Abstract
Background: fludarabine (F) has become the standard first line therapy for chronic lymphocytic leukemia (CLL) in younger patients. Treatment of early stage patients with chlorambucil without risk stratification has not been shown to prolong survival. In recent years effective and potentially curative approaches such as nucleosides analogues, stem cell transplantation or monoclonal antibodies have been developed. The attraction of monoclonal antibodies is based on selective targeting of tumor - relevant surface markers and a distinct mechanism of action (antibody-dependent cellular cytotoxicity).
Aims: to assess the efficacy, safety and quality of life of F in previously untreated B-cell CLL patients in a group of medical institutions in Uruguay during 11 years (1995–2006).
Methods: 168 patients between the period 1995 – 2006 were evaluated.120 of them received F intravenous formulation (1995–2006) and 48 the oral one (2002–2006). Age: 48 – 85 years old, media 67 years old. Gender: male 90, female 78. Inclusion criteria for B-cell CLL was Binet stages B, C and A progressive (Ap), 18 to 85 years old, non multiorganic failure, performance status 0 – 2 (WHO), written informed consent. First condition was non previous treatment. Staging: Binet A 12/168, B 116/168 & C 40/168. Treatment: as first line therapy all the patients received (minimum): 6 cycles of i.v. Fludarabine (Fludara®, Schering) 25 mg/m2/daily (5 days) e/30 days or Oral Fludarabine, 40 mg/m2/daily (5 days), 6 cycles.
Results: on this B-cell CLL cohort the overall response rate (ORR) was 78% (CR+PR), 80% of them have immunophenotypic response. Safety: on the 1100 cycles in 168 patients, the toxicity was: 1 AIHA, 2 pancytopenia, 3 plaquetopenia. Grade 3–4 infection rate was 1,3%. No alopecia was observed in any patient. Kaposi sarcoma (0,7%). Mortality rate: 1,7% (3/168 patients). Other adverse factors to overall survival were, age over 65 (p=0,0001) and hepatic impairment (p=0,0001). Toxicity: (WHO>2): granulocytopenia 28%, thrombocytopenia 8%, infection 2%. Although fludarabine-treated patients experienced more significant myelosuppression, no difference in the treatment group was demonstrated. Causes of death: Richter 12%, sepsis 5%, associated disease 34%, second malignancy 17% and others 30%. Comparing oral with intravenous formulation in overall survival the results were: CLL 34% vs 36% (p= NS).
Conclusions: fludarabine monofosfate (Fludara®) looks like an effective and safe treatment for B-cell CLL. The oral and intravenous formulations have a similar response rate in elderly and young patients. The challenge remains to integrate new information to apply novel therapies in a disease-specific and risk-adapted maner. A longer follow up and a larger trial, might be needed to confirm these results.
Treatment-naive CLL: lessons from phase 2 and phase 3 clinical trials