Chronic Lymphocytic Leukemia (CLL) is a type of cancer that affects lymphocytes, a type of white blood cell produced in the bone marrow. While often slow-growing, understanding its potential to progress is important as it influences monitoring strategies and treatment decisions.
Defining CLL Progression
CLL progression refers to a shift from an indolent state to a more active or aggressive phase. Initially, CLL often presents with few or no symptoms and may not require immediate treatment. However, over time, the number of abnormal lymphocytes can increase, and these cells may begin to accumulate in various parts of the body, affecting normal organ function.
Progression is characterized by an increase in disease activity, such as a rapid rise in lymphocyte count, which might double in less than six months or increase by more than 50% in two months. It can also involve the enlargement of lymph nodes, the spleen (splenomegaly), or the liver (hepatomegaly). The development of new or worsening symptoms also indicates progression, distinguishing it from the initial diagnosis or a period of stable disease.
Identifying Progression
Detecting CLL progression involves regular monitoring through physical exams and blood tests. A significant increase in white blood cell counts, particularly lymphocytes, is a common indicator. Worsening anemia, characterized by a low red blood cell count, or thrombocytopenia, a low platelet count, can also signal progression. Anemia can lead to symptoms like extreme tiredness, weakness, and shortness of breath, while thrombocytopenia may cause easy bruising or bleeding.
Patients may also develop B symptoms, including unexplained fever, drenching night sweats, and significant unintentional weight loss (over 10% of body weight within six months). Physical examination can reveal newly enlarged lymph nodes in areas like the neck, armpits, or groin, or an enlarged spleen or liver, which might cause discomfort or a feeling of fullness. Imaging tests, such as CT scans, are sometimes used to assess the size of lymph nodes and internal organs.
Factors Affecting Progression
The rate and likelihood of CLL progression are influenced by several biological and genetic factors. One significant marker is the mutational status of the immunoglobulin heavy chain variable (IGHV) gene. Patients with unmutated IGHV genes tend to have a more aggressive disease course and a shorter time to first treatment compared to those with mutated IGHV.
Chromosomal abnormalities also play a role, with deletions in chromosomes 17p or 11q being associated with a less favorable outlook. Specifically, the deletion of 17p, often accompanied by a mutation in the TP53 gene, indicates a high-risk form of CLL that may be resistant to certain traditional therapies. Other gene mutations, such as those in NOTCH1, SF3B1, and BIRC3, have also been linked to shorter survival times. Additionally, a complex karyotype (multiple chromosomal abnormalities) is considered a strong predictor of inferior outcomes, even with newer treatments.
Approaches to Managing Progressive CLL
Once CLL progresses, the strategy typically shifts from “watch and wait” to active treatment. Treatment decisions are highly individualized, taking into account the patient’s specific progression factors, overall health, and prior therapies.
Targeted therapies have transformed CLL management. Bruton’s tyrosine kinase (BTK) inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, block a protein involved in B-cell growth and survival. BCL-2 inhibitors, like venetoclax, work by targeting a protein that helps cancer cells survive, leading to their programmed death. These agents are often used as first-line treatments or when CLL progresses after initial therapy.
If CLL progresses after targeted therapies, options like chemotherapy or immunotherapy, including anti-CD20 antibodies such as rituximab, may be considered. For selected younger patients who have progressed through multiple novel agents, an allogeneic stem cell transplant might be considered as a potential cure.