Initiating Therapy for Chronic Lymphocytic Leukemia

The majority of patients with chronic lymphocytic leukemia (CLL) are diagnosed at an early stage. Often, CLL is found incidentally; however, symptoms typically do not begin until an advanced stage. The standard management for CLL in the early-stage setting is observation. Studies evaluating patients randomly assigned to “watch and wait” versus early initiation of chemotherapy showed no difference in overall survival; however, toxicity was greater in patients receiving therapy sooner.

Criteria for initiating therapy in a patient with CLL include the following:

• Increased tumor burden, resulting in cytopenias
• Lymphadenopathy
• Uncontrolled autoimmune cytopenias
• Symptoms of significant fatigue or night sweats, fever without evidence of infection, or unintentional weight loss.

An increase in white blood cell count, in and of itself and in the absence of cytopenias, is not an indication to start therapy, according to both Jennifer Brown, MD, PhD, and William Wierda, MD, PhD. Wierda says he has patients in whom he allows white blood cell counts to rise into the 100,000-to-200,000/mm³ range.

If patients do not develop any of the features that trigger treatment initiation, he continues to monitor them. However, important parameters for initiating therapy include a white blood cell count that is rapidly rising (eg, a doubling time of >6 months). In these patients who have rapidly progressing disease, symptoms will also usually appear. A hemoglobin level that is consistently less than 10 g/dL or platelets less than 100 billion/L are also triggers to start treatment.

The indicators for initiating therapy have not changed with the introduction of novel therapies for CLL. Although responses have been dramatic, the follow-up in clinical trials of these agents has been relatively short. Therefore, it is unclear what the benefit of long-term therapy would be in patients who have relatively little tumor burden and are asymptomatic. In fact, data on the genetics of CLL suggest that treatment may exert selection for adverse clones. This may also be possible for novel therapies, notes Brown. Randomized trials showing a benefit with early introduction of novel agents in patients with CLL would be required to change practice to one of early treatment initiation, she adds.

One of the problems with the older trials of chemotherapy is that they enrolled all patients, including those with low-level disease who would have never progressed to needing treatment, explains Wierda. In addition, the studies were done in an era of less effective therapies. With the availability of newer chemoimmunotherapy and small-molecule inhibitors, it might be easier to show a benefit with earlier therapy, he adds.