Phase I-II study of low dose CdA combined with valproic acid (VPA) in previously treated B-cell chronic lymphocytic leukemia (CLL) patients. 

Study Objective

Primary:

• To determine the tolerability of VPA in combination with low dose CdA in patients with advanced B-CLL.

Secondary:

• To determine the minimal dose of VPA able to achieve adequate plasma levels of VPA and effective inhibition of VPA cellular targets (“biological dose”) including inhibition of histone deacetylation and gene-expression modifications.
• To determine the therapeutic response and survivals in patients treated with CdA combined with VPA. These items will be analyzed in specific sub-groups such as in patients with p53 alterations.
• To correlate VPA pharmacokinetics (plasma levels, intracellular levels, HDAC inhibition, gene expression profile changes…) with toxicity and disease response.

Participation conditions

Inclusion criteria

• B-CLL, as defined by the NCIWG criteria
• Patients must have intermediate or high-risk categories of the modified 3-stage Rai and Binet stagings
• Patient MUST have progressive or symptomatic disease as defined by any of the following conditions:
  • o Progressive lymphocytosis with a lymphocyte count increased > 50% over the last 2 month period or an anticipation of the doubling time in less than 6 months
  • o Progressive or symptomatic splenomegaly or hepatomegaly
  • o Progressive or symptomatic lymphadenopathy
  • o Evidence of progressive marrow failure as manifested by development or worsening of anemia and/or thrombocytopenia
  • o 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 CLL. Patients may have received any of the following prior treatment regimens: fludarabine-containing combinations, alemtuzumab single agent or combination, rituximab combinations, chlorambucil, cyclophosphamide +/- prednisone, CVP, or other forms of immunotherapy…
• Patients must have adequate organ function:
  • o Neutrophils > 500/mm³
  • o Platelets > 50.000/mm³
  • o Creatinine clearance (measured or calculated) ³ 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 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
• CIRS (Cumulative Illness rating Scale) > 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
• CNS 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-h 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 NYHA 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: HIV, 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
 

Centre Hospitalier de Luxembourg