Chlorambucil—Still Not Bad: A Reappraisal

Although chlorambucil has been used in the management of chronic lymphocytic leukemia (CLL) for 55 years, the optimal dose and treatment duration have not been established. We summarized data from 4 UK randomized CLL trials over the past 30 years in which chlorambucil, as a single agent, was one of the study arms. Overall response rates (ORR) ranged from 57% to 75% when using doses of 60–70 mg/m2 per 28-day cycle. This compares favorably with an ORR of 31% to 55% in other studies that used lower doses. Response rates improved when patients received 6 or more courses. Studies that used chlorambucil as a comparator, at lower doses or with fewer courses, resulted in consistently lower ORR. Comparisons with single-agent fludarabine in 2 randomized trials (LRF CLL4 and German CLL5) showed similar progression-free survival. Chlorambucil compares favorably with fludarabine and bendamustine with respect to myelotoxicity, neutropenia, and fever, even at 70 mg/m2 per cycle and in the elderly. Resistance to chlorambucil does not preclude a good response to newer treatments used as second-line treatment, which explains the good survival after progression observed in patients randomized to chlorambucil in LRF CLL4. Chlorambucil is currently being combined with anti-CD20 monoclonal antibodies in several phase II and III trials. It remains a useful drug for patients unfit to receive more intensive combinations. However, both the dose and duration of treatment are important.