Trial of Donor Lymphocyte Infusion (DLI) and Activated DLI Following Relapse After Allogeneic Stem Cell Transplant

You are being asked to participate in this research study because your disease has relapsed
after allogeneic bone marrow transplantation (putting normal bone marrow from one person
into another that was a brother/sister, a matched family member, or an unrelated donor).
This study is testing a treatment for your relapsed disease after bone marrow transplant
(BMT) that uses infusions of your bone marrow donor's immune cells (system which protects
the body from disease); these immune cells are white blood cells called leukocytes or
lymphocytes (called T cells). In allogeneic BMT, we know that the donor's immune system
(system which protects the body from disease and is comprised primarily of lymphocytes, or
white blood cells) is very important for the control and elimination of leukemia after bone
marrow transplantation. Many studies have shown that treatment with transfusions of the bone
marrow donor's lymphocytes can lead to a complete remission in patients that have relapsed
after BMT. This procedure is called donor lymphocyte infusion, or "DLI". The conventional or
standard way to give donor lymphocyte infusions (referred to as DLI) is to take the
lymphocytes from the blood of the original bone marrow donor blood and infuse them directly
into a patient with relapsed disease without any processing of the lymphocytes.

Some patients have a very good chance of achieving remission after donor lymphocyte
infusions (such as patients with early stages of CML). Standard DLI after allogeneic BMT
have been less effective for patients with advanced leukemia (AML, ALL, or "accelerated
phase" and "blast crisis" CML), or patients with other diseases such as myelodysplasia, CLL,
Hodgkin's lymphoma and non-Hodgkin's lymphoma. Because of your disease, your physician
estimates a chance of less than 4 in 10 (40%) or less of responding to standard donor
lymphocyte infusions (DLI).

In a recent clinical trial, we tested the safety of a new way to give DLI that might make
this treatment more effective. The donor lymphocytes (or T cells) are activated in the
laboratory before given to patients to try and make them more active. The donor's T cells
are activated by exposure to 2 compounds or antibodies that bind (or stick to) two compounds
on T cells called CD3 and CD28. When these antibodies stick to both CD3 and CD28 on the T
cells, the T cells becomes stimulated (or "activated") and grows. CD3 and CD28 are the
coating of a T cell and a T cell is part of the body's immune system.

It is believed that when T cells are exposed to both of antibodies to CD3 and CD28 compounds
at the same time, they become activated or "stimulated" and may be more effective in
fighting infections or cancer cells. We call this therapy "activated donor lymphocyte
infusions, or activated DLI (aDLI)".

In a previous study in which patients received standard DLI and aDLI, we felt that responses
were at least as good as conventional DLI but too few patients were treated to know if
responses might be better. Unfortunately, as noted in other studies using DLI, about half of
the patients did not respond, and about half of the patients in remission had later relapse
of their disease.

This current study is being performed to see whether it is safe and effective to administer
higher doses of activated DLI or repeated doses of activated DLI.

- Patients who are in remission at 3 months after receiving the initial activated DLI
will be treated with more activated donor lymphocytes every 3 months for a total of 4
more times (3 months, 6 months, 9 months and 12 months after the first infusion) to
test if it is safe to give repeated doses of activated DLI and to see if repeated doses
will prevent subsequent relapse.

- For those patients who are not in remission 6-12 weeks after the initial activated DLI,
we will test whether it is safe and effective to give higher doses of activated donor
lymphocytes. Using the experimental procedures that activate the donor lymphocytes,
lymphocytes can also be grown up in the laboratory and 10 times more lymphocytes can be
given to you than can be obtained using more conventional DLI.

For this study, similar to our previous study with aDLI, all patients will receive standard
donor lymphocyte infusions first, and in addition will receive activated donor lymphocytes
approximately 12 days later (DLI followed by aDLI). Depending of the response to this
treatment, and depending on possible side effects (such as graft-vs-host disease as
described below), patients in remission will then receive additional aDLI every 3 months for
4 more times, and patients not in remission within 6-12 weeks will receive higher dose aDLI.
The timing of the higher dose aDLI will be determined by your physician depending on your
disease and the rate of progression of your disease. The aDLI can be given as early as 6
weeks, or as late as 12 weeks (3 months).

In the previous study the highest dose of aDLI a patient received is the same as the dose to
be initially administered in this study which is 1 x 108 CD3+ cells/kg. However, this
research study will also include doses higher than those used in the previous study.
Patients in remission will receive the same dose of 1 x 108 CD3+ cells/kg on 4 additional
occasions as long as no unacceptable side effects are observed. Patients that are not in
remission will receive a dose that is 10 times higher.

Inclusion Criteria:

- Prior allogeneic stem cell transplant.

- Expected survival > 4 weeks

- Original bone marrow donor available for leukocyte donation.

- Absence of active acute GVHD > grade I, or chronic GVHD.

- Off all immune suppression for GVHD for 28 days (an exception may be made for
patients with acute leukemia whose disease is progressing rapidly and a 28 day
waiting period after discontinuation of immune suppression is not practical or
appropriate).

- Creatinine < 2.5 mg/dl.

- Relapsed or persistent advanced malignancy with less than a 50% chance of responding
to unstimulated DLI:

a. CML: Relapse with accelerated phase, or blast phase disease b. AML, ALL i.
Cytogenetic relapse (less than 5% blasts).

1. The patient's leukemia-specific chromosome abnormality is detectable by standard
cytogenetics in more than 25% of cells at any time greater than day 50
post-transplant.

ii. Hematologic relapse: More than 5% blasts in the marrow or peripheral blood.

c. MDS d. Non-Hodgkin's Lymphoma or Hodgkin's Disease i. Relapse: Recurrent
disease by serial physical exam, radiographic studies, or molecular studies. If
possible, tumor should be re-biopsied to determine histology and rule out
possibility of EBV-related lymphoproliferative disease e. CLL f. Myeloma

Exclusion Criteria:

- Active chronic or acute GVHD > grade I.

- Requirement for active immunosuppression to treat GVHD.

- Pregnant or lactating women. The safety of this therapy on unborn children or effects
on breast milk are not known.

- Uncontrolled active infection

- Any uncontrolled active medical disorder that would preclude participation as
outlined.