Lenalidomide Combined With Vorinostat/Gemcitabine/Busulfan/Melphalan With Autologous Stem-Cell Transplantation in Diffuse Large B-Cell Lymphoma of the ABC Subtype

Central Venous Catheter:

Many of the drugs given in this study and the stem cell transplant will be given by vein
through a central venous catheter (CVC). A CVC is a sterile flexible tube and needle that
will be placed into a large vein while you are under local anesthesia. Blood samples will
also be drawn through your CVC. The CVC 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.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of lenalidomide based on when you join this study. Up to 3 dose levels of lenalidomide
will be tested. At least 2 participants will be enrolled at each dose level. The first group
of participants will receive the lowest dose level. Each new group will receive a higher dose
than the group before it, if no intolerable side effects were seen. This will continue until
the highest tolerable dose of lenalidomide is found.

All participants will receive the same dose level of vorinostat, gemcitabine, busulfan,
rituximab, and melphalan. However, if the first group of participants have any bad side
effects, the dose level of gemcitabine may be lowered for all other groups.

Busulfan Test Dose:

In stem cell transplants, the days before you receive your stem cells are called minus days.
The day you receive the stem cells is called Day 0. The days after you receive your stem
cells are called plus days.

You will receive a test dose of busulfan by vein over about 60 minutes. This low-level test
dose of busulfan is to check how the level of busulfan in your blood levels changes over
time. This information will be used to decide the next dose needed to match your body size.
You will most likely receive this as an outpatient during the week before you are admitted to
the hospital. If it cannot be given as an outpatient, you will be admitted to the hospital on
Day -11 (11 days before your stem cells are returned to your body) and the test dose will be
given on Day -10.

Blood (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK) testing of busulfan
11 times. PK testing measures the amount of study drug in the body at different time points
and will help the study doctor determine what your dose of busulfan should be on study. These
blood samples will be drawn at various timepoints before you receive busulfan and over about
the next 11 hours. The blood samples will be repeated again on the first day of high-dose
busulfan treatment (Day -8). A temporary heparin lock line will be placed in your vein to
lower the number of needle sticks needed for these draws. If it is not possible for the PK
tests to be performed, you will receive the standard fixed dose of busulfan.

You will also receive palifermin by vein over about 30 seconds each day to help decrease the
risk of side effects in the mouth and throat either during the 2 days before you are admitted
(inpatient) or during the 3 days before you are admitted (outpatient) You may ask the study
staff about the risks of palifermin.

Study Drug Administration (all patients):

Beginning on Day -8, you will swish caphosol and glutamine liquids in your mouth 4 times a
day, for about 2 minutes each time. You will swish these liquids every day until you leave
the hospital. You will swallow the glutamine. These drugs are used to help decrease the risk
of side effects in the mouth and throat.

On Days -9 through Day -2, you will take lenalidomide and vorinostat by mouth, with food.

If you the doctor thinks it is needed, you will receive rituximab by vein over 3-6 hours as
part of standard of care, on Day -9.

On Day -8, you will receive gemcitabine by vein over 4½ hours.

On Days -8 through Day -5, you will receive busulfan by vein over 2 hours.

On Day -3, you will receive gemcitabine by vein over 4½ hours and then melphalan by vein over
30 minutes.

On Day -2, you will receive melphalan by vein over 30 minutes.

On Day -1, you will rest (you will not receive chemotherapy).

On Day 0, you will receive your stem cells by vein over about 30-60 minutes.

You will receive 3 more doses of palifermin by vein over 15-30 seconds on Days 0, +1, and +2.

As part of standard care, you will receive G-CSF (filgrastim) as an injection under your skin
1 time each day starting on Day +5 until your blood cell levels return to normal. You may ask
the study staff about the risks of filgrastim.

Pregnancy Tests:

If you can become pregnant and have regular menstrual cycles, blood (up to 2 teaspoons) will
be drawn for a pregnancy test on the following schedule:

- Within 10-14 days and within 24 hours before your first dose of lenalidomide, even if
you have not had a menstrual period due to treatment or you have only had 1 menstrual
period in the past 24 months.

- One (1) time each week for 4 weeks, then every 4 weeks while taking lenalidomide.

- Four (4) weeks after you stop taking lenalidomide.

If you have irregular menstrual cycles, you will have pregnancy tests every week for the
first 28 days, then every 14 days while you are taking lenalidomide, again when you have been
taken off of lenalidomide therapy, and then 14 and 28 days after you have stopped taking
lenalidomide.

Length of Study:

As part of standard care, you will remain in the hospital for about 3-4 weeks after the
transplant. After you are released from the hospital, you will continue as an outpatient in
the Houston area to be monitored for infections and transplant-related complications.

You will be taken off study about 100 days after the transplant. You may be taken off study
early if the disease gets worse, if intolerable side effects occur, if you are unable to
follow study directions, or if you choose to leave the study early.

If for any reason you want to leave the study early, you must talk to the study doctor. It
may be life-threatening to leave the study after you have started to receive the study drugs
but before you receive the stem cell transplant because your blood cell counts will be
dangerously low.

Follow-Up:

About 100 days after the transplant:

- You will have a physical exam.

- Blood (about 4 teaspoons) and urine will be collected for routine tests and to check
your kidney and liver function.

- If the doctor thinks it is needed, you will have computed tomography (CT) and/or
positron emission tomography (PET) scans to check the status of the disease.

- If the doctor thinks it is needed, you may have a bone marrow aspiration and biopsy to
check the status of the disease. To collect a bone marrow aspiration/biopsy, an area of
the hip is numbed with anesthetic, and a small amount of bone marrow and bone is
withdrawn through a large needle.

This is an investigational study. Lenalidomide is FDA approved and commercially available for
the treatment of multiple myeloma (MM) and myelodysplastic syndrome (MDS). Rituximab is FDA
approved and commercially available for the treatment of non-Hodgkin's lymphoma and certain
types of leukemia. Vorinostat is FDA approved and commercially available for the treatment of
cutaneous T-cell lymphoma (CTCL). Gemcitabine is FDA approved and commercially available for
the treatment of non-small cell lung cancer (NSCLC), breast cancer, pancreatic cancer, and
ovarian cancer. Busulfan is FDA approved and commercially available for the treatment of
chronic myeloid leukemia (CML). Melphalan is FDA approved and commercially available for the
treatment of lymphoma.

The use of these study drugs in combination to treat DLBCL is considered investigational. The
study doctor can explain how the study drugs are designed to work.

Up to 30 participants will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Age 15-65

2. Patients with ABC (determined by immunohistochemistry using the Hans algorithmI) DLBCL
with primary refractory disease, relapse <12 months after initial therapy, secondary
International Prognostic Index (IPI) >1, less than partial response to salvage
treatment or exposure to >3 salvage regimens

3. Adequate renal function, as defined by an estimated serum creatinine clearance >/= 50
ml/min (MDRD method) and/or serum creatinine
4. Adequate hepatic function (SGOT and/or SGPT
5. Adequate pulmonary function with FEV1, FVC and DLCO (corrected for Hgb) >/= 50%

6. Adequate cardiac function with left ventricular ejection fraction >/= 40%. No
uncontrolled arrhythmias or symptomatic cardiac disease

7. ECOG performance status <2

8. Negative Beta HCG in woman with child-bearing potential

9. All study participants must be registered into the mandatory Revlimid REMS program,
and be willing and able to comply with the requirements of the REMS program.

10. Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS program.

Exclusion Criteria:

1. Grade >/= 3 non-hematologic toxicity from previous therapy that has not resolved to

2. Prior whole brain irradiation

3. Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/= 10,000
copies/mL, or >/= 2,000 IU/mL)

4. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic
hepatitis C or positive hepatitis C serology

5. Active infection requiring parenteral antibiotics

6. HIV infection, unless receiving effective antiretroviral therapy with undetectable
viral load and normal CD4 counts

7. Radiation therapy in the month prior to enrollment

8. History of arterial thromboembolic events in the past 3 months and of venous
thromboembolic events in the past month

9. History of hypersensitivity of lenalidomide or thalidomide