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Intro To (CLL) Chronic Lymphocytic Leukemia

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(CLL) Chronic Lymphocytic Leukemia

Intro To (CLL) Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia is a cancer of the blood and bone marrow cells that generally develops gradually. CLL is one of the most common types of cancer in adults. It usually occurs after adulthood and its prevalence is rare in children.


Physiologically, the bone marrow is a spongy tissue present in the bones containing the stem cells, which produce the blood cells. The stem cell of the blood may develop into a myeloid stem cell or a lymphoid stem cell. 


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A myeloid stem cell may give rise to the following three different types of blood cells.

  • Red blood cells (erythrocytes): that transport the oxygen and nutrients to the body. 
  • White blood cells (lymphocytes); develop the immune system of the body.
  • Platelets (thrombocytes) are responsible for blood clots to stop bleeding.


A lymphoid stem cell matures into any of the three types of lymphocytes (white blood cells):

  • B lymphocytes are responsible for the development of antibodies.
  • T lymphocytes that help B lymphocytes to develop antibodies.
  • Natural killer cells (NKC) that fight cancer cells and viruses.

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In CLL, many lymphocytes turn into abnormal cells called leukemia cells. Such leukemia cells are not able to fight infection effectively. As the number of such leukemic cells increases, the number of normal blood cells decreases [1].



CLL causes and risk factors:


In the United States, more than 20,000 new cases of CLL occur every year. CLL is one of the most common types of leukemia in adults. It accounts for about 1 in 4 new leukemia cases Its prevalence is more after the age of 60 and very rare before 40 years of age. 


It is still unknown that what is the cause of the CLL is. There is no strong relation between radiation, chemical exposure, infections, and diet with CLL. 

The following factors are considered as risk factors to CLL. 

  • Your age: more prevalence is in elderly. 
  • Your race: white people are at more risk than others. 
  • Family history: a family history of CLL may increase the risk. 
  • Chemical exposure: certain chemicals increase the risk of CLL e.g., herbicides, insecticides. 


Genetic mutation is the only risk factor for the CLL, but scientists are working on the exact mechanism and causes of this mutation [2]


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Symptoms of CLL:

Initially, CCL has no symptoms. Its symptoms appear as it progresses. Following are the most common symptoms that may appear in CCL patients. If you feel the following symptoms, you must visit your doctor. 

  • Enlarged lymph nodes
  • Frequent infections
  • Unexplained Weight loss
  • Weakness/feeling tired
  • Body pain
  • Night sweats 
  • Anemia
  • High temperature



The diagnosis of the CLL is very important. Whenever a patient with above-mentioned symptoms, then it is necessary to go with proper screening of the CLL. It starts with blood tests, then x-ray and scans and leads to further final diagnosis. 

A few of the tests that you may have to undergo are outlined below:

  • Blood test: very initial test to determine the number and shapes of different blood cells. 
  • X-rays and scans are carried out to evaluate the swollen lymph nodes and spleen. 
  • Bone marrow biopsy: to confirm the CLL, a sample of bone marrow cells is taken and evaluated for the presence of CLL cells.  
  • Lymph node biopsy: sample of the lymph node is also taken and evaluated for the confirmation of the CLL. 
  • Mutation tests: genetic mutation is also evaluated by taking the samples of bone marrow to know the gene and its abnormality [3].


Life expectancy in patients of CLL:

Life expectancy varies from patient to patient, and it also depends upon the time of diagnosis. Some patients die 2-3 years after the diagnosis because of more complications and others live with it for 5-10 years from initial diagnosis and proper treatment. 

  • It is also proved that about 80% of the patients survive after diagnosis with a CLL of 15-64 of age. 
  • Adults of age more than 65 years survive for 5 years or more after diagnosis with CLL. 
  • Generally, 70% of males and 75% of females affected with CLL survive for 5 years after diagnosis [4]


Treatment options for CLL:

Chronic lymphocytic leukemia [2] is curable but the recovery rate is very less. As described earlier, the patient with the CLL can live for years but it is very rare that the patient is fully recovering and free from any type of lymphoma or leukemia. 

Treatment of CLL depends on many factors such as the stage at which it is diagnosed, presence of symptoms and their severity, general health condition, age, and patient’s preference. 

 If the patient is not experiencing any kind of signs and symptoms, then there is no need for treatment as it is proved from previous studies that treatment at this stage does not increase the life-years but produces many side effects. 


If your doctor suggests that your CLL requires treatment, you may have the following options [5]:

  • Watchful waiting: Watchful waiting is closely monitoring the patient’s health without administering any drug or medicine. This therapy is used in asymptomatic patients at the early stage of the CLL. This is also called observation. 
  • Chemotherapy: Chemotherapy is a drug treatment that kills quickly growing cells, including cancer cells. Chemotherapy treatments can be administered through a vein or taken in pill form. Cyclophosphamide is an alkylating agent used in the management of leukemia or any other type of cancer. Cyclophosphamide basically binds with the DNA and stops the synthesis of the proteins and hence blocks the cell’s abnormal growth resulting in the death of cancer cells. Cyclophosphamide is usually used in combination with rituximab. Depending on your situation, your doctor may use a single chemotherapy drug, or you may receive a combination of drugs.


The medicines used to treat CLL can cause some significant side effects, including:

  • Continuous tiredness
  • Feeling weak and sick
  • Increased and frequent risk of infections
  • Frequent bruising or bleeding
  • Anemia – shortness of breath, weakness, and pale skin
  • Hair loss or thinning
  • Irregular heartbeat


  • Radiation therapy: Radiation therapy is one of the cancer treatments options that uses high-energy x-rays or other types of radiation to kill cancer cells or control them from increasing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body affected with CLL, such as a group of lymph nodes or the spleen. This treatment may be used to reduce pain related to a swollen spleen or lymph nodes. 


  • Targeted drug therapy: Targeted drug treatments directly focus on specific abnormalities present within the body. By controlling these abnormalities, targeted drug treatments kill the CLL cells. This therapy has usually less harmful effects. Following are the different types of targeted drug therapy methods used to treat the CLL. Most of the drugs of this group target the CD20 protein receptors of the cancerous cells. 
    • Tyrosine kinase inhibitor (TKI) therapy: This treatment inhibits the enzyme, tyrosine kinase, responsible for the conversion of stem cells into cancerous cells of CLL.  Ibrutinib, acalabrutinib, idelalisib, and duvelisib are TKI drugs used to manage different types of CLL.
    •  BCL2 inhibitor therapy: These drugs block the protein called B-cell lymphoma 2 (BCL2), present on the CCL cells. It is a family of cell proteins that undergo the cells through the process of apoptosis i.e., programmed cell death. In this way, either the CCL cells are died or become more sensitive to other anticancer drugs. Venetoclax the first drug developed and approved by FDA in 2016, is a type of BCL2 therapy used to treat different types of CLL [6].
    •  Monoclonal antibodies are the proteins of the immune system developed in the labs to manage many disorders including CLL. In CLL, these drugs bind with the specific receptor on the CLL cells and block their growth. These drugs later kill the CLL cells. Different drugs are used in combination to treat the CLL at different stages. The antibodies then kill the cancer cells, block their growth, or keep them from spreading. Such drugs are mostly given as IV infusion. Different monoclonal antibodies used in the treatment of CLL are ibrutinib, rituximab, Rituxan, venetoclax. Rituximab is one of the most prescribed monoclonal antibodies to treat CLL. Rituximab has better efficacy and safety profile as compared to other drugs and it is mostly used in combination with other anticancer drugs. Almost all the Monoclonal antibodies attack the CD20 receptors of the cancer cells. 


  • Bone marrow transplant: In bone marrow transplant (stem cell transplant), the abnormal and cancerous bone marrow of the patient is replaced with the healthy and normal bone marrow of the donor. Thus, the patient’s body starts producing healthy blood cells and it takes life towards a normal state. But this method is very costly and does not give effective and satisfactory outcomes. 


  • Immunotherapy: Immunotherapy is the latest and most effective treatment option which uses the immunity of the patient to fight cancer. Patients’ immune system does not work to fight the CLL cells. As these cells produce such kind of proteins that escape the CLL cells from host immune system. Immunotherapy helps the body to fight such cells and support the natural defense system of the body [7]
    • IVIG Therapy to treat CLL: Most of the CLL patients don’t produce enough antibodies (immunoglobulins, or IgG) to combat the infection. Which results in frequent attacks of different infections of lungs and sinus. Hence such patients are evaluated based on signs and symptoms and their severity to analyze whether IVIG therapy should be started or no. 
    • The start of the treatment with IVIG vary from patient to patient, and from clinician to clinician. On other hand, some of the cancer centers/ oncology hospitals and oncologists wait for the IgG level to drop below the certain level. While some clinicians start the use of IVIG with are without low IgG levels in the body to prevent further harmful effect of CLL. Mostly, IVIG therapy is administered once in month initially, later its dose can be adjusted according to the need of the patient. 
    • Studies has proved that IVIG is much effective in preventing infections in CLL patients. A meta-analysis conducted in 2009, of nine trials, has proved that treatment of CLL and multiple myeloma patients with polyvalent IVIG versus a control group with primary outcomes of all-cause mortality and major infections. They found that while no survival benefit could be demonstrated, there was a magnificent decrease in the development of major infections and a significant reduction in clinically documented infections.
    • Another crossover study found that low-dose IVIG therapy was just as effective as high-dose IVIG therapy. In the study, 42 CLL patients with hypogammaglobulinemia (IgG levels less than 600 mg/dL) and/or a history of at least one episode of severe infection in the six months preceding inclusion in the study were randomly allocated to receive either an infusion of 300 mg/kg IVIG every four weeks for six months or no treatment. They were then switched to observation or IVIG for another 12 months, and then received IVIG or no therapy for an additional six months. Results showed a significantly lower incidence of infectious episodes during IVIG prophylaxis in 30 patients who completed the six-month period of either observation or IVIG therapy, as well as the 17 patients who completed 12 months of either observation or IVIG prophylaxis [8].


Most Effective Treatment Plans for CLL:

Treatment protocols may change with the stage and severity of cancer and the patient’s general physical health. Treatment options for high-risk patients are different from others. Different treatment plans are given below:

  • A better option is gone for stem cell transplantation if the physical health and fitness of the patient allow for it. 
  • Alemtuzumab a monoclonal antibody, monotherapy of this drug also proved very effective in more than 60% of the CLL patients. Its efficacy is proved in multiple studies. 
  • Ibrutinib (Imbruvica), as monotherapy or in combination with rituximab (Rituxan) is a better choice to treat the lymphoma of CLL. 
  •  Venetoclax (Venclexta) as monotherapy or can be used in combination with Obinutuzumab- a monoclonal antibody. Monotherapy and combination selection depends upon the condition of the patient and the stage of cancer. Venetoclax is also used in combination with rituximab. 

Many complications are associated with this chemotherapy treatment and must be managed with an appropriate anticancer drug. Multiple other drugs are used in accordance with the complications of the patient.




Figure 2: Treatment strategy flow chart for CLL. *Fit is defined in the United States as patients younger than 65 years and with good performance status. BR = bendamustine and rituximab; FCR = fludarabine, cyclophosphamide, and rituximab; IGHV = immunoglobulin heavy chain variable gene.


  1. Burger, J.A. Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL): from understanding the basics towards therapeutic targeting. in Seminars in cancer biology. 2010. Elsevier.
  2. https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq. 2021  [cited 2021 10-10-2021]; Available from: https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq.
  3. Matutes, E., et al., The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. 1994. 8(10): p. 1640-1645.
  4. Delgado, J., et al., Chronic lymphocytic leukemia: a prognostic model comprising only two biomarkers (IGHV mutational status and FISH cytogenetics) separates patients with different outcome and simplifies the CLL‐IPI. 2017. 92(4): p. 375-380.
  5. Schiffer, C.A. and E.J.U.U. Atallah, Larson RA ed. UpToDate. Waltham, MA: UpToDate, Overview of the treatment of chronic myeloid leukemia. 2020.
  6. Whitaker, J.A., et al., The humoral immune response to high-dose influenza vaccine in persons with monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL). 2021. 39(7): p. 1122-1130.
  7. Logue, J.M., et al., Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma. 2021. 106(4): p. 978.
  8. Brem, E.A. and S. O’Brien, Frontline Management of CLL in 2021. JCO Oncology Practice, 2021: p. OP.21.00258.

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