Treatment algorithms in CLL.

CLL therapy has changed dramatically over the last few years. This development has been aided by progress in 2 areas: (1) a better understanding of CLL biology (and with it discovery and characterization of new prognostic markers); and (2) emergence of novel agents. The combined impact of advances in these areas is leading to new concepts and approaches in CLL therapy. Treatment of CLL has been traditionally revolving around chemotherapy, initially alkylators such as chlorambucil, and nowadays more heavily focused around nucleoside analogs such as fludarabine. Although overall response rates (OR) exceed 50%, complete remission (CR) rates remain modest at B/10% in the case of chlorambucil and at /35% for fludarabine. Fludarabine proved more effective than chlorambucil in terms of superior response rates and more favorable progression-free survival in a number of randomized studies.[1 /3] The German CLL Study Group (GCLLSG) randomized 86 patients /65 years with symptomatic and previously untreated CLL to receive either fludarabine (25 mg/m i.v. daily days 1 to 5 every 4 weeks for a total of 6 courses) or chlorambucil (0.4 mg kg 1 days 1 and 15 for 12 months).[3] CR rates (13% vs. 0%; p /0.028) and OR rates (85% versus 68%; p /0.038) were significantly higher for fludarabine than for chlorambucil. Although fludarabine-treated patients experienced more significant myelosuppression, no difference among treatment arms was demonstrated in the number and severity of infections. In addition, quality of life parameters improved significantly following treatment with fludarabine. More recently, two randomized studies have shown that the combination of fludarabine with cyclophosphamide is more effective than fludarabine alone in achieving higher CR and OR rates and prolonging progression-free survival.[5,6] However, no improvement of overall survival has ever been shown with single-agent fludarabine, and the impact of fludarabine/cyclosphosphamide combinations on overall survival remains to be determined. Monoclonal antibodies (Moabs) have had a major impact on therapeutic options for patients with lymphoproliferative disorders including CLL. The attraction of moabs is based on selective targeting of tumor-relevant and more or less specific surface markers, and a distinct mechanism of action involving elements of human effector functions such as the complement system and ADCC (antibody-dependent cellular cytotoxicity). Alemtuzumab (anti-CD52) and rituximab (anti-CD20) remain the most active moabs for CLL. Rituximab has achieved OR rates in 51% and alemtuzumab in 87% of untreated and symptomatic CLL patients.[7,8] Furthermore, alemtuzumab remains the only approved first-line therapy for fludarabine-refractory CLL where response rates of 33% with survival benefit in responding patients has been shown.[9] Despite impressive results as single agents however, most patients will eventually relapse so that recent years have seen an emergence of combination strategies involving moabs in an effort to optimize their potential and increase response rates further. Based on in vitro data suggesting sensitization of CLL cells by rituximab to the cytotoxic and apoptotic effects of chemotherapy drugs such as fludarabine, and data showing downregulation of complement defense proteins (CD46, CD55, CD59) by purine nucleoside analogs, chemoimmunotherapy regimens have been developed that combine rituximab with nucleoside analogs such as fludarabine (FR), the combination of fludarabine plus cyclophosphamide (FCR), or with pentostatin plus cyclophosphamide (PCR).[10 /12] All chemoimmunotherapy regimens show higher CR and OR rates than would be expected with chemotherapy or monoclonal antibodies alone (Table 1).