Anti-CD20 Monoclonal Antibodies in Association With Purine Analogs
In an attempt to maintain the efficacy of FCR regimen while decreasing toxicity, Foon et al. proposed a modified FCR regimen called FCR-Lite (fludarabine 20 mg/m2, and cyclophosphamide 150 mg/m2 for three consecutive days, rituximab 500 mg/m2 on days 1 and 14 of a 28-day cycle). Fifty untreated CLL patients with a median age of 58 years (range: 36–85) treated with the FCR-Lite regimen achieved a 100% ORR (CR: 79%) while median duration of CR was 22.3 months. Grade 3–4 neutropenia was noted in 13% of the cycles of therapy. However, the small number of patients older than 70 years included in this Phase II study should prevent from considering FCR-Lite a first choice of therapy for elderly, unfit CLL patients, not eligible for classic FCR.
Recently, two CLL cooperative groups reported results of Phase II studies including patients more than 65 years old who received a modified FCR regimen.[47–48] According to these experiences, it seems that lower doses of either fludarabine or cyclophosphamide, preferably given orally and associated with standard rituximab, yield valuable results in terms of response rate (i.e., ORR: 70%). However, in both trials unfit patients were not included, in addition, in the Czech CLL Study Group study an excess of severe infections (i.e., 13%) was reported.
Rituximab in association with pentostatin-based regimens have been explored in CLL patients. Pentostatin, cyclophosphamide, rituximab (PCR) is a regimen of chemoimmunotherapy in which fludarabine was substituted with pentostatin. A PCR Phase II study enrolled 65 untreated CLL patients whose median age was 63 years and 28% were above 70 years. The ORR was 91%, CR 41% and PFS 32.6 months. A randomized Phase III study compared prospectively a modified FCR regimen (F: 20 mg/m2 days 1–5; C: 600 mg/m2 day 1; R: 375 mg/m2 day 1; 28-day cycles) with PCR (P: 4 mg/m2 day 1; C: 600 mg/m2 day 1; R: 375 mg/m2 day 1; 21-day cycles) in 184 untreated CLL patients with a median age of 64 years. This study actually failed to demonstrate a reduced incidence of infections with PCR while the CR rate was slightly higher in patients treated with FCR (14 vs 7%). It should be pointed out that this was a 'community–based' study and in both arms the percentage of responses were lower in comparison with those obtained at single institutions.
In conclusion, when compared with standard FCR, PCR seems to be less effective in terms of response rate and duration of response, however, possibly because of the lower toxicity profile, an acceptable dose intensity could be maintained with the PRC regimen in elderly patients. Interestingly, treatment with PCR was manageable also in patients with a reduced creatinine clearance (<70 ml/min).
Expert Rev Hematol. 2013;6(4):441-449. © 2013 Expert Reviews Ltd.