Elderly patients with chronic lymphocytic leukemia (CLL) and younger patients with comorbidities often receive treatment with chlorambucil despite the relative low response rates. Adding an anti-CD20 monoclonal antibody to chlorambucil therapy has been shown to increase the response rates substantially and does not negatively affect tolerability.
A retrospective analysis using results from 15 Italian centers was undertaken to assess the safety and efficacy of the chlorambucil plus rituximab regimen as a frontline therapy in patients aged ≥65 years and/or patients with unfit CLL (Cumulative Illness Rating Scale >6), and to identify patients for whom this regimen could be especially effective.
A subgroup analysis stratified patients according to fluorescence in situ hybridization (FISH) and IGHV mutation. The high-risk group included patients with deletion (del)17p, the intermediate-risk group included patients with del11q and/or no IGHV mutation, and the low-risk group comprised patients without del11q or del17p and/or no IGHV mutation.
A total of 102 patients who had received treatment between 2009 and 2011 were included in the study. The median number of cycles administered was 8 (range, 2-12) with chlorambucil and 6 (range, 1-9) with rituximab. The main 2 treatment schedules were chlorambucil 1 mg/kg administered at each cycle every 28 days, with a fixed daily dose of 10 mg starting from day 1 and repeated during the 8 cycles, and chlorambucil 8 mg/m2 administered each day for 7 days of the 8 cycles of 28 days each. From the third cycle, rituximab was added to chlorambucil; rituximab was given on day 1 of each cycle; rituximab at 375 mg/m2 was used at the first dose and 500 mg/m2 for the next 5 cycles.
Based on an intent-to-treat analysis, the overall response rate (ORR) with this regimen was 87.1%. Overall, 31.7% of patients had a complete response and 55.4% had a partial response. No significant differences in ORR were reported based on age, fitness status, Eastern Cooperative Oncology Group performance status, bulky disease, cytogenetic risk abnormalities, IGHV mutational status, ZAP-70, or CD38 expression. The median progression-free survival (PFS) was 43.7 months and the time to retreatment was 72.3 months.
The median overall survival was not reached by the time of the analysis; 86.1% and 81.2% of patients were alive at 48 months and 60 months, respectively.
The most common serious adverse event (AE) was grade 3 or 4 neutropenia. Grade 3 or 4 extra-hematologic AEs were uncommon. According to a subgroup analysis, patients in the low-risk group had a significantly better PFS than those in the intermediate-risk group (65.8 months vs 35.2 months, respectively); 54.9% of patients had progression-free disease at 60 months of treatment.
These results indicate that in elderly and/or unfit patients with CLL, treatment with chlorambucil and rituximab is associated with low toxicity, high ORR, and durable PFS. Particularly good results were seen in patients with an IGHV mutation and no del17p or del11q, suggesting that in this low-risk subset of unfit patients, chlorambucil plus rituximab could represent the optimal therapeutic option.