CLL2M is a phase 2, multicenter, open label study to investigate the possible therapeutic benefits of using bendamustine in combination with rituximab for the treatment of patients with previously untreated or relapsed CLL.

Conventional chemotherapy and also high dose chemotherapy with autologous stem cell transplantation are not curative treatment options in B-CLL; nearly all patients will eventually relapse. Also monoclonal antibodies are not curative for B-CLL patients in monotherapy, their impact on survival in combination with conventional chemotherapy is currently validated. In addition, there is no standard combination therapy for patients with relapsed CLL. Therefore there is an urgent medical need to identify new strategies.

The combination of rituximab (monoclonal antibody) and bendamustine (chemotherapy) has shown encouraging activity in patients with relapsed/refractory NHL or mantle cell lymphoma. In vitro studies have been used to investigate the effects of bendamustine and rituximab on programmed cell death (apoptosis) and have shown synergistic effects of both drugs. The mechanisms of action of these two active drugs may provide a treatment with good therapeutic potential in CLL. However, though bendamustine has been used for over 30 years there is still a need to define a standard regimen for the use of bendamustine in combination with monoclonal antibodies (mAb) especially in the treatment of CLL.

Inclusion Criteria:

• 18 years of age or older

• Diagnosis of B-CLL in need of treatment

  • Previously untreated Binet stage C or Binet B with need of treatment according to NCI-criteria
  • Relapsed or refractory disease after at least one but not more than 3 prior regimens. Patients who previously received bendamustine must have had at least a partial response with duration of response of at least six months.

• World Health Organization performance status of 0-2

• Life expectancy >12 weeks

• Anti-cancer therapy, major surgery, or irradiation was completed >3 weeks before registration in this study. Patient must have recovered from the acute side effects incurred as a result of previous therapy.

• Serum creatinine ≤1.5 the institutional upper limit of normal (ULN) or Creatinine clearance >30 ml/min/1.73 m²

• Adequate liver function as indicated by a total bilirubin, AST, and ALT ≤2 the institutional ULN value, unless directly attributable to the patient's tumor.

• Female patients with childbearing potential must have a negative serum pregnancy test within two weeks of first dose of study drug(s). Male and female patients must agree to use an effective contraceptive method while on study treatment and for a minimum of six months following study therapy.

• Signed, written informed consent.

Exclusion Criteria:

• Previously treated with >3 prior regimens for B-CLL.
• Known central nervous system (CNS) involvement with B-CLL.
• Patients who have progressed with more aggressive B-cell cancers such as Richter's syndrome.
• History of anaphylaxis following exposure to monoclonal antibodies.
• Known to be human immunodeficiency virus (HIV), hepatitis B, or C positive.
• Active infection or history of severe infection (grade 4) within 3 months prior to study registration.
• Medical condition requiring prolonged use of oral corticosteroids (> 1 month).
• Use of investigational agents within 30 days prior to study randomization.
• Active secondary malignancy.
• ANC <1.5x109/L or platelet count <75x109/L, unless due to bone marrow involvement of CLL.
• Other severe, concurrent diseases, including tuberculosis, mental disorders, serious cardiac functional capacity (Class III or IV as defined by the New York Heart Association Classification), severe diabetes, severe hypertension, pulmonary disease (chronic obstructive pulmonary disease [COPD] with hypoxemia), or major organ malfunction (liver, kidney) that could interfere with the patient's ability to participate in the study.
• Pregnant or nursing women.
• Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up.
• Participation in another clinical trial