Trial Information

Fludarabine-Based Conditioning for Allogeneic Marrow Transplantation From HLA-Compatible Unrelated Donors in Severe Aplastic Anemia

Your bone marrow normally produces white cells, red cells, and platelets. Once ready, these
cells are released into the bloodstream. Aplastic anemia is a blood disorder where the bone
marrow has stopped working and produces very few or no cells to be released into the
bloodstream. If not successfully treated, this condition will almost always lead to death,
primarily because of infection or bleeding. A bone marrow transplant is an option for you
because your doctors believe it may cure your aplastic anemia. As you do not have a
matched, sibling donor, a matched, unrelated donor (i.e. not a blood relative) has been
selected for you. Before you receive a matched, unrelated donor marrow transplant, you will
receive medications and low dose total body irradiation (TBI) to kill immune cells in your
body that might reject the cells from your donor. This will allow your body to accept the
donor marrow. This is called engraftment.

Cyclophosphamide is a medication that will be used in this study to lower your immune system
in order to allow your body to accept the donor marrow cells.

If you are found eligible to take part in this study, you will be given medications and TBI
before your bone marrow transplant to allow your body to accept your donor's stem cells.
This is called the conditioning regimen. Before your transplant, a catheter (i.e. a soft
plastic tube) will be inserted into a vein under the collarbone to allow for medications and
fluids to be given.

The conditioning regimen includes a combination of drugs used to kill the cells in your body
that may reject the donor cells. The drugs to be used in this study are fludarabine,
cyclophosphamide, and ATG, as well as low-dose to TBI. All participants in this study will
receive the same amount of fludarabine, ATG and low-dose TBI. You will receive fludarabine
on the fifth, fourth, third and second days before your transplant by intravenous infusion
through your catheter over about 30 minutes.

You will receive ATG on the fourth, third, and second days before your transplant. This will
be given intravenously through your catheter over 4 to 6 hours. ATG is an animal product,
and your study doctor may decide to use a horse or a rabbit product. Both products have
similar side effects and efficacy. You will receive TBI on the day before your transplant.

Different groups of patients will get different amounts of cyclophosphamide. You will
receive cyclophosphamide for a total of either 1 or 2 days before your transplant. The
number of days depends on your group. You will be placed in the group that is being tested
at that time. Your doctor will tell you which group you are in. Neither you nor your
doctor can choose the group. Sometimes there may be a short waiting period for a new patient
to be entered in the study, and you should discuss with your doctor how this waiting period
may affect you.

The main purpose of this study is to find the best dose of cyclophosphamide. This means
that small groups of patients are treated with a given dose of cyclophosphamide and followed
closely until it can be shown that the new marrow has been accepted by the body and the
treatment has not caused any unacceptable harm. In the early part of the study,
participants were receiving cyclophosphamide for either 3, 2, 1 or 0 days. The doctors who
are conducting the study have by now gained some experience with this conditioning schedule,
and this has helped them to narrow down the number of possible doses of cyclophosphamide
that you, as a new participant, may receive. You should be aware that some participants who
received 3 days of cyclophosphamide (the highest dose) suffered severe side effects
(including death), and therefore, new patients are no longer being placed in this group.
You should also be aware that participants who received zero days of cyclophosphamide (the
lowest dose) experienced graft rejection (meaning, their body did not accept the new marrow,
and the new cells failed to grow). Therefore, new participants are no longer being assigned
to this group. Participants who now come to transplantation will be treated with either 1
or 2 days of cyclophosphamide.

After the conditioning regimen, the donor marrow cells will be given to you through your
catheter. The cells will travel into the bloodstream to reach your bone marrow where they
are expected to make healthy, new blood cells. This step is necessary to replace your
diseased marrow and because the high dosages of drugs given to you during the conditioning
regimen may also damage or destroy healthy cells in your bone marrow. Until the new cells
begin producing healthy blood cells, you will be at an increased risk of bleeding or
developing an infection.

Following the transplant (at least every week until roughly 100 days after transplant, then
every 3-6 months for 2 years after that), you will have a complete medical history and
physical exam, including measurement of height and weight. Blood (about 2-4 tablespoons) and
urine may be collected for routine tests. You will also have a bone marrow aspiration and
biopsy at 30 and 100 days after transplant and then every 4-6 months for 2 years after that.

You will be expected to take medications such as cyclosporine (or tacrolimus) by mouth for
no less than 6-9 months to prevent graft-versus-host disease. You will also be expected to
stay at the transplant center for at least 3 months after your transplant. You will be
asked to return to the transplant center for regular follow-up care. The standard tests
will be done at that time.

You will be in the study for up to 2 years. Follow-up for transplant will last as long as
you require care. However, researchers would like to keep track of your medical condition
for the rest of your life by contacting you and the doctor providing your regular medical
care by phone or mail once a year. Keeping in touch with you and checking on your condition
every year helps researchers to look at the long-term effects of the study and
transplantation in general. It is not necessary for you to agree to follow-up for longer
than 2 years to participate in this study. After 2 years, you will continue to be followed
by your transplant doctor, but no longer as part of the study.

You can be taken off the study (with or without your consent) for several reasons. You may
be taken off study if you no longer meet the study requirements. Ask you doctor if you would
like more information about this. You can be taken off study if you need a medical treatment
not allowed in this study, or the study chair decides that it would be in your best interest
to leave the study. You may be taken off study if intolerable side effects occur. You will
be taken off study if your transplant fails to take. In this case, your doctor will decide
what the best treatment for you will be. You may be taken off study if you are unable to
follow study instructions or keep study appointments. You may also be taken off study if
the study is stopped by the Food and Drug Administration (FDA) or the National Institutes of
Health (NIH).

This is an investigational study. All of the drugs and medications used in this study are
FDA-approved and commercially available. Up to 81 participants will be enrolled in this
multicenter study. Up to 7 will be enrolled at MD Anderson.