Low Dose Oral Fludarabine Plus Cyclophosphamide in Elderly Patients with Untreated and Refractory Chronic Lymphocytic Leukemia.

The intravenous regimen of fludarabine plus cyclophosphamide (FC) at conventional doses is highly effective in Chronic lymphocytic leukemia (CLL), where it is currently indicated in first line therapy, and low-grade non Hodgkin lymphomas (LG-NHL). We have shown that intravenous or oral FC regimens at reduced doses remain highly effective in elderly patients with LG-NHL other than CLL. We tested tolerability and efficacy of oral FC at reduced doses in elderly patients with previously untreated (UT-CLL) or relapsed/refractory CLL (R-CLL). Twenty-five patients (>60 years) with UT-CLL (n=13) or R-CLL (n=12) were given oral F (25mg/m²/day, 40 mg total dose) and C (150mg/m²/day, 200 mg total dose) in an outpatient regimen for 4 consecutive days every 4 weeks for a maximum of 4 cycles. Patients were evaluated after every cycle for toxicity and hematological response. Toxicity was defined according to NCI criteria. Responses were defined as Complete (CR) when a normalization of blood count and misurable masses (lymph nodes and spleen) was documented, partial (PR) when at least a 50% reduction of lymphocytosis or nodes/splenomegaly occured, no response (NR) when disease was stable (less than PR) or progressed (>25% increment of tumor manifestations). Progression, new treatment or death was defined as “event”. Median age of the whole population was 70 years (range 61–80), 70 (61–80) in the UT-CLL, 71 (62–79) in the R-CLL. M:F distribution was 14:11 (7:6 in UT-CLL, 7:5 in R-CLL). Performance status was ≥1 in 80% patients. Of 25 patients, 16 (64%) were diagnosed CLL in stage A, 8 (32%) in stage B, 1 (4%) in stage C. Tumor IGHV gene was unmutated in 90% cases (in 85% UT-CLL, in 100% R-CLL). CD38 was positive in 68% (77% UT-CLL, 55% R-CLL) and ZAP-70 in 68% (82%, 67%). Chromosomal deletions of 11q or 17p regions were documented in 25.5% patients (27% UT-CLL, 25% R-CLL). The R-CLL had received 1–4 (median 2) treatment lines prior to FC. Median time from diagnosis or from prior treatment to FC was 24 months (range 1–77), 37 (1–77) in the UT-CLL, 12 (3–48) in the R-CLL. Overall, biological risk and clinical characteristics were indicative of an aggressive behavior of the investigated cohort. Patients received median 3 cycles (4 in UT-CLL, 3 in R-CLL). Nine-of-25 (36%) reduced the number of cycles because of fatigue (1 patient), heart failure (1), idiopathic thrombocytopenic purpura (1) in the UT-CLL (3/13) or infection (2), femur fracture (1), prolonged isolated thrombocytopenia or pancitopenia (2) and idiopathic thrombocytopenic purpura (1) in the R-CLL (6/12). Overall, 23/25 patients (92%) obtained a response (11/25 CR, 44%; 12/25 PR, 48%). Among UT-CLL, all responded to treatment (8/13 CR, 61.5%; 5/13 PR, 38.5%). Among R-CLL, 10/12 (83.5%) responded (3/12 CR, 25%; 7/12 PR, 58.5%; 2/12 NR, 16.5%). With a median follow-up of 23 months, 14/25 patients (56%) were event-free and 23/25 (92%) were alive. Among UT-CLL (median follow-up 12 months), 9/13 (69%) were event-free and all were alive. Among R-CLL (median follow-up 25 months), 5/12 (42%) were event-free and 10/12 (83%) were alive. Deaths occurred in the 2 R-CLL that had not responded to treatment, after 2 and 4 years, respectively. Despite the poor risk of the investigated population, this low-dose oral FC treatment showed good efficacy both in untreated and refractory/relapsed CLL. The treatment may be useful in elderly patients who cannot benefit of more aggressive or eradicating strategies and is easy to administer on an outpatient basis.