What is Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes)?
Chronic lymphocytic leukemia (CLL) is the most widespread type of leukemia, a blood disease, in Western countries. This is marked by an abnormal increase in a specific type of immune cell called mature B-cells. CLL and a disease called small lymphocytic leukemia (SLL) are often referred to interchangeably. Though, CLL is used when a patient shows involvement of certain immune cells in the blood exceeding 5000, whereas SLL is used when the abnormal growth of immune cells is confined to the lymph nodes.
Scientific advancements in recent times have helped us better understand the different genetics associated with CLL. This brief introduction of CLL will outline the various genetic aspects of the disease and shed light on how this knowledge helps manage the disease effectively.
What Causes Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes)?
Chronic lymphocytic leukemia, or CLL, is a condition that results from an abnormal growth and spread of certain white blood cells known as B lymphocytes. These abnormal cells can infiltrate the bone marrow, bloodstream, and lymph nodes in our body. Various triggers like genetic issues and changes in cellular components could possibly cause this abnormal growth.
Both genetic and environmental factors influence the occurrence of CLL. It is more often seen in the western world than in regions like Asia and Africa. Also, it is found that if you have a relative with CLL, you face an 8.5 times greater risk of getting it yourself. It also occurs more commonly in identical twins as compared to non-identical twins.
Relatives of CLL patients also have a higher chance of developing a condition known as monoclonal B cell lymphocytosis. Researchers have found that a field of study called epigenetics, which involves changes in gene activity, also plays a role in CLL. Examples of such changes include modifications of proteins called histones that help with gene activity regulation, and overactive gene-regulating regions. Variations in DNA sequence (known as single nucleotide polymorphisms or SNPs) also increase the risk of CLL.
Exposure to certain environmental factors, like Agent Orange and insecticides, can also be linked to CLL. For example, veterans who were exposed to Agent Orange while in military service are allowed access to benefits, recognizing the risk. Furthermore, some evidence suggests that insecticides might be another risk factor. There is limited proof that viral infections and exposure to a type of high-energy radiation, ionizing radiation, may increase CLL risk. However, other potential lifestyle risk factors such as blood transfusions and diet haven’t been substantiated by current research.
Risk Factors and Frequency for Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes)
Chronic lymphocytic leukemia, or CLL, is a disease that varies significantly in occurrence based on factors like geographical region, gender, race, and age. Worldwide, there are about 191,000 cases of CLL with 61,000 deaths. The rates of CLL differ greatly depending on the country, with Japan and China having incidence rates about 10% of Western countries.
- In Asia, the rate of CLL is 0.01%, compared to Europe and the United States, where it is 0.06%.
- However, some African countries have higher rates of CLL than Asian countries, but not higher than the U.S. or Europe.
- In the Western world, CLL is the most common type of leukemia, and the United States accounts for 25 to 35% of all leukemia cases.
- There are about 20,160 new cases of CLL diagnosed in the U.S. each year, with 12,360 being males and 7,530 females.
- It has been found that CLL occurs more frequently in males, with a male-to-female ratio of 1.2:1 to 1.7:1. There are 6.75 cases per 100,000 in males, compared to 3.65 per 100,000 in females.
- This trend is similar in Europe, with 5.87 cases per 100,000 in males and 4.01 cases per 100,000 in females.
- Also, CLL often affects older individuals, with the median age at diagnosis being around 70 years old.
- When it comes to race, white individuals have the highest incidence of CLL, followed by Hispanic and African Americans. The lowest incidence is found in the Asian population.
Signs and Symptoms of Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes)
Chronic lymphocytic leukemia, a type of blood cancer, is often discovered by chance during a blood test, as many patients do not show symptoms at first. However, some people may experience symptoms classified as “B” symptoms. These include:
- Fevers above 100.5 F (38 C) for two weeks or longer, without any signs of an infection
- Night sweats not caused by an infection
- Extreme fatigue
- An unexpected weight loss of 10 percent or more of body weight over the past six months
During a physical check-up, enlarged lymph nodes may be detected in 50 to 90% of patients. These enlarged lymph nodes are usually round, firm, and painless, and they move easily when touched.
The disease can also cause swelling of the spleen and liver in some patients. However, the likelihood of this happening varies, with it being detected in 25 to 55% of patients for spleen enlargement, and 15 to 25% of patients for liver enlargement.
In a small percentage of patients (about 5%), the disease may show up on the skin in various forms such as small raised spots, blisters, ulcers, flat spots, or lumps.
In rare instances, an unusually high number of white blood cells can lead to strokes or mini-strokes due to increased thickness of the blood.
Testing for Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes)
If a doctor suspects chronic lymphocytic leukemia (CLL) based on certain clinical findings or laboratory results like increased lymphocyte count, decreased blood cell count, or abnormal proteins in the blood, they may conduct several tests. A complete blood count, peripheral smear, and flow cytometry are some of the tests required for diagnosing CLL.
CLL is typically diagnosed based on guidelines updated in 2018 by the International Workshop on Chronic Lymphocytic Leukemia. According to these guidelines, CLL is diagnosed if a person has a specific type of B-cell lymphocyte count of 5,000 or more per microliter of blood for at least three months.
Looking at the patient’s blood under a microscope may show “smudge cells,” leukemia cells with thin edges and a dense nucleus. Lab tests with flow cytometry can reveal if the B lymphocytes are clonal, meaning they all descended from a single cell. This can help confirm a CLL diagnosis.
Other findings could include the presence of two types of B-cell-related proteins (CD23, CD19, and CD20) and mature B and T-cell proteins (CD5). Very occasionally, the B-cells might show two different light chain restrictions, kappa and lambda. Studies estimate this situation happens in around 1.4% of CLL cases.
More sophisticated tests like fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) can help predict the course of the disease and the effectiveness of different treatment options. For instance, genetic changes like the loss of the ATM gene, or the TP53 gene, are associated with a poor response to certain drugs. These gene changes are estimated to affect roughly 7 to 10% of CLL patients who haven’t received treatment yet, and 10-47% of all CLL patients. NGS can also detect mutations in the immunoglobulin heavy chain variable region (IGHV) gene. CLL with mutated IGHV is usually less aggressive and has a lower frequency of other significant mutations.
Treatment Options for Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes)
Patients who aren’t showing strong symptoms or abnormal lab results are typically monitored rather than treated straight away. This is because there’s no proof that treatment will help if someone doesn’t have significant symptoms yet, and might even cause harm without any benefit.
Doctors use a sort of rating system called the International Prognostic Score (IPS-E). This system looks at three specific factors: your lymphocyte count (a type of white blood cell), whether you have any visible lumps from lymph nodes that could be felt, and if your immune system gene (IGHV) has mutated. The score then predicts the chances of needing treatment for asymptomatic patients. If you have none of these risk factors, you’re considered low risk, with a 1% chance of needing treatment after a year and 8% after five years. If you have one risk factor, your risk is higher, with a 3% chance of needing treatment after one year and 28% after five years. If you have two or three risk factors, you’re considered high risk, with a 14% chance of needing treatment after one year and 61% after five years.
On the other hand, patients with clear symptoms or abnormal lab results require immediate treatment. The International Workshop on Chronic Lymphocytic Leukaemia (iWCLL) says that a patient must meet at least one of the following criteria to be diagnosed with the active disease: signs of worsened bone marrow failure like new or worsening low platelet counts, anaemia, enlarged spleen or lymph nodes, autoimmune conditions unresponsive to steroids, symptoms outside of the lymph nodes, and severe weight loss, tiredness, fever, or night sweats.
There are multiple combinations of treatments for CLL, including several classes of drugs. However, there isn’t a lot of evidence to show which treatments are best to use together. The treatment choice depends on factors like the stage of CLL, the cellular and genetic characteristics of the disease, overall patient health, and the goals of treatment. Some genetic factors can affect how well treatment will work.
For example, if a patient has a certain genetic mutation (either del 17p or TP53), they usually don’t respond well to certain chemotherapy treatments. But we have evidence that other drugs, such as BTK inhibitors like ibrutinib and acalabrutinib, and the BCL-2 inhibitor venetoclax, do work well alone or in combination with anti-CD 20 monoclonal antibody drugs.
Another important factor is the IGHV mutation status. If the IGHV gene is unmutated, it indicates aggressive CLL. For such cases, BCL-2 inhibitors and BTK inhibitors are more effective compared to other treatments.
What else can Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes) be?
When diagnosing a case of lymphocytosis (an excessive amount of lymphocytes in the blood) that may be caused by a clonal disorder (a growth of cells from a single parent cell), some medical conditions can present similar symptoms. Here are a few examples:
- Prolymphocytic Leukemia: This condition often comes with symptoms such as swollen lymph nodes and enlarged organs. However, it’s different from chronic lymphocytic leukemia (CLL) since the cells that can be seen under a microscope look different.
- Hairy Cell Leukemia (HCL): HCL might reveal symptoms like lymphocytosis, enlarged organs, and lower than normal blood cell counts. But typically, unlike CLL, it doesn’t cause swollen lymph nodes. Also, the cells look quite distinctive when viewed under a microscope.
- Follicular Lymphoma (FL): FL and CLL have many similarities, such as similar cell size and symptoms like swelling of lymph nodes. A key difference is that a biopsy from FL will show a nodular growth pattern not usually seen in CLL. Even if CLL shows a similar pattern, further examination will reveal differences in cell structure.
- Lymphoplasmacytic Lymphoma (LPL): LPL has many similar symptoms to CLL. However, LPL shows a specific change in the proteins in the blood, and if CLL has this change, it is less pronounced than in LPL.
- Mantle Cell Lymphoma (MCL): MCL shares many clinical and cell features with CLL. However, there are still significant differences such as certain protein expressions that distinguish them.
- Splenic Marginal Zone Lymphoma (SMZL): Both CLL and SMZL can have similar cell findings and symptoms like spleen enlargement. Yet, SMZL can express certain markers not seen in CLL.
Meanwhile, certain infections can cause reactive lymphocytosis, which is a temporary lymphocyte increase rather than the persistent increase seen in clonal disorders. For example, pertussis (whooping cough), infectious mononucleosis (mono), and toxoplasmosis can cause significant lymphocytosis. During viral infections, looking at a blood smear can reveal atypical lymphocytes, which are unusually large immune cells. However, in these cases, lymphocytosis is temporary, and the white blood cell counts usually return to normal within a few weeks. This is unlike cases of CLL, where lymphocytosis is persistent. Also, the cell studies in reactive lymphocytosis don’t show the specific markers required for a CLL diagnosis.
What to expect with Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes)
The outlook for Chronic Lymphocytic Leukemia (CLL) patients largely depends on two main criteria: the Rai and Binet staging systems and other factors causing a decrease in blood cells, such as marrow failure, immune-related disorders, or previous therapy. A significant study revealed that CLL patients with immune-related disorders generally fare better than those whose problems are caused by bone marrow issues. Both the Rai and Binet systems directly relate to a patient’s prognosis.
Historical data shows that patients in the low-risk Rai stage 0, which accounted for 18% of cases, lived for over 12.5 years on average. For the intermediate risk groups, Rai stage I and stage II, which were 23% and 31% of cases respectively, their median survival was 8.4 years and about 6 years, respectively. Patients at high risk, Rai stage III and IV, made up 17% and 11% of cases, respectively, and these patients on average lived about 1.5 years.
The Binet system also groups patients into low, intermediate, and high-risk categories. Data from the ’80s shows that Binet stage A patients lived as long as age-matched healthy individuals, while stage B and stage C patients lived on average for 7 and 2 years, respectively.
Beyond the Rai and Binet systems, other tools can predict disease outcomes based on patients’ genetics. These include the CLL international prognostic index (CLL-IPI), CLL1 prognostic model (CLL1-PM), International Prognostic Score for Early-stage CLL (IPS-E), and the Four Factor Prognostic Model for Ibrutinib.
The CLL-IPI considers several factors, each assigned points, to calculate a risk score. With more points, the prognosis worsens. Similarly, the CLL1-PM and IPS-E scores are used for the early stage of CLL. Higher scores on the CLL1-PM, calculated from several factors, also indicate a worse prognosis. The IPS-E classifies patients based on three factors: extent of enlarged lymph nodes, high numbers of lymphocytes, and certain genetic features. More factors place the patient in a higher risk group.
The Four Factor Prognostic Model takes into account four factors. A score of 0-1 indicates low risk, 2 points mean intermediate risk, and 3-4 points signify high risk.
Recent scientific and technological advancements have allowed for the identification of genetic markers that help predict the disease course and outcomes. Significant predictive markers include TP53 mutations and a specific genetic deletion (Del 17p), which are associated with worse outcomes. Another essential predictor is IGHV mutations that are found in about half of CLL cases. Having more than five abnormalities also predicts a poor outcome.
Finally, two other factors linked with worse outcomes are a rapid increase in lymphocytes within 12 months and a higher level of Beta-2 microglobulin in the blood.
Possible Complications When Diagnosed with Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes)
In patients with chronic lymphocytic leukemia, infections are a common problem both before and after treatment. This is mostly due to a weak immune system, which leaves them open to infections like herpes simplex virus, cytomegalovirus, pneumocystis jirovecii, aspergillus, and various mycobacterial pathogens.
This condition also leads to complications related to the blood, including anemia. This is often due to factors like the progression of the disease in the bone marrow, chemotherapy, autoimmune hemolytic anemia, an enlarged spleen, red cell aplasia, and blood loss in the digestive system. Autoimmune hemolytic anemia, in particular, can be seen in about 4 to 10% of chronic lymphocytic leukemia patients.
Red cell aplasia is fairly rare, with its rate of occurrence somewhat unclear; however, it’s thought to be seen in about 0.5% of chronic lymphocytic leukemia cases. Thrombocytopenia, or low platelet count, can happen at any time due to factors like disease burden, treatments, infections, and autoimmune disease. Immune thrombocytopenia is a notable complication, showing up in 2 to 5% of cases.
Potential Complications:
- Common Infections
- Anemia
- Autoimmune hemolytic anemia
- Red cell aplasia
- Thrombocytopenia
- Immune thrombocytopenia
Leukostasis, which can become a severe issue when white blood cell counts exceed 400,000/microL, is a medical emergency. There can also be complications related to the digestive system, including severe colitis and life-threatening diarrhea due to certain drugs. These drugs can also cause liver damage and potentially deadly pneumonitis.
In addition to these complications, chronic lymphocytic leukemia patients are also at risk for secondary cancers. These primarily include blood and solid cancers, such as colon, lung, prostate, and breast cancer. There’s also aggressive lymphoma, or Richter syndrome, which occurs in about 1 to 10% of cases.
Preventing Chronic Lymphocytic Leukemia With Variant Genetics (Genetic Contributions of Chronic Leukemia of Leukocytes)
Education is key in caring for patients who have chronic lymphocytic leukemia. This learning process starts from the time they are diagnosed and continues throughout their treatment. It involves a team of healthcare professionals the patient meets. This educational approach is especially important for patients diagnosed at an early stage or without active disease. For these patients, firm scientific research suggests that watching and waiting, without treatment, is often the best approach.
However, explaining to the patient, their family, or caregivers why doing nothing is the best action at that time can be challenging. That’s because they might be expecting immediate treatment. Another important aspect of patient education is discussing the option of clinical trials. Even if the recommended course of action is to observe, some patients may still have the chance to participate in these trials.
Lastly, doctors treating patients with chronic lymphocytic leukemia need to stay updated about the available clinical trials, latest research, and new treatment recommendations. This isn’t just generally a good practice for all doctors, but it is particularly relevant in treating this disease due to the continually evolving research, guidelines, and available medications.
