Low Dose CdA Combined With Valproic Acid (VPA) in Previously Treated B-cell Chronic Lymphocytic Leukemia(B-CLL)
Low Dose CdA Combined With Valproic Acid (VPA) in Previously Treated B-cell Chronic Lymphocytic Leukemia(B-CLL)
Rationale New chemotherapeutic agents are needed in relapsing B-Cell Chronic Lymphocytic
 Leukemia (B-CLL) to overcome resistance of CLL cells. Valproic acid (VPA) is an inhibitor of
 histone deacetylase (HDAC) used as an anticonvulsant and mood-stabilizing drug for decades.
 VPA mediates apoptosis in CLL cells through caspase activation. VPA shows toxicity toward CLL
 cells displaying alterations in the p53 pathway. The combination of VPA with fludarabine or
 2-Chlorodeoxyadenosine (CdA, Cladribine) results in synergistic loss of B-CLL cell viability,
 and significant increase in apoptosis. The highest index of synergism is observed between VPA
 and CdA, a purine nucleoside analog active in B-CLL.

 Study design Overall, the study will be proposed to previously treated patients with advanced
 B-CLL, who are not eligible for aggressive approaches, and who exhibit progressive disease. A
 total of 33 patients will be included. Estimated enrolment time is 2 years.

 -  First part: It is planned to start therapy with single VPA during 2 months, targeting
 plasma levels that have been reported to be active in vitro toward CLL cells (but that
 do not exceed therapeutic levels in seizure prevention), and in parallel, to verify
 whether cellular targets of VPA have been actually inhibited in leukemic B-lymphocytes.

 -  Second part: After the VPA preloading period (2 months), patients will be evaluated to
 receive CdA. CdA will be given at 5.6 mg/m²/day intravenously during 3 days, a
 reduced-dose schedule which is less toxic - at no obvious cost of loss of efficacy - as
 compared to the standard dosage of 5 days. CdA was chosen because it displays the
 highest level of in vitro synergism with VPA. Four monthly courses of CdA will be given.
 Patients will then be evaluated. VPA will be stopped at the time of response evaluation
 (scheduled 28 days after the last course of CdA).
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