FCR Plus Sargramostim (GM-CSF) as Frontline Therapy for Symptomatic Chronic Lymphocytic Leukemia
FCR Plus Sargramostim (GM-CSF) as Frontline Therapy for Symptomatic Chronic Lymphocytic Leukemia
The goal of this clinical research study is to learn if using a combination of fludarabine,
 cyclophosphamide, and rituximab, with sargramostim (GM-CSF) can help to control previously
 untreated chronic lymphocytic leukemia (CLL). The safety of this combination will also be
 studied. This study will evaluate antibody-dependent cellular cytotoxicity (ADCC) and its
 relationship to response.
Fludarabine and cyclophosphamide are designed to enter CLL cells and destroy the "machinery"
 that allows CLL cells to multiply. Rituximab is designed to bind to CLL cells and cause cell
 death. GM-CSF is designed to help the bone marrow to produce white cells. It may also
 increase the target molecule called cluster of differentiation antigen 20 (CD20) for
 rituximab on the surface of the CLL cells which may improve the activity of rituximab.

 Before you can start treatment on this study, you will have what are called "screening
 tests." These tests will help the doctor decide if you are eligible to take part in the
 study. You will have a complete physical exam. Blood (about 2 tablespoons) will be drawn for
 routine tests. The routine blood draw will include a test for hepatitis B, unless this has
 been done within the last 6 months. This routine blood draw will also include a pregnancy
 test for women who are able to have children. To be eligible to take part in this study, the
 pregnancy test must be negative. A bone marrow aspirate and biopsy will be collected. To
 collect a bone marrow aspirate and biopsy, an area of the hip or chest bone is numbed with
 anesthetic and a small amount of bone marrow and bone is withdrawn through a large needle.

 If you are found to be eligible to take part in the study, you will receive GM-CSF thorough a
 needle under your skin on Day 1. Each study cycle is about 4 weeks, but may be longer
 depending on side effects or leukemia response.

 You will receive rituximab through a needle in your vein on Day 2. The first infusion may
 take up to 8 hours. For every dose of rituximab after that, the infusion may take 2-4 hours.
 The length of the infusion time depends on whether you have any reactions to the infusion.
 The dose level of rituximab may be increased for Cycles 2-6 as well. The drugs Tylenol
 (acetaminophen) and Benadryl (diphenhydramine hydrochloride) will be given before each dose
 of rituximab. This will be done to decrease the risk of side effects. If side effects do
 occur during rituximab treatment, the drug may have to be stopped until the side effects go
 away and then restarted, so your time in the outpatient area may be longer if that occurs.

 On Days 3-5 of the first treatment cycle, fludarabine and cyclophosphamide will be given
 through a needle in your vein. Each infusion will take about 30 minutes. After the first
 treatment cycle, fludarabine and cyclophosphamide will be given on Days 2, 3, and 4 for every
 cycle after that.

 During each cycle, the day after you receive fludarabine and cyclophosphamide, you will begin
 to receive GM-CSF. You will receive the drug for 1 week or until your white cell count has
 returned to an acceptable level.

 Cycle 1 will be given at M.D. Anderson's outpatient clinic. In some cases, Cycle 1 may be
 given in the inpatient area. The other 5 cycles can be given either at M.D. Anderson or at
 another location.

 With the exception of rituximab, the same doses of all other drugs will be used throughout
 the study unless side effects become severe. In that case, the dose may be lowered, or the
 treatment may be stopped.

 During each cycle, blood (about 1 tablespoon) will be drawn once every 1-2 weeks for routine
 tests.

 You will have a bone marrow biopsy performed at the end of Cycles 3 and 6 to check the status
 of the disease.

 You may remain on study for up to 6 cycles. You will be taken off study if the disease gets
 worse or if intolerable side effects occur.

 Once you are off study, blood (about 2 teaspoons) will be drawn every 6-12 months for routine
 tests.

 This is an investigational study. Fludarabine, cyclophosphamide, rituximab, and GM-CSF are
 all FDA approved and commercially available. However, their use in this study and in this
 combination is considered investigational. Up to 60 patients will take part in the study. All
 will be enrolled at M.D. Anderson.
Inclusion Criteria:

 -  Untreated CLL, CLL/PLL, or SLL (small lymphocytic lymphoma) with indication for
 therapy. Indications for therapy include at least one of the following: (1) one or
 more disease-related symptoms [fever, night sweats, weight loss > 10% in prior 6
 months, pronounced fatigue]; (2) advanced stage disease (Rai stage >/= 3 or Binet
 stage C); (3) autoimmune anemia and/or thrombocytopenia that is unresponsive to other
 therapies; (4) massive or progressive hepatomegaly and/or splenomegaly and/or
 lymphadenopathy; (5) recurrent infections; (6) rapid lymphocyte doubling time of < 6
 months.

 -  Patients who have been treated with not more than one regimen of immunotherapy (e.g.
 rituximab, alemtuzumab, rituximab plus alemtuzumab) for a diagnosis of CLL, CLL/PLL,
 or SLL (small lymphocytic lymphoma).

 -  Beta-2-microglobulin </= 4 mg/dL.

 -  Adequate liver function (total bilirubin </= 2.5 mg/dL, serum glutamate pyruvate
 transaminase (SGPT) </=4 x ULN) and renal function (serum creatinine </= 2.0 mg/dL
 and/or creatinine clearance < 30 mL/hour). Patients with renal or liver dysfunction
 due to suspected organ infiltration by lymphocytes may be eligible after discussion
 with the Principal Investigator, but upper limits for creatinine even under these
 circumstances must be creatinine < 3mg/dL and bilirubin < 6 mg/dL. Patients with
 Gilbert's syndrome may be entered on study with bilirubin levels </= 4 mg/dL.

 -  Eastern Cooperative Oncology Group (ECOG) performance status </= 2.

 -  Signed informed consent in keeping with the policies of the hospital.

 -  Male and female patients who are fertile agree to use an effective barrier method of
 birth control (ie, latex condom, diaphragm, cervical cap, etc) to avoid pregnancy.
 Female patients of childbearing potential (non-childbearing is defined as >/= 1 year
 after menses cease and/or surgically sterilized) need a negative serum or urine
 pregnancy test within 2 days of study enrollment..

 Exclusion Criteria:

 -  Active hepatitis B (at least one of the following markers positive: HBsAg, hepatitis B
 e antigen (HBeAg), immunoglobulin M (IgM) anti-HBc, hepatitis B virus (HBV) DNA).

 -  Concurrent chemotherapy or immunotherapy.

 -  Pregnant patients.

 -  History of HIV

 -  Symptomatic central nervous system (CNS) disease