Assessment of safety and efficacy of with fludarabine and cyclophosphamide (FC) combined with ofatumumab (FCO2) in previously untreated "young" patients with Chronic Lymphocytic Leukemia (CLL).

Given that:

• rituximab, fludarabine and cyclophosphamide (FCR) front-line treatment was associated with a high OR rate, superior PFS and OS as compared to fludarabine and cyclophosphamide regimen;
• a direct relationship between the dose of rituximab and the response rate has been reported;
• ofatumumab, as single agent, proved activity in CLL patients with refractory disease;
• ofatumumab, fludarabine and cylophosphamide (O-FC) front-line treatment has been associated with a high complete response (CR) rate;
• the expected grade 3-4 granulocytopenia could led to reduce the dose intensity of study drugs (FC) and increase the infection rate; a schedule combining FC with an increased dose of ofatumumab associated to primary phrophylaxis of granulocytopenia could be associated with an improvement in the CR rate. The purpose of this study is to determine whether we could improve the CR rate of the golden standard treatment for fit patients with CLL , the FCR regimen, with a chemoimmunotherapy including FC combined with an increased dose of the monoclonal antibody ofatumumab, given every other week (FCO2) associated with a primary prophylaxis of granulocytopenia.

Inclusion Criteria:

• B-cell CLL diagnosis by 2008 revised IWCLL criteria.
• Treatment requirement according to the 2008 revised IWCLL criteria.
• No previous treatment.
• Age > 18 year and . 65 years.
• ECOG performance status of 0-1 at study entry and CIRS score .6.
• Adequate renal function (creatinine clearance.60 ml/min estimated using the Cockcroft-Gaultequation) .
• For male and female subjects of childbearing potential, agreement to use effective contraception.
• Signed written informed const according to ICH/EU/GCP and national local laws.

Exclusion Criteria:

• Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease and/or laboratory abnormality which in the opinion of the investigator may represent a risk for the patient and/or that would prevent the subject from signing the informed consent form.

• Pregnant or lactating females.

• Known positive serology for HIV.

• Positive serology for Hepatitis B (HBV) defined as a positive test for HBsAg and HBV-DNA.

• HCV-RNA positive.

• Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection, tuberculosis and active hepatitis.

• History of tuberculosis within the last five years or recent exposure to tuberculosis equal to or less than 6 months.

• Known presence of alcohol and/or drug abuse.

• Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to the inclusion in the study, congestive heart failure (NYHA III-IV), arrhythmia unless controlled by therapy.. grade 2 neuropathy; history of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.

• Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.

• One or more laboratory abnormalities:

  1. Calculated creatinine clearance (Cockroft-Gault)<60mL/min.
  2. Absolute granulocyte count <1500/ƒÊL not disease related.
  3. Platelet count < 75000/ƒÊL not disease related.
  4. GOT, GPT, GT, alkaline phosphatase > 1,5 x upper limit of normal value unless due to disease involvement); serum bilirubin >1.5mg/dL, subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones)

• Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study

• Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.