherapy, such patients will not be eligible for
the transplant phase of the protocol, and will thus be taken off study.

Creatinine clearance greater than or equal to 60 ml/min or serum creatinine of less
than or equal to 1.5 mg/dl.

DLCO greater than 50% of predicted.

Left ventricular ejection fraction of greater than or equal to 45% by MUGA or ECHO.

Ability to give informed consent.

Durable power of attorney form completed.

INCLUSION CRITERIA - Donor:

Must be sibling, matched with recipient at 6/6 of the HLA loci (A, B, and DR).

Adequate venous access for peripheral apheresis, or consent to use a temporary
central venous catheter for apheresis.

Must be at least 12 years of age.

Ability to give informed consent. For donors under 18 years of age, an assent form
must be completed.

EXCLUSION CRITERIA - Patient:

Infection that is not responding to anti-microbial therapy.

Active CNS involvement by tumor.

HIV positive (due to unacceptable risk after allogeneic transplantation).

Hepatitis B or C surface antigen positive.

Lactating or pregnant females (due to risk to fetus or newborn).

History of psychiatric disorder which may compromise compliance with transplant
protocol, or which does not allow for appropriate informed consent (as determined by
principal investigator or study chairman).

EXCLUSION CRITERIA - Donor:

History of psychiatric disorder which may compromise compliance with transplant
protocol, or which does not allow for appropriate informed consent.

History of hypertension that is not controlled by medication, stroke, or severe heart
disease. Individuals with symptomatic angina, or a history of coronary artery bypass
grafting or angioplasty will be considered to have severe heart disease, and thus
will not be eligible to be a donor.

Anemia (Hb less than 11 gm/dl) or thrombocytopenia (PLT less than 100,000 per ul).

Lactating or pregnant females.

HIV positive.

Hepatitis B or C antigen positive.

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

Daniel H Fowler, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

990143

NCT ID:

NCT00001830

Start Date:

July 1999

Completion Date:

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • Graft Vs Host Disease
  • Hodgkin's Disease
  • Multiple Myeloma
  • Non Hodgkin's Lymphoma
  • Bone Marrow Transplantation
  • Chronic Lymphocytic Leukemia
  • Immunotherapy
  • Lymphoma
  • Multiple Myeloma
  • Graft vs. Host Disease
  • Lymphoid Malignancy
  • Leukemia
  • Graft vs Host Disease
  • Hodgkin Disease
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

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