Studies of Chemotherapy Alone
In the UK CLL4 trial, comparing chlorambucil, fludarabine and fludarabine plus cyclophosphamide (FC), roughly one-third of the patients enrolled were older than 70 years. In this study, progression-free survival (PFS) was significantly better with FC than with fludarabine alone or chlorambucil. However, all three groups were alike with respect to OS. Neutropenia was more frequently observed with FC and fludarabine in comparison with chlorambucil, however, no differences in the rate of therapy-related side effects was observed across age groups. The GCLLSG CLL5 was the first large prospective trial specifically devised for elderly CLL patients. In brief, patients older than 65 years with an ECOG 0–2 performance status were randomized to receive either fludarabine or chlorambucil. Despite the higher overall response rate (ORR) observed with fludarabine, no difference was observed in terms of PFS and OS. Grade 3–4 neutropenia and infections were uniformly observed in the two arms.
In a Phase III randomized trial, previously untreated CLL patients received chlorambucil or bendamustine. Age below 75 years was a required inclusion criterion; nonetheless, 25% of patients enrolled were between 70 and 75 years. Efficacy of bendamustine was greater than efficacy of chlorambucil in terms of ORR and PFS, but not in terms of OS. The occurrence of grade 3–4 neutropenia was 23% in bendamustine arm versus 11% in the chlorambucil arm. Finally, therapy with bendamustine did not impact negatively on the quality of life.
Based on the observed lower myelotoxicity of pentostatin in comparison with fludarabine, a Phase I/II study evaluated different doses of pentostatin in combination with chlorambucil and prednisone in 55 CLL patients (36 untreated). On the basis of the dose-finding study, a dosage of 2 mg/m2 of pentostatin was given to 43 patients. The ORR was 87% with a median duration of response of 33 months. Unfortunately, the study presented a high incidence (31%) of severe infections.
Expert Rev Hematol. 2013;6(4):441-449. © 2013 Expert Reviews Ltd.