Indications for Treatment
Patients with asymptomatic, early-stage CLL should be monitored without initiating therapy. This so-called “watch and wait” approach is based on studies that failed to show a survival benefit for the treatment of early-stage disease.[21-24] Indeed, as a significant number of patients ultimately never require treatment for CLL, treating patients early will expose many unnecessarily to the toxicity of chemotherapy. With recent breakthroughs in both new treatments and prognostic markers, this issue is being revisited with ongoing studies that apply a risk-adapted approach to early-stage patients.
The International Workshop on CLL (IWCLL) Working Group has made specific recommendations as to when treatment should be initiated in current clinical practice. These include patients with symptoms such as unintentional weight loss of 10% or more within the prior 6 months, significant fatigue, night sweats, and fever that is not due to an infection. Symptomatic anemia or thrombocytopenia secondary to progressive marrow failure (Rai stage III or IV) is also considered a reason to treat. It is important to distinguish these cytopenias from immune-mediated cytopenias, which commonly occur in CLL. In the case of immune-mediated cytopenias, a trial of steroids should be given rather than immediately initiating chemotherapy.
Symptomatic or massive splenomegaly, lymphadenopathy, progressive lymphocytosis (with an increase of more than 50% over a 2-month period in lymphocyte count or a lymphocyte doubling time of less than 6 months) are other indications for treatment. In considering lymphocyte counts, it is important to look at a trend rather than a single result. A transient increase in lymphocyte counts often occurs due to a variety of factors including infections, steroid use, and inflammation. There is no evidence to support treatment based on absolute lymphocyte count alone, although many oncologists initiate treatment at 250,000/µL due to purely theoretical concerns of hyperviscosity.
Until recently, the alkylating agent chlorambucil(Drug information on chlorambucil) (Leukeran) was essentially the sole choice of treatment for CLL, offering a typically modest goal of palliation with a partial response. Its use is waning with the advent of newer therapies. Estimates of overall response rate for chlorambucil either alone or in combination with prednisone(Drug information on prednisone) range from 38% to 75% with very few complete remissions.[25-27] Clinical trials have failed to show an advantage of combinations such as COP (cyclophosphamide, vincristine [Oncovin], prednisone) or CHOP (cyclophosphamide, doxorubicin HCl, vincristine, prednisone) over chlorambucil.[25-27] Cyclophosphamide(Drug information on cyclophosphamide), another alkylating agent, is currently used in modern combination regimens.
Chlorambucil has been largely supplanted by newer agents, with purine analogs being the backbone of most modern regimens. Fludarabine has been the most widely tested purine analog in CLL. Its superiority has been demonstrated over chlorambucil and alkylator-containing combination regimens. In a North American trial, Rai and colleagues compared chlorambucil to fludarabine in previously untreated CLL patients in a prospective, randomized phase III trial. The results showed a significantly higher overall response rate (63% vs 37%) and complete remission rate (20% vs 4%) for the fludarabine-containing arm. Median progression-free survival and duration of response were prolonged in the fludarabine-containing arm, but overall survival was not significantly different. This may have been due to the crossover design of the study. Patients who initially failed on chlorambucil had a 46% response rate when they crossed over to fludarabine, whereas only 7% of those patients with disease progression after receiving fludarabine showed a response to chlorambucil.
A study comparing fludarabine to chlorambucil in patients over 65 years of age was carried out by the German CLL Study Group with similar results, including significantly higher complete and overall response rates as well as improved quality of life. Other studies from Europe compared single-agent fludarabine to alkylator-based combinations and found fludarabine to be superior in terms of both complete response rates and durability of remissions.[30,31] Generally, fludarabine has shown greater myelosuppression than chlorambucil, with a higher incidence of neutropenia, but without increased infections.
Notably, these trials comparing fludarabine to alkylators and alkylator-based combinations, failed to show a survival advantage for fludarabine. Again, this is likely due to the crossover design of most of these trials. The superior activity of fludarabine in CLL, however, is clear. Other purine analogs—ie, pentostatin and cladribine(Drug information on cladribine) (2-CdA)—have also been shown to have significant activity in CLL, both in the upfront and relapsed settings.[32-36]
Although bendamustine (Treanda) has been used in Eastern Europe since the 1970s, it is new to the United States and Western Europe, and it recently received US Food and Drug Administration (FDA) approval for its use in front-line CLL therapy. The structure of bendamustine is that of a nitrogen mustard derivative with alkylating properties and a benzimidazole ring believed to impart it with antimetabolite activity similar to that of a purine analog. Its approval was based on a randomized, controlled, multicenter comparison to chlorambucil in 319 patients with previously untreated CLL. The overall response rate was 68% for bendamustine vs 31% for chlorambucil (P < .0001). Bendamustine therapy also produced a superior median progression-free survival (21.6 vs 8.3 months). Adverse reactions in the bendamustine arm included anemia and neutropenic fever, resulting in a greater need for red blood cell transfusions and a higher number of hospital admissions in this group of patients. The number of deaths were similar in both treatment arms, and the toxicities were generally manageable. Bendamustine’s use continues to grow, but the role of this agent is still evolving.
Three phase III trials have compared the combination of fludarabine plus cyclophosphamide (FC) to fludarabine alone, all demonstrating the superiority of combination chemotherapy over single-agent fludarabine.[38-40]
The US Intergroup E2997 trial randomized 278 patients to FC or fludarabine alone. Patients treated on the FC containing arm achieved a superior overall response rate (74% vs 59%), complete response rate (23% vs 4%), and duration of progression-free survival (32 vs 19 months). The German CLL study group also compared FC to fludarabine in previously untreated patients age 65 or younger and demonstrated superiority in the FC arm in overall response rate (94% vs 83%), complete response rate (24% vs 7%), and median progression-free survival (48 vs 20 months). Investigators in the United Kingdom conducted a three-arm trial of 777 patients randomized to chlorambucil, fludarabine, or FC. Once again, a superiority in overall response rate, complete response rate, and 5-year progression-free survival was observed in the combination-chemotherapy arm.