Chronic Lymphocytic Leukemia: A slow progressing B cells cancer of the elderly

Introduction

Chronic lymphocytic leukemia (CLL) is a type of cancer that begins in the bone marrow. It is characterized clinically by the overproduction and accumulation of small mature-looking but functionally incompetent B-lymphocytes in blood, bone marrow and lymphoid tissues. The bone marrow is the spongy tissue inside bones where blood cells are made. CLL is a cancer of the B cells, which are a type of white blood cell that helps the body fight infection.

CLL cells are abnormal and grow out of control in the bone marrow. Over time, the accumulation of CLL cells can crowd out the healthy white blood cells, making it difficult for the body to fight infection. CLL can also spread to other parts of the body, such as the lymph nodes, liver, and spleen.

CLL is a slow-growing cancer, and many people with CLL do not need treatment right away. However, when treatment is needed, there are a number of options available, including chemotherapy, immunotherapy, and targeted therapy.

The prognosis for people with CLL is generally good. With treatment, most people with CLL can live long and active lives.

Here are some of the key things to know about CLL:

  • It is the most common type of leukemia in adults.
  • It is more common in men than in women.
  • It is typically diagnosed in people over the age of 50.
  • The exact cause of CLL is unknown, but it is thought to be caused by a combination of genetic and environmental factors.
  • There are no known ways to prevent CLL.
  • There are a number of effective treatments available for CLL.

Most patients present with leukemia whereas a small minority present with small lymphocytic lymphoma. In earlier classifications of lymphoid malignancies, CLL and SLL were considered to be separate entities but they are now accepted to be different clinical manifestations of the same disease.

NCCN Guidelines for Patients Chronic Lymphocytic Leukemia

What are the clinical signs and symptoms of CLL?

The clinical signs and symptoms of CLL can vary depending on the stage of the disease and the location of the CLL cells. Many people with CLL do not have any symptoms when they are first diagnosed. The disease is often found when a person’s doctor orders blood tests for an unrelated reason.

The most common clinical signs and symptoms of CLL include:

  • Enlarged lymph nodes: CLL cells can build up in the lymph nodes, causing them to become enlarged. The lymph nodes are small, bean-shaped organs that are located throughout the body. They help to filter bacteria and other harmful substances from the blood. Symmetrical enlargement of cervical, axillary or inguinal lymph nodes is the most frequent clinical sign. The nodes are usually discrete and non-tender.
  • Fatigue: CLL cells can crowd out the healthy red blood cells in the bone marrow, which can lead to anemia. Anemia is a condition in which the blood does not have enough healthy red blood cells to carry oxygen to the body’s tissues. This can cause fatigue, weakness, and shortness of breath.
  • Night sweats: CLL cells can produce substances that cause night sweats. Night sweats are episodes of excessive sweating that occur during sleep.
  • Fever: CLL cells can cause the body to develop a fever. A fever is a sign that the body is fighting an infection. However, people with CLL may develop a fever even if they do not have an infection. Immunosuppression is a significant problem resulting from hypogammaglobulinemia and cellular immune dysfunction. 
  • Unexplained weight loss: CLL cells can use up the body’s energy stores, which can lead to unexplained weight loss.
  • Pain or fullness in the abdomen: CLL cells can build up in the liver and spleen, causing them to become enlarged. This can cause pain or fullness in the abdomen.

Other clinical signs and symptoms of CLL may include:

  • Easy bruising and bleeding: CLL cells can crowd out the healthy platelets in the bone marrow, which can lead to thrombocytopenia. Thrombocytopenia is a condition in which the blood does not have enough platelets. Platelets are blood cells that help the blood to clot. People with thrombocytopenia may bruise and bleed easily.
  • Frequent infections: CLL cells can crowd out the healthy white blood cells in the bone marrow, which can make it difficult for the body to fight infection. People with CLL may experience frequent infections, including pneumonia, urinary tract infections, and skin infections.

What are the laboratory investigations for CLL?

Image depicting a peripheral blood smear showcasing the hallmark findings of CLL
This image showcases the characteristic features of chronic lymphocytic leukemia (CLL) in a peripheral blood smear. Prolymphocytes, the hallmark cells of CLL, are readily identifiable due to their medium size, prominent nucleoli, and more abundant pale cytoplasm compared to B-CLL cells. Their chromatin is condensed but less dense than that of B-CLL cells. The presence of a notched nucleus in a large lymphocyte highlights the morphological diversity of lymphocytes in CLL. “File:Chronic lymphocytic leukemia with prolymphocytes.jpg” by SpicyMilkBoy is licensed under CC BY-SA 4.0.

Laboratory investigations are used to diagnose CLL, monitor the progression of the disease, and assess the response to treatment. Some of the most common laboratory investigations used for CLL include:

  • Full blood count (FBC): A FBC measures the number of different types of blood cells in the blood, including red blood cells, white blood cells, and platelets. A FBC can show anemia, thrombocytopenia, and lymphocytosis (an increased number of lymphocytes) in patients with CLL. Normocytic normochromic anemia is present in later stages as a result of marrow infiltration or hypersplenism
  • Peripheral blood smear: A peripheral blood smear is a test that examines the different types of blood cells in a sample of blood under a microscope. A peripheral blood smear show lymphocytosis with smudge or smear cells
  • Bone marrow biopsy: A bone marrow biopsy is a procedure in which a small sample of bone marrow is removed and examined under a microscope. A bone marrow biopsy can show the presence of CLL cells and other abnormalities.
  • Flow cytometry: Flow cytometry is a test that uses lasers to examine the characteristics of individual cells. Flow cytometry can be used to identify CLL cells and to distinguish them from other types of white blood cells. In CLL, cells co‐express the surface antigen CD5 with the B‐cell antigens CD19, CD20, and CD23. The levels of surface immunoglobulin, CD20, and CD79b are characteristically low compared to those found on normal B cells. Each clone of leukemia cells is restricted to expression of either kappa or lambda immunoglobulin light chains. It should be noted that the expression of CD5 can also be observed in other lymphoid malignancies, such as mantle cell lymphoma. A recent, large harmonization effort has confirmed that a panel of CD19, CD5, CD20, CD23, kappa and lambda is usually sufficient to establish the diagnosis. In borderline cases, markers such as CD43, CD79b, CD81, CD200, CD10, or ROR1 may help to refine the diagnosis.
  • Immunoglobulin studies: Immunoglobulin studies measure the levels of different types of immunoglobulins (antibodies) in the blood. There are reduced concentrations of serum immunoglobulins.
  • Genetic testing: Genetic testing can be used to identify genetic mutations that are associated with CLL. Genetic testing can be helpful for diagnosing CLL and for predicting the prognosis of patients with CLL.

In addition to the laboratory investigations listed above, other laboratory tests may be used to monitor the progression of CLL and to assess the response to treatment. These tests may include:

  • Serum beta-2 microglobulin (B2M): B2M is a protein that is released into the blood by CLL cells and other types of cells. Elevated levels of B2M are associated with a more aggressive form of CLL.
  • Lactate dehydrogenase (LDH): LDH is an enzyme that is released into the blood when cells are damaged. Elevated levels of LDH are associated with a more aggressive form of CLL.
  • Imaging tests: Imaging tests, such as X-rays, computed tomography (CT) scans, and positron emission tomography (PET) scans, may be used to look for enlarged lymph nodes and other signs of CLL.

How is CLL staged?

Two widely accepted clinical staging systems co‐exist, named after the first authors of the original publications, Rai and Binet. Both systems describe three major prognostic groups with discrete clinical outcomes.

The Binet staging system

The Binet staging system is based on two factors: the number of involved lymph node areas as defined by the presence of enlarged lymph nodes of greater than 1 cm in diameter or organomegaly and the presence of anemia or thrombocytopenia.

The Binet staging system has three stages:

  • Stage A: Fewer than 3 lymph node areas are involved and there is no anemia or thrombocytopenia.
  • Stage B: 3 or more lymph node areas are involved and there is no anemia or thrombocytopenia.
  • Stage C: There is anemia or thrombocytopenia, regardless of the number of involved lymph node areas

The areas of involvement considered or lymph node regions  are

  1. Head and neck, including the Waldeyer ring (this counts as one area, even if more than one group of nodes is enlarged)
  2. Axillae (involvement of both axillae counts as one area)
  3. Groins, including superficial femoral (involvement of both groins counts as one area)
  4. Palpable spleen
  5. Palpable liver (clinically enlarged)

The Binet staging system is important for determining the prognosis of patients with CLL and for guiding treatment decisions. Patients with early-stage CLL (Binet stage A) have a better prognosis than patients with advanced-stage CLL (Binet stage C).


The Modified Rai Staging System 

The Rai staging system is based on three factors: the number of lymphocytes in the blood, the presence of enlarged lymph nodes, and the presence of anemia or thrombocytopenia.

The modified Rai staging system defines

Low‐risk disease: Patients who have lymphocytosis with leukemia cells in the blood and/or marrow (lymphoid cells >30%) (former Rai stage 0).

Intermediate Risk: Patients with lymphocytosis, enlarged nodes in any site, and splenomegaly and/or hepatomegaly (lymph nodes being palpable or not) (formerly considered Rai stage I or stage II).

High‐risk disease: Patients with disease‐related anemia (as defined by a hemoglobin [Hb] level less than 11 g/dL) (formerly stage III) or thrombocytopenia (as defined by a platelet count of less than 100 × 109/L) (formerly stage IV).

The Rai staging system is important for determining the prognosis of patients with CLL and for guiding treatment decisions. Patients with early-stage CLL (Rai stage 0 or I) have a better prognosis than patients with advanced-stage CLL (Rai stage III or IV).

What is the prognosis for CLL?

The prognosis for patients with chronic lymphocytic leukemia (CLL) is based on a number of factors, including the stage of the disease, the patient’s age and health, and the presence of certain genetic mutations. Cytogenetics is the study of chromosomes, and cytogenetic abnormalities can be found in up to 50% of patients with CLL.

The following cytogenetic abnormalities are associated with a poor prognosis in CLL:

  • Deletion of 17p (del(17p)): Del(17p) is the most common cytogenetic abnormality in CLL, and it is associated with a poor prognosis. Patients with del(17p) have a shorter median survival time than patients without del(17p). Deletions of the short arm of chromosome 17 show marked resistance against genotoxic chemotherapies as the deletions almost always include band 17p13 where the prominent tumour suppressor gene TP53 is located
  • Trisomy 12 (tris(12)): Tris(12) is the second most common cytogenetic abnormality in CLL, and it is also associated with a poor prognosis. Patients with tris(12) have a shorter median survival time than patients without tris(12).
  • Deletion of 11q (del(11q)): Del(11q) is a less common cytogenetic abnormality in CLL, but it is associated with a very poor prognosis. Patients with del(11q) have a median survival time of less than 2 years. Deletions of the long arm of chromosome 11 typically show bulky lymphadenopathy, rapid progression and reduced overall survival.
  • Complex karyotype: A complex karyotype is defined as the presence of 3 or more cytogenetic abnormalities in a single cell. Patients with a complex karyotype have a very poor prognosis, with a median survival time of less than 1 year.
  • Expression of ZAP-70: A signaling protein that is not found in normal B cells and tumors with unmutated immunoglobulin genes.

Cytogenetic abnormalities associated with a good prognosis in CLL

The following cytogenetic abnormalities are associated with a good prognosis in CLL:

  • Deletion of 13q (del(13q)): Del(13q) is the most common cytogenetic abnormality in CLL, and it is associated with a good prognosis. Patients with del(13q) have a longer median survival time than patients without del(13q).
  • Normal karyotype: Patients with a normal karyotype have the best prognosis of all patients with CLL. However, tumors with normal fluorescence in situ hybridization (FISH) cytogenetics and trisomy 12 have an intermediate prognosis.
  • Mutated Ig variable region genes.
Image showcasing various prognostic factors and their influence on disease progression and survival of CLL
This compelling illustration unveils the intricacies of classical and new staging systems, highlighting the significance of prognostic factors in determining disease progression and survival. Classical staging systems, like Rai and Binet, categorize CLL based on the extent of lymphadenopathy and organ involvement, providing an initial assessment of prognosis. New staging systems, incorporating molecular testing, refine prognostication by considering genetic mutations and serum protein levels.

What are the current available treatment options?

As for treatment, as many as 60% of CLL patients never require treatment. Indications for treatment include cytopaenias like anemia and/or thrombocytopenia, bulky symptomatic lymphadenopathy and/or splenomegaly, presence of autoantibodies, presence of B symptoms like fever, night sweats and weight loss, and transformation to an aggressive lymphoma. 

There have been significant advances in the treatment of chronic lymphocytic leukemia (CLL) in recent years, with the development of new targeted therapies and immunotherapies. These new treatments have resulted in longer survival times and improved quality of life for patients with CLL.

The treatment for CLL depends on a number of factors, including the stage of the disease, the patient’s age and health, and the presence of certain genetic mutations. Some patients with CLL do not need treatment right away, while others need to start treatment right away.

The current standard paradigm of treatment is to use chemoimmunotherapy, specifically with purine analogs and or alkylating agents combined with anti-B-cell monoclonal antibodies. Recent advances in therapy include the use of oral kinase inhibitors targeting Bruton tyrosine kinase and PI3 kinase.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs that target specific molecules on cancer cells. Targeted therapy drugs can help to kill CLL cells while sparing healthy cells.

Some of the targeted therapy drugs that are used to treat CLL include:

  • Ibrutinib (Imbruvica)
  • Zanubrutinib (Brukinsa)
  • Acalabrutinib (Calquence)
  • Venetoclax (Venclexta)

Immunotherapy

Immunotherapy is a type of treatment that uses the patient’s own immune system to fight cancer. Immunotherapy drugs can help to activate the immune system to kill CLL cells.

Some of the immunotherapy drugs that are used to treat CLL include:

  • Rituximab (Rituxan)
  • Obinutuzumab (Gazyva)
  • Ofatumumab (Arzerra)

Chemotherapy

Chemotherapy is a type of treatment that uses drugs to kill cancer cells. Chemotherapy is often used to treat CLL that is progressing or that is causing symptoms.

Some of the chemotherapy drugs that are used to treat CLL include:

  • Fludarabine
  • Cyclophosphamide
  • Bendamustine

Stem cell transplantation

Stem cell transplantation is a procedure in which healthy stem cells are transplanted into the patient’s body. Stem cells are the immature cells that develop into different types of blood cells.

Stem cell transplantation may be an option for patients with CLL who have relapsed after initial treatment or who have not responded to initial treatment. Patients may eventually succumb due to the development of resistant disease, superimposed infections, or less commonly, transformation to a more aggressive lymphoma. 

Clinical trials

Clinical trials are research studies that test new treatments for CLL. Clinical trials can be a good option for patients with CLL who have not responded to other treatments or who have relapsed after initial treatment.

Figure 2 from A New Era is Coming up in the Treatment of Chronic Lymphocytic Leukemia published in Lymphoma and Chronic Lymphocytic Leukemias” by Libertas Academica is licensed under CC BY 2.0.

Treatment of CLL based on stage

The treatment for CLL depends on the stage of the disease, the patient’s age and health, and the presence of certain genetic mutations.

  • Patients with early-stage CLL (Rai stage 0 or I): Patients with early-stage CLL may not need treatment right away. However, some patients with early-stage CLL may benefit from early treatment, such as targeted therapy.
  • Patients with intermediate-stage CLL (Rai stage II or III): Patients with intermediate-stage CLL will eventually need treatment. Treatment options for intermediate-stage CLL include targeted therapy, immunotherapy, and chemotherapy.
  • Patients with advanced-stage CLL (Rai stage IV): Patients with advanced-stage CLL will need treatment right away. Treatment options for advanced-stage CLL include targeted therapy, immunotherapy, and chemotherapy.
Image depicting the various treatment options of CLL, including watchful waiting, chemotherapy, targeted therapy, and immunotherapy
This microscopic snapshot provides valuable insights into the therapeutic options available for CLL management.

Key Points of Chronic Lymphocytic Leukemia (CLL) 

Definition

A slow progressing cancer due to overgrowth and accumulation of small incompetent mature-looking B-lymphocytes in the blood, bone marrow and lymphoid tissues. Small lymphocytic leukemia is a different clinical manifestation of this disorder. 

Incidence

  • Peak at > 65 years old
  • Common in Western societies
  • Male:female ratio is 2.8:1

Signs and symptoms

  • Discrete, non-tender symmetrical enlargement of the cervical, axillary or inguinal lymph nodes
  • Splenomegaly
  • Anemia
  • Immunosuppression due to hypogammaglobulinemia

Laboratory investigations

Peripheral blood and bone marrow smear

PBF: Lymphocytosis with smudge cells. Normochromic normocytic anemia in bone marrow infiltration. 

Other Laboratory investigations

  • Immunophenotyping: CD5+, CD19+, CD20+, CD23+ and surface immunoglobulin+
  • FISH: Trisomy 12 (intermediate prognosis) , del17p (least favorable prognosis), del11q (least favorable prognosis), del13q (best prognosis) 
  • ↓ serum immunoglobulins 

Staging

Rai stageCharacteristics
Rai 0Lymphocytosis only >15 x 109/L
Rai ILymphocytosis + lymphadenopathy
Rai IILymphocytosis + hepato-/splenomegaly ± lymphadenopathy
Rai IIILymphocytosis + anemia (Hb < 11g/dL) ± lymphadenopathy ± organomegaly
Rai IVLymphocytosis + platelets < 100 x 109/L ± lymphadenopathy ± organomegaly
Binet stageLymphadenopathy/OrganomegalyHemoglobin (g/dL)Platelets (x 109/L)
Binet A≤  2 areas involved > 10> 100
Binet B≥ 3 areas involved ≥ 10≥ 100
Binet CNot considered< 10< 100

*Lymphadenopathy (> 1cm) /Organomegaly areas: 

  • Head and neck (uni- or bilateral)
  • Axillar (uni- or bilateral)
  • Inguinal (uni- or bilateral)
  • Splenomegaly
  • Hepatomegaly

Treatment and management

  • No treatment for Rai 0 – II stage and Binet A – B stage
  • Chemoimmunotherapy e.g. purine analogs/ alkylating agents + anti-B cell monoclonal antibodies
  • Oral kinase inhibitors
  • Stem cell transplantation

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

References

  1. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. doi: 10.1182/blood-2007-06-093906. Epub 2008 Jan 23. Erratum in: Blood. 2008 Dec 15;112(13):5259. PMID: 18216293; PMCID: PMC2972576.
  2. Eichhorst B, Robak T, Montserrat E, Ghia P, Niemann CU, Kater AP, Gregor M, Cymbalista F, Buske C, Hillmen P, Hallek M, Mey U; ESMO Guidelines Committee. Electronic address: [email protected]. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Jan;32(1):23-33. doi: 10.1016/j.annonc.2020.09.019. Epub 2020 Oct 19. PMID: 33091559.
  3. Mukkamalla SKR, Taneja A, Malipeddi D, et al. Chronic Lymphocytic Leukemia. [Updated 2023 Mar 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
  4. Shadman M. Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review. JAMA. 2023 Mar 21;329(11):918-932. doi: 10.1001/jama.2023.1946. PMID: 36943212.
  5. National Comprehensive Cancer Network® (NCCN®). NCCN Guidelines for Patients® Chronic Lymphocytic Leukemia. 2022.
  6.  Hallek M, Eichhorst B,  Catovsky D. Chronic Lymphocytic Leukemia (Hematologic Malignancies) 1st ed. 2019 Edition (Springer).
  7. Carr JH. Clinical Hematology Atlas 6th Edition (Elsevier).

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