One step back but 2 steps forward.

There have been major advances reported over the past decade in previously untreated chronic lymphocytic leukemia (CLL) with chemo-immunotherapy approaches now the treatment of choice.2 A decade ago, chlorambucil was the treatment of choice. However, CLL is a disease of the elderly with a median age at diagnosis of 72 years, and almost 70% of CLL patients are older than 65 years at the time of diagnosis. These more elderly patients have been vastly underrepresented in clinical trials. Moreover, elderly patients may not have sufficiently good performance status to tolerate the aggressive chemo-immunotherapy approaches. There were elderly patients included in a randomized clinical trial in the United Kingdom comparing treatment with chlorambucil, fludarabine, or fludarabine and chlorambucil. These patients appeared to tolerate combination chemotherapy.3 However, there was considerable patient selection bias here, considering that physicians must have been prepared to treat these patients with combination chemotherapy so only patients with sufficiently good performance status to tolerate the more aggressive regimens were enrolled. Of note, among the patients in the United Kingdom who were older than 70 years, there was also no improved outcome for those patients receiving fludarabine alone. The advance in the CLL5 study is that both study arms were deemed tolerable for the intended patient population and therefore the results are likely to be more applicable to the more elderly patients seen in practice. This multicenter phase 3 trial enrolled patients older than 65 years and compared first-line therapy with fludarabine to chlorambucil. Chlorambucil was the first effective agent used in the treatment of CLL. The drug has largely fallen out of fashion in the United States but continues to be widely used in Europe. A total of 193 patients with a median age of 70 years were randomized to receive intravenous fludarabine or oral chlorambucil. The results demonstrated that, although patients receiving fludarabine had a higher response rate than those receiving chlorambucil, there was no difference in progression-free survival or overall survival. In fact, as shown in Figure 2 of the article, median survival was 18 months longer for those receiving chlorambucil, although the differences did not achieve statistical significance.1 The results demonstrate no clinical benefit for fludarabine over chlorambucil as first-line therapy of elderly CLL patients. It is clear that the performance status is more important than the chronological age of the patient. It is extremely important to assess the patient’s comorbidities and fitness before recommending treatment. Several different methods are used to assess the fitness of patients. The International Society of Geriatric Oncology Chemotherapy Taskforce published consensus recommendations on chemotherapy in the elderly.4 The authors concluded that there is a lack of evidence-based data with regard to The cumulative illness rating score can be used to determine the appropriate chemotherapy treatment in CLL. Professional illustration by Debra T. Dartez.