The goal of this clinical research study is to learn if adding Zevalin (ibritumomab tiuxetan)
to low-intensity chemotherapy (the combination of rituximab, bendamustine, and fludarabine),
followed by an allogeneic stem cell transplant, can help to control lymphoma. The safety of
this combination will also be studied.
Two (2) forms of ibritumomab tiuxetan will be used in this study. 90Y-ibritumomab tiuxetan is
designed to attach to lymphoma cells and destroy the cells using a radioactive particle that
is attached to it. 111In-ibritumomab tiuxetan is like 90Y- ibritumomab tiuxetan, but the
radioactive particle that is attached to it does not kill lymphoma cells. The radioactive
particle makes the drug able to be seen inside your body. It is being used in this study to
predict how fast the study drug will travel in the body and how long the drug stays in the
body.
Rituximab is designed to attach to lymphoma cells, which may cause them to die.
Bendamustine is designed to damage and destroy the DNA (genetic material) of cancer cells.
Fludarabine is designed to make cancer cells less able to repair damaged DNA. This may
increase the likelihood of the cells dying.
Study Drug Administration and Procedures:
The chemotherapy, some of the other drugs in this study, and the stem cell transplant will be
given by vein through your central venous catheter (CVC). A central venous catheter is a
sterile flexible tube that will be placed into a large vein while you are under local
anesthesia and will remain in your body during treatment. Your doctor will explain this
procedure to you in more detail, and you will be required to sign a separate consent form.
Blood samples will also be drawn through the CVC.
On Days -22 (22 days before you receive the stem cell transplant), you will receive rituximab
by vein over 3-4 hours. You will then receive 111In-ibritumomab tiuxetan by vein over 30
minutes.
From Day -22 through Day -16, you will have scans called whole-body planar scintigraphy
imaging. In these scans, a special camera will capture 2-dimensional images of the whole body
to see where the radioactive 111In- ibritumomab tiuxetan that was injected on Day -22 has
spread. No additional radiation will be used in this scan. Scintigraphy will be performed
right after the injection, then 3-6 hours after the injection, then 24, 72, and 144 hours
(+/- 2 hours) after the injection.
After the last scintigraphy imaging scan, the scans will be reviewed to learn how much
radiation has traveled to different organs and to decide how much 90Y- ibritumomab should be
used.
On Day-14, you will receive rituximab by vein over 3-4 hours. You will then receive the
calculated dose of 90Y-ibritumomab tiuxetan by vein over 30 minutes.
On Days -5, -4, and -3, you will receive fludarabine and bendamustine by vein over 1 hour
each day.
On Days -3 through Day 100, if your stem cells are from cord blood, you will receive
mycophenolate mofetil (MMF) by vein or by mouth. MMF is designed to block the donor cells
from growing and spreading in a way that could cause graft versus host disease (GVHD -- a
condition in which transplanted tissue attacks the recipient's body).
Starting on Day -2, if your stem cells are from a related or matched unrelated donor, you
will receive tacrolimus by vein as a continuous (nonstop) infusion until you are able to take
it by mouth to help prevent GVHD. You will then take tacrolimus by mouth 2 times a day for
about 3 months. After that, your tacrolimus dose may be lowered if you do not have GVHD. Your
doctor will discuss this with you.
On Days -2 and -1, if your stems cells are from a matched unrelated donor or from cord blood,
you will receive thymoglobulin (ATG) by vein over about 4 hours. ATG is designed to weaken
your immune system to reduce the risk of rejecting of the transplant.
On Day 0, you will receive the blood stem cells by vein over about 30-45 minutes. Blood (less
than 1 teaspoon) will also be drawn to measure how much (if any) radiation from the 90Y-
ibritumomab tiuxetan is left in the blood.
Starting on Day 0, if your stem cells are from cord blood, you will receive filgrastim
(G-CSF) through a needle under the skin 1 time a day every day until your white blood count
begins to recover. G-CSF is designed to help cells in the bone marrow to divide, which helps
raise white blood cells counts more quickly, lower fever, and decrease the risk of infection.
On Days 1, 3, and 6, if your stem cells are from a related or matched unrelated donor, you
will receive methotrexate over 30 minutes each day by vein to help prevent GVHD. Patients
receiving a matched unrelated donor will also be given methotrexate on Day 11 after the
transplant.
Starting on Day 7, if your stem cells are from a related or matched unrelated donor, you will
receive G-CSF through a needle under the skin 1 time a day every day until your white blood
count begins to recover.
When your doctor thinks they are needed, you will also receive antibiotics and antifungal
drugs to help prevent and/or treat infections. Your doctor will tell you more about how these
drugs are given and possible side effects.
You will be in the hospital for about 3-4 weeks after you receive the stem cell transplant.
During this time, the following tests and procedures will be performed at any point that your
doctor thinks they are needed:
- You will have a physical exam, including measurement of your vital signs (blood
pressure, heart rate, temperature, and breathing rate).
- You will be asked about how you are feeling and about any side effects you may be
having.
- Blood (about 4-6 teaspoons) will be collected for routine tests, to check your kidney
and liver function, and to learn if and how well the transplant is working.
The following may also be performed if at any point the doctor thinks they are needed:
- You may have imaging scans to check the status of the disease and/or to check for
possible infections.
- You may have a bone marrow biopsy to check the status of the disease. To collect a bone
marrow biopsy, an area of the hip or other site is numbed with anesthetic, and a small
amount of bone marrow and bone is withdrawn through a needle.
- You may have transfusions of blood and/or platelets.
You must stay in the Houston area for about 100 days after the stem cell transplant.
Long-Term Follow-Up:
About 3, 6, and 12 months after the stem cell transplant:
- Blood (about 6 teaspoons) will be collected for routine tests, to check kidney and liver
function, and to see how well the transplant has taken.
- You will have CT and PET scans to check the status of the disease.
- You will have a bone marrow biopsy/aspirate to check the status of the disease.
About 2 and 3 years after the stem cell transplant, you will receive a phone call that will
take less than 10 minutes to learn how you are doing.
Length of Study:
You will be on study for up to about 3 years. You may be taken off study early if the disease
gets worse, if you have any intolerable side effects, of if you are unable to follow study
directions.
You should talk to the study doctor if you want to leave the study early. If you are taken
off study early, you still may need to return for routine post-transplant follow-up visits,
if your transplant doctor decides it is needed. It may be life-threatening to leave the study
after you have begun to receive the study drugs but before you receive the stem cells.
This is an investigational study. Ibritumomab tiuxetan, rituximab, bendamustine, and
fludarabine are FDA approved and commercially available for the treatment of lymphoma. The
dose of ibritumomab tiuxetan in this study is designed to be higher than the FDA approved
dose. The use of ibritumomab tiuxetan and bendamustine in combination with the other study
drugs and a stem cell transplant for the treatment of lymphoma is investigational.
Up to 20 patients will take part in this study. All will be enrolled at MD Anderson.
Inclusion Criteria:
1. 18 to 70 years of age.
2. Patients with the following CD20+ lymphoid malignancies who are eligible for
allogeneic transplantation: a. Relapsed or refractory follicular lymphoma; b. Relapsed
or refractory or high risk mantle cell lymphoma (hi ki67; blastic); c. Recurrent or
refractory marginal zone; d. Recurrent or refractory CLL/small lymphocytic lymphoma;
e. Double-hit lymphoma; f. Diffuse large B cell lymphoma; g. Richter's patients; or h.
Refractory or recurrent Burkitts.
3. Patients who meet criterion #2 or have any of the following are eligible: a. Less than
PR to salvage chemotherapy; b. Kinetic failure; c. Having received more than 3 lines
of therapy; d. Failure to mobilize autologous stem cell; e. 10% or more marrow
involvement; f. 6 months post autologous stem cell transplant.
4. Patients must have a fully-matched related donor or a matched unrelated donor
identified. Double cord (at least 4/6 matched) can be used if no adult matched donor
is available.
5. Performance score of at least 80% by Karnofsky or 0 to 2 ECOG.
6. Left ventricular EF >/= 45% with no uncontrolled arrythmias or symptomatic heart
disease.
7. FEV1, FVC >/= 60% and corrected DLCO >/= 60%.
8. Serum creatinine </=1.6 mg/dL. Serum bilirubin < 2 mg/dL (unless due to Gilbert's
Syndrome).
9. SGPT < 2 X upper limit of normal.
10. Men and women of reproductive potential must agree to follow accepted birth control
methods (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with
spermicide, condom with spermicide, or abstinence) for the duration of the study.
11. Negative Beta HCG test within 30 days in a woman with child bearing potential defined
as not post-menopausal for 12 months or no previous surgical sterilization). Pregnancy
testing is not required for post-menopausal or surgically sterilized women.
Exclusion Criteria:
1. Patient with active CNS involvement with lymphoid malignancy.
2. Known infection with HIV, HTLV-I, Hepatitis B, or Hepatitis C.
3. Patients with other malignancies diagnosed within 2 years prior to study registration.
Skin squamous or basal cell carcinoma are exceptions.
4. Active bacterial, viral or fungal infections.
5. History of stroke within 6 months prior to study registration.
6. A prior allogeneic stem cell transplant.
7. Patient has received other investigational drugs within 3 weeks before study
registration.
8. Presence of circulating malignant lymphoid cells or bone marrow with lymphoma that
constituted more than 25% of the cellular elements.
9. Serious nonmalignant or malignant disease or psychiatric illness, which, in the
opinion of the investigator would compromise protocol objectives or interfere with
participation.
10. Patients who are breast-feeding.
