Oral Fludarabine and Cyclophosphamide Plus Rituximab in the Treatment of the Chronic Lymphocytic Leukemia.

The association of Fludarabine, Cyclophospamide and Rituximab is the most efficient treatment for Chronich Lynphocitic Leukemia (CLL) but the intravenous formulation and the necessity of hospital admission limit its wide application. We tested the safety and feasibility of the association of oral Fludarabine and oral Cyclophosphamide with iv Rituximab in a outpatient setting in a group of CLL patients who could not be treated by standard therapy.

Methods. From June 2004 to July 2005 eighteen patients were treated in the Hematology Department in Cagliari, Italy. Informed consent was obtained by all patients before entering the trial. Ten patients were males and 8 were females; median age was 62 years (range 31–74). Binet clinical stage was C in 6 patients and B in progression or with B symptoms or with bulky disease in the remaining twelve. All patients were CD5/CD19 positive and positive for the rearrangement of immunoglobulins heavy chains by polymerase chain reaction (PCR). Nine have been previously treated by 1–5 lines of chemotherapy and nine were untreated. Chemotherapy schedule consisted of oral Fludarabine 40 mg/m² on days 1 to 3, oral Cyclophospamide 250 mg/m² days 1 to 3 and Rituximab 375 mg/m² i.v day 0 starting from the second course of chemotherapy. Courses were repeated every 28 days for a total of 6 cycles. All patients received broad spectrum anti-infective prophylaxis by levofloxacin 500 mg/day and fluconazol 100 mg/day.

Results. The first twelve patients were treated without prophylactic growth factors and ten of them (83%) developed WHO grade 4 neutropenia requiring therapeutic growth factors (filgrastim/lenograstim for 3–6 days). Subsequently 6 patients received prophylactic peg-filgrastim in a single dose on day 4 in every course and none had WHO grade >2 neutropenia There were no grade >2 WHO organ toxicity nor toxic deaths. No life treating infection was registered and no hospital admission was required. Two patients (11%) interrupted the treatment because of side effects (one patient had reaction to Rituximab and one developed haemolytic anaemia). At the time of this writing 13 patients had completed the planned course of treatment in the scheduled time. Treatment is ongoing without major problems in the remaining three. Disease response was evaluated in these 13 patients. Eight (62%) obtained a complete, clinical and molecular, remission as documented by disappearance of the immunoglobulin heavy chains rearrangement by PCR while 5 (38%) obtained a very good partial response. Overall response rate was 100%. With a medium follow up of 6 months (range 1–8) no patients presented relapse or progression disease.

Conclusion. The association of oral Fludarabine and oral Cyclophosphamide with Rituximab is a feasible treatment in outpatients setting with excellent patient compliance in association with prophylactic granulocyte growth factors. Preliminary efficacy results are not different to those obtained with standard intravenous formulation. Longer follow up is necessary to confirm efficacy.