Early-stage Asymptomatic CLL

Overview

Patients with early-stage CLL have Binet Stage A or RAI Stage 0-II disease and no symptoms. In general, patients with asymptomatic early-stage CLL should not be treated unless they are participating in a clinical trial evaluating the effects of therapy on patients with adverse prognostic features.

A variety of factors ultimately influence a patient's decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient's chance of cure, or prolong a patient's survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.

The following is a general overview of the treatment of early-stage asymptomatic CLL. The specific characteristics of your cancer and circumstances unique to your situation may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.

The major dilemma regarding treatment of CLL is when to initiate treatment and whether earlier more aggressive treatments can improve a patient's outcome. However, these are research questions and patients with asymptomatic early stage CLL should not be treated outside a clinical study as there is no definitive data that such treatment prolongs survival or improves the chances for cure.

When to Initiate Treatment?

In contrast to past experience many patients will present with early-stage asymptomatic CLL. It is clear that patients with early-stage CLL are a heterogenous group; approximately 30-50% will develop progressive disease within a short period of time, while the remainder may live for decades and not require therapy. It should also be remembered that patients with early-stage CLL can become symptomatic without a change in the stage of their cancer. In this case, patients with symptomatic Binet stage A or RAI stage I-II are treated the same as more advanced patients with symptomatic CLL. Go to Symptomatic Advanced (RAI Stage III-IV, Binet Stage B-C) Chronic Lymphocytic Leukemia for information about treatment.

The following is a list of accepted indications for the treatment of CLL:

  • Anemia (hemoglobin level less than 11.0 g/dL)
  • Thrombocytopenia (platelet count less than 100,000/mm3)
  • Massive or progressive enlargement of lymph nodes
  • A lymphocyte doubling time of less than 6 months
  • Fever, weight loss, night sweats or profound fatigue

Patient Information

Patients with newly diagnosed asymptomatic CLL should be informed about the potential for disease progression and the need for close monitoring. Patients with early-stage CLL are at risk for developing infections, autoimmune diseases and transformation to a diffuse lymphoma called Richter transformation. Delay of therapy is more important for elderly patients who may have other diseases which could increase the toxicities of therapy. Younger patients without significant other health problems may opt for earlier treatment in the hope of prolonging survival.

Strategies to Improve Treatment of Early-stage CLL:

Future progress in the treatment of limited CLL will result from continued participation in appropriate clinical trials. Areas of active exploration to improve the treatment of CLL include the following:

Identification of High-Risk Patients with RAI Stage 0-1 or Binet Stage A CLL: Researchers are developing new prognostic tools to identify patients with early-stage asymptomatic CLL who might benefit from earlier therapy before symptoms develop.1 These new tests include: immunoglobulin variable-region heavy chain mutational status, cytogenetic abnormalities assessed by fluorescent in situ hybridization (FISH), and Z-chain–associated protein kinase 70 expression (ZAP-70)2.

Researchers from Germany have suggested that thymidine kinase, beta-2 microglobulin, absolute lymphocyte count, age and sex could help predict progression of patients with early-stage CLL. 3 These tests could assist physicians in determining which patients with early-stage CLL need to be treated and which patients can delay therapy.

The importance of more accurate approaches to risk assessment is illustrated by the limitations of the original staging systems. For instance, researchers have found that 27% of patients with RAI stage 0 will have abnormal abdominal computed tomography (CT) scans indicating lymph node involvement.4 These authors found that an abnormal abdominal CT correlated with increased bone marrow infiltration, higher lymphocyte count, increased ZAP-70 expression (a marker for poor prognosis) and a short lymphocyte doubling time. Patients with an abnormal CT also had a median time to disease progression of 3.5 years while for patients without an abnormal CT scan the median time to disease progression was longer.

Patients with the above adverse prognostic factors are at high risk of progression if they receive no therapy, and randomized studies are underway to determine if such patients benefit from earlier treatment. In these studies, patients with adverse prognostic features are randomly allocated to treatment or watchful waiting to determine if early treatment improves survival. Some physicians are already using these tests to direct therapy in asymptomatic early-stage CLL. However, there are currently no convincing data to suggest that earlier treatment of asymptomatic patients with adverse prognostic features improves survival.

References:


1 Shanafelt TD, Byrd JC, Call TG, et al. Narrative review: Initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. Annals of Internal Medicine 2006;145:435-447.

2 Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. New England Journal of Medicine. 2004; 351: 893-901.

3 Bergmann MA, Eichhorst BF, Busch R, et al. Prospective evaluation of prognostic parameters in early stage chronic lymphocytic leukemia (CLL): Results of the CLL1-protocol of the German CLL Study Group (CCLLSG). Blood 2007;193a, abstract 625.

4 Muntanola A, Bosch F, Arguis P, Abdominal computed tomorgraphy predicts progression in patients with RAI stage 0 chronic lymphocytic leukemia. Journal of Clinical Oncology 2007;25:1576-1580.