Nonmyeloablative Stem Cell Transplantation for Chronic Lymphocytic Leukemia (CLL)

Nonmyeloablative Stem Cell Transplantation With or Without Lenalidomide for Chronic Lymphocytic Leukemia (RV-CLL-PI-0294)

The goal of this clinical research study is to learn if lenalidomide, when given with a stem cell transplant and chemotherapy (bendamustine, fludarabine, and rituximab), can help to control CLL. The safety of this treatment combination will also be studied.

The Study Drugs Lenalidomide is designed to change the body's immune system. It may also interfere with the development of tiny blood vessels that help support tumor growth. Therefore, in theory, it may decrease or prevent the growth of cancer cells.

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 (the genetic material of cells). This may increase the likelihood of the cells dying.

Rituximab is designed to attach to leukemia cells, which may cause them to die.

Before receiving the study drugs, 21 or more days must have passed since your last biological therapy, chemotherapy, radiotherapy, or other investigational therapy.

Before you begin therapy, you will have the following tests and procedures performed. The blood may need to be drawn daily. The doctor will tell you how often the other tests will need to be performed:

• You will have a physical exam.
• You will have blood transfusions of blood and platelets as needed.
• Blood (about 2 tablespoons) and urine will be collected for routine tests.
• Blood (about 6-10 tablespoons) will be drawn to check the effects of the transplant.
• You will have a chest x-ray and CT scans to check the status of the disease.
• You will have an ECG.
• You will have a bone marrow biopsy and aspirate, when the doctor thinks it is needed.

Study Treatment:

If you are found to be eligible to take part in this study, you will begin treatment within 30 days after the screening visit. All liquid study drugs will be given through a central venous catheter (CVC) that will be left in place throughout treatment. A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

On Days -13, -6, +1, and +8, you will receive rituximab over 5-7 hours by CVC.

On Days -5 to -3, you will receive fludarabine over 1 hour and bendamustine over 1 hour by CVC. You will be given standard drugs such as hydrocortisone and Tylenol to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.

On Days -2 to -1, if the donor is not related or is not completely matched, you will receive thymoglobulin (ATG) over 4 hours by CVC. This will help to reduce the risk of your body rejecting the transplant.

On Days -2 to -1, if the donor is related, you will "rest" (not receive chemotherapy).

On Day -2, you will start to receive tacrolimus by CVC to help prevent graft-versus-host disease. This will be changed to a dose of tacrolimus by mouth, once you are discharged from the hospital. You will continue to take tacrolimus by mouth for 6-8 months following your transplant.

On Day 0, the blood stem cells that were collected from your donor will be transplanted (given back to your body) through the CVC over 30-45 minutes.

On Days 1, 3, and 6 after the stem cell transplant (and Day 11 if the donor is not related or not completely matched), you will receive methotrexate over 30-60 minutes by CVC to help prevent graft-versus-host disease.

On Day 7 after the transplant, G-CSF (filgrastim) will be injected under your skin once a day until your white blood cell counts recover. Filgrastim is designed to help increase the number of white blood cells.

Treatment with Lenalidomide:

If your blood cell counts are high enough and if you have not experienced side effects, between Days 90 and 100 after the transplant, you will be randomly assigned (as in the flip of a coin) into 1 of 2 groups. If you are in Group 1 you will take lenalidomide in addition to the treatment listed above. If you are in Group 2, you will not take lenalidomide.

If you are in Group 1, you will take lenalidomide 1 time every day for 3-12 months, depending on the disease response to the treatment.

You should swallow lenalidomide capsules whole, with water, at the same time each day. Do not break, chew, or open the capsules.

If you miss a dose of lenalidomide, take it as soon as you remember on the same day. If you miss taking your dose for the entire day, take your regular dose the next scheduled day (do NOT take double your regular dose to make up for the missed dose).

If you take more than the prescribed dose of lenalidomide you should seek emergency medical care (if needed) and contact the study staff right away.

You will be given standard drugs such as aspirin, Coumadin (warfarin), heparin, and/or allopurinol to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.

If the doctor thinks it is needed, your dose and schedule of lenalidomide will be changed.

If you are in Group 2, you will take no additional drugs.

Pregnancy Tests While Taking Lenalidomide:

Women who are able to become pregnant must have 2 negative pregnancy tests: the first test within 10-14 days before lenalidomide is prescribed and the second test within 24 hours before lenalidomide is prescribed. This blood test will be taken as part of a routine blood draw. The prescription must be filled within 7 days.

Once a week for the first month you take lenalidomide, women who are able to become pregnant will have blood (about 1 teaspoon) drawn for a pregnancy test. Then, in females with regular menstrual cycles, blood (about 1 teaspoon) will be drawn for pregnancy testing every 4 weeks, at the end of study, and 28 days after the last dose of lenalidomide. If menstrual cycles are irregular, blood (about 1 teaspoon) will be drawn every 2 weeks, at the end of study, and 14 and 28 days after the last dose of lenalidomide.

Study Visits (both Groups):

You must stay in the Houston area for about 100 days after the stem cell transplant.

Between Days 25 and 35 and then about 3 months after the stem cell transplant:

• You will have a physical exam.
• You will have CT scans to check the status of the disease.
• You will have PET scan to check the status of the disease, if the doctor thinks it is needed.
• Blood (about 2 tablespoons) will be drawn for routine tests and to check the level of tacrolimus.
• You will have a bone marrow biopsy/aspirate to check the status of the disease.

Study Visits (Group 1):

If you are in Group 1, blood (about 2 tablespoons) will be drawn for routine tests weekly until the maximum dose of lenalidomide is reached, then once every 2 weeks while you are taking lenalidomide.

Follow-up:

Every 3 months during the first 18 months and then every 6 months up to 3 years:

• You will have a physical exam.
• You will have CT scans to check the status of the disease.
• You will have PET scans to check the status of the disease, if the doctor thinks it is needed.
• Blood (about 2 tablespoons) will be drawn for routine tests.
• You will have a bone marrow biopsy to check the status of the disease.

Length of Study:

You will be on study up to about 3 years. You will be taken off study if the disease gets worse or you experience any intolerable side effects.

End-of-Study Visit:

After you are off study, you will have an end-of-study visit:

• You will have a physical exam.
• You will have CT scans to check the status of the disease.
• You will have PET scans to check the status of the disease, if the doctor thinks it is needed.
• Blood (about 2 tablespoons) will be drawn for routine tests.
• You will have a bone marrow biopsy to check the status of the disease.

Data Confidentiality Plan:

Data will be collected in the SCT&CT departmental database (BMTWeb). This database is password-protected, contains audit tracking, and follows all federal guidelines. Your personal identifying information will be removed for this analysis; no sensitive information will be shared.

This is an investigational study. All of the drugs used in this study are FDA approved and commercially available for the treatment of CLL. The use of the drugs together in this study is investigational.

Up to 80 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Age 18-75 years at the time of signing the informed consent form.
2. Disease: CLL in relapse, after failing conventional chemo-antibody combination therapy; CLL patients who failed to achieve CR with frontline conventional chemo-antibody; CLL patients with 17p deletion; CLL in Richter's.
3. Able to adhere to the study visit schedule and other protocol requirements.
4. Donor: HLA compatible related (HLA-A,-B,-DRBI matched or with one-antigen mismatched) or HLA compatible unrelated.
5. ECOG performance status of </= 2 at study entry
6. FEV1, FVC and DLCO >/= 40%.
7. Left ventricular EF > 40% with no uncontrolled arrhythmias or symptomatic heart disease.
8. Serum creatinine </= 1.6 mg/dL. Serum bilirubin < 1.6 mg/dL.
9. SGPT < 2x upper limit of normal.
10. Voluntary signed, written IRB-approved informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
11. All previous cancer therapy, including radiation, hormonal therapy and surgery, must have been discontinued at least 3 weeks prior to treatment in this study.
12. Disease free of prior malignancies for >/= 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix or breast.
13. Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to study entry.
14. Disease must be chemosensitive (ie, patients must have PR or better based on CT Scans, PET Scan, and bone marrow biopsy).
15. Patients suspected to have Richter's transformation (such as elevated LDH) and/or who are PET positive, should have a lymph node biopsy to assess histological status of the disease
16. Patients must be off of alemtuzumab for 6 weeks prior to consenting.

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
2. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide).
3. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
4. Use of any other experimental drug or therapy within 28 days of baseline.
5. Known hypersensitivity to thalidomide, lenalidomide, bendamustine, fludarabine. For patients will unrelated donors: Known hypersensitivity to thymoglobulin.
6. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
7. Concurrent use of other anti-cancer agents or treatments.
8. Known positive for HIV or infectious hepatitis, type A, B or C.
9. Sinuses should be evaluated by either CT neck or CT sinuses to exclude infections
10. Deep-vein thrombosis or pulmonary embolism within 3 months of study entry.
11. History of serious infection requiring hospitalization within the last 3 months of consenting.