This phase II trial studies the side effects and how well cladribine and rituximab work in treating patients with hairy cell leukemia. Drugs used in chemotherapy, such as cladribine, work in different ways to stop the growth of cancer cells either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cladribine together with rituximab may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To demonstrate the efficacy in achieving complete response of combination of cladribine administered intravenously over 2 hours for 5 days followed by rituximab weekly for 8 weeks in patients with untreated or previously treated hairy cell leukemia.

II. To examine the efficacy of rituximab to eradicate minimal residual disease (MRD) after cladribine therapy (as assessed by immunophenotyping of bone marrow and peripheral blood).

III. To examine the effect of addition of rituximab to cladribine on the long term disease-free (DFS) and overall survival (OS) (as compared with historical controls).

IV. To evaluate potential predictors of outcome including molecular and flow evaluations of MRD, as well as other potential molecular predictors such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF).

OUTLINE:

Patients receive cladribine intravenously (IV) over 2 hours once daily (QD) on days 1-5 and rituximab IV once weekly for 8 weeks beginning on day 28 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Inclusion Criteria:

• Age 18 years and older
• Diagnosis of hairy cell leukemia (HCL) established by bone marrow examination
• Patients with relapsed disease are eligible if they have had no more than one prior therapy
• Women of child-bearing potential must use birth control (oral contraceptive, barrier, abstinence or any other acceptable method) for the duration of the study
• Performance status =< 3
• Creatinine less than or equal to 2.0 unless related to the disease
• Bilirubin less than or equal to 3.0
• Transaminases less than or equal 3 x upper limit of normal unless related to the disease
• No prior investigational agent in the 4 weeks prior to initiation of therapy

Exclusion Criteria:

• Unable or unwilling to sign the consent form
• Known infection with human immunodeficiency virus (HIV), hepatitis B or C
• Presence of active infection
• Presence of central nervous system (CNS) metastases
• New York Heart Association classification III or IV heart disease
• Prior chemotherapy (last 4 weeks)