Low Dose CdA Combined With Valproic Acid (VPA) in Previously Treated B-cell Chronic Lymphocytic Leukemia(B-CLL)

Inclusion Criteria:

• B-cell Chronic Lymphocytic Leukemia (CLL)
• Patients must have intermediate or high-risk categories of the modified 3-stage Rai and Binet staging

• Patient MUST have progressive or symptomatic disease as defined by any of the following conditions:

  • Progressive lymphocytosis with a lymphocyte count increased > 50% over the last 2 months period or an anticipation of the doubling time in less than 6 months
  • Progressive or symptomatic splenomegaly or hepatomegaly
  • Progressive or symptomatic lymphadenopathy
  • Evidence of progressive marrow failure as manifested by development or worsening of anemia and/or thrombocytopenia
  • Presence of any B-symptoms: weight loss ≥ 10% within the previous 6 months, fever > 38.0°C for ≥ 2 weeks without evidence of infection, or night sweats without evidence of infection
• Patient must have received one or more prior therapies for Chronic Lymphocytic Leukemia. Patients may have received any of the following prior treatment regimens: fludarabine-containing combinations, alemtuzumab single agent or combination, rituximab combinations, chlorambucil, cyclophosphamide +/- prednisone, or other forms of immunotherapy…

• Patients must have adequate organ function:

  • Neutrophils > 500/mm³
  • Platelets > 50.000/mm³
  • Creatinine clearance (measured or calculated) > 40 ml/min
• Age > 18 years
• Patient's ECOG performance status must be 0-2
• Patient's written informed consent
• Life expectancy > 6 months

Exclusion Criteria:

• Patients having received Valproic Acid (VPA) within 3 months
• Previous, suspected or known hypersensitivity to VPA, or any of its derivatives
• Liver porphyria
• Epilepsy due to mitochondrial diseases
• Ongoing treatment with VPA-interacting drugs
• Cumulative Illness rating Scale (CIRS) > 6
• Prior allogenic or autologous bone marrow transplantation less than 12 months
• Patient having received any anticancer agents (chemotherapy, immunotherapy or targeted agents) within 4 weeks
• Central Nervous System involvement
• Concomitant disease requiring prolonged use of corticosteroids (> 1 month)
• Transformation into an aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma)
• Creatinine clearance < 40 ml/min calculated according to the formula of Cockcroft and Gault. Patients with a calculated creatinine clearance below 40 ml/min may be eligible if (1) a measured creatinine clearance (based on 24 hours urine collection or other reliable method) is > 40 ml/min, or (2) a new calculation conducted after adequate hydration is > 40 ml/min.
• Any coexisting medical or psychological condition that would preclude participation to the required study procedures
• Patient with mental deficiency preventing proper understanding of the requirements of treatment
• Pregnancy, lactating woman, females of childbearing potential or male patient who are unwilling to use adequate contraception
• Clinically significant auto-immune cytopenia, Coombs-positive hemolytic anemia as judged by the treating physician
• Patients with a history of another malignancy in complete remission less than 2 years, except basal cell skin cancer, stage 0 (in situ) cervical carcinoma or tumor treated curatively by surgery
• Any severe co-morbidities such as New York Heart Association Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarrhythmias requiring ongoing treatment, or severe uncontrolled myocardiopathy, uncontrolled hypertension, severe chronic obstructive pulmonary disease with hypoxemia or uncontrolled diabetes mellitus
• Active bacterial, viral or fungal infection
• Seropositivity for: Human Immunodeficiency Virus, hepatitis C or hepatitis B (unless clearly due to vaccination)
• Liver insufficiency
• Total bilirubin > 2 x the upper limit of normal (ULN)
• Prior history of severe hepatic or pancreatic disorder
• Alkaline phosphatases and aminotransferases (AST, ALT) > 2 x ULN