The goal of this clinical research study is to find the highest tolerable dose of fludarabine and cytarabine that can be given in combination with oxaliplatin and rituximab in the treatment of chronic lymphocytic leukemia (CLL), prolymphocytic leukemia, or Richter's transformation. Once the highest tolerable dose for this drug combination is found, the next goal of the study will be to find out if this combination therapy is effective in shrinking or slowing the growth of these diseases.

Cytarabine is designed to insert itself into DNA (the genetic material of cells) and stop the DNA from repairing itself.

Oxaliplatin is designed to kill cancer cells by damaging their DNA.

Fludarabine is designed to make cancer cells less able to repair damaged DNA. This may increase the likelihood of the cells dying.

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

During the Phase I portion of the study, researchers will be testing different doses of the study drug combination. Oxaliplatin and rituximab will be given at the same dose level. However, fludarabine and cytarabine will be given daily for 2 days to the first 3 participants, daily for 3 days to the next 3 participants, and daily for 4 days to the next 3 participants. Although the plan is to treat 3, up to 6 participants may be treated in each of these groups.

If participants who receive the fludarabine and cytarabine for 2 or 3 days do not experience intolerable side effects, after the second cycle they may receive the next higher dose (an additional day of fludarabine and cytarabine) for the following cycles.

Once the highest tolerated dose of fludarabine and cytarabine given in combination with oxaliplatin and rituximab is found, the next group of participants entering the study will take part in the Phase II portion of the study. Participants in the Phase II portion will receive the study drugs at the highest tolerated dose found in the Phase I portion of the study. The goal of this part of the study is to look at how effective the drug combination is in treating patients with Richter's syndrome, prolymphocytic leukemia, and aggressive, relapsed, or refractory CLL. The same dose levels for all 4 drugs will be used throughout the Phase II portion of the study, unless intolerable side effects occur. In that case, the dose may be lowered or the treatment may be stopped.

• Each cycle will be repeated every 4-6 weeks, depending on your blood counts and your medical condition.
• You will receive oxaliplatin through a needle in your vein over about 2 hours on Days 1-4 of every 28-day study "cycle."
• You will receive rituximab by vein over about 4-6 hours on Day 3 of the first cycle and on Day 1 on every cycle after that.
• Starting on Day 2, you will receive fludarabine by vein over about 30 minutes and cytarabine by vein over about 2 hours for 2, 3, or 4 days.
• On Day 6, you will receive peg-filgrastim subcutaneously (through a needle just under your skin) to help increase your white blood cell count.
• On the days that you receive the study drugs, you will also be given fluids (such as saline) by vein to keep you from becoming dehydrated. If you receive the treatment as an outpatient, this means that the visit may take up to 8 hours.
• Additional drugs will be given before each dose of rituximab to lower the risk of side effects. If side effects do occur, rituximab may have to be stopped until the side effects go away, at which point the drug may be restarted. This may make your time in the outpatient area longer.
• The first study cycle will be given at MD Anderson. Depending on your response, up to 5 more cycles will be given either at MD Anderson or at home with your regular doctor.
• Every 1-2 weeks, blood samples (about 1 teaspoon each) will be drawn for routine tests.
• At the end of every cycle, you will have a physical exam and blood (about 1 teaspoon) will be drawn to determine whether you should receive another cycle.
• You will have a bone marrow biopsy/aspirate at the end of the 3rd and 6th cycles. The biopsy at the end of cycle 3 will be used to determine if you are responding to treatment and will determine whether you should continue to receive the study drug combination.

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

Once you are no longer receiving treatment, you will have an end-of-treatment visit. At this visit, you will have a physical exam and blood (about 1 teaspoon) will be drawn for routine tests.

If you achieve remission, after your last cycle is complete, you will have blood drawn (about 2 teaspoons each) every 3 months for routine tests. These tests will continue for as long as you are in remission.

This is an investigational study. Fludarabine, cytarabine, oxaliplatin, and rituximab are all FDA approved and commercially available. The use of these drugs together is investigational. Up to 102 patients will take part in this multicenter study. Up to 90 will be enrolled at The University of Texas (UT) MD Anderson Cancer Center.

Inclusion Criteria:

• All patients with histologically or cytologically confirmed Richter's transformation, prolymphocytic leukemia, aggressive, or relapsed/refractory B-cell chronic lymphocytic leukemia are eligible for this protocol.
• Patients must be 18 years of age or older.
• Patients must have a performance status of 0-2 (Zubrod scale).
• Patients must have adequate renal function (serum creatinine <= 2 mg/dL or creatinine clearance > 50 mL/min). Patients with renal dysfunction due to organ infiltration by disease may be eligible after discussion with the principal investigator (PI) and consideration of appropriate dose adjustments.
• Patients must have adequate hepatic function (bilirubin <= 2 mg/dl; aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) < 2.5 * the upper limit of normal (ULN) for the reference lab unless due to leukemia or congenital hemolytic disorder [for bilirubin]). Patients with hepatic dysfunction due to organ infiltration by disease may be eligible after discussion with the PI and consideration of appropriate dose adjustments.
• Female patients of childbearing potential (including those < 1 year post-menopausal) and male patients must agree to use contraception.
• Patients must sign an informed consent indicating that they are aware of the investigational nature of this study.
• Patients must have platelet counts > 20,000, unless lower counts are due to disease involvement or autoimmune disorders.

Exclusion Criteria:

• Untreated or uncontrolled life-threatening infection.
• Oxaliplatin, fludarabine, cytarabine or rituximab intolerance.
• Pregnancy or lactation.
• Chemotherapy and/or radiation therapy within 4 weeks.
• Medical condition, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.

Adverse event collection from Day 1 of first cycle of therapy through sixth cycle then follow-up (every three to six months following first year) until off study. Enrollment started May 2007 and completion including follow up was January 2011.