Chronic lymphocytic leukemia (CLL)

Content

Introduction

Chronic lymphocytic leukemia (CLL), is a chronic lymphoproliferative disease also called chronic lymphocytic leukemia, characterized by the abnormal proliferation of mature lymphocytes (in 95% of cases of B lymphocytes and in 5% of T lymphocytes), apparently normal, which, however, are cancerous because they are not completely differentiated and, therefore, not very active from an immunological point of view. It has a slow progression over time and is the most frequent form of leukemia in adults, especially in the population between 67 and 72 years old.

Effects of chronic lymphocytic leukemia

Lymphocytes are cells of the immune system that monitor the organism and activate the defenses against microorganisms (bacteria and viruses), tumor cells, or other potentially dangerous agents. They are distinguished in B or T according to the type of response they are in. able to determine.

In chronic lymphocytic leukemia, the mother cell that will give rise to the lymphocytes undergoes a malignant transformation and produces a lymphocyte clone, that is to say a large number of identical cells that no longer respond to physiological stimuli and become immortal. They thus continue to reproduce and accumulate in the blood, bone marrow, lymphatic organs (lymph nodes and spleen) and, sometimes, also in other organs, causing lymphadenomegaly and splenomegaly.An uncontrolled increase in these lymphocytes results in a decrease in granulocytes, monocytes, red blood cells and platelets, leading to anemia, bleeding and hematoma.

Spread in the population

Chronic lymphatic leukemia is the most common leukemia in the Western world and is typical in the "elderly. The average age in which it is ascertained (diagnosed) is around 65 years and only in 15% of cases is it discovered before the age of 60, has a prevalence in males. It affects about 5 in 100,000 people each year and the number of new cases (incidence) increases with increasing age. In Italy, estimates speak of about 1,600 new cases each year among men and 1,150 among women. In eastern populations the incidence is very low, even if the latter live in western countries; this suggests a genetic predisposition, rather than an environmental conditioning, theory also supported by the evidence that 10% of patients have affected family members from CLL or other diseases of the lymphatic system.

The stage of the disease

Chronic lymphatic leukemia is a disease with a variable course. In some people it can remain stable for more than ten years while in others it can progress rapidly. Knowing its phase is important in choosing the most suitable treatment (Video). Its diagnosis is made randomly following blood tests, usually following a lymphocytosis (> 5000 / mmc) that persists for at least 3 months.

For chronic lymphocytic leukemia there are several systems of staging, which in other words, allow you to assign a stage to the disease based on defined criteria. The clinical stage is defined according to 2 staging criteria:

  • the staging according to Ray, which divides the disease into 5 stages, from 0 to IV correlated with a different survival:
    • 0 only peripheral and medullary lymphocytosis
    • I lymphocytosis + adenomegaly
    • II lymphocytosis + splenomegaly and / or hepatomegaly
    • III lymphocytosis + anemia (Hb <11 g / dl)
    • IV lymphocytosis + thrombocytopenia (<100,000 / mmc)
  • staging according to Binet, which divides the disease into 3 stages, from A to C. This stage enhances, for prognostic purposes, the importance of the tumor mass which can affect 5 different lymphoid areas: cervical, axillary, inguinal, spleen and liver.
    • stage A: absolute lymphocytosis> 10000 / ul in the blood and involvement of less than three lymphoid areas, absence of anemia and thrombocytopenia (Hb> 10 gr / dl, PLTS> 100000 / mmc)
    • stage B: as stage A, but involving 3 or more infoid areas
    • stage C: anemia and thrombocytopenia (Hb <10 gr / dl, PLTS <100000 / mmc), regardless of the number of lymphoid areas involved

Such classification systems, which are very widespread and useful in clinical practice, since they are based on clinical characteristics and blood counts, have, however, the limit of not taking into account the new biological parameters that doctors use today to define the " evolution of the disease and choosing the therapy. Among these parameters we find: the dosage of beta 2 microglobulin, which indicates the evolution towards malignancy and dosage of the lactic dehydrogenase enzyme (LDH). The presence of cytogenetic alterations (IGHV), in particular the TP53 mutation.

The disease is defined as refractory when it does not respond to treatment.

Although chronic lymphocytic leukemia cannot normally be cured, treatments allow it to be kept under control for many years. The probability of success depends on the stage (if it is limited or if it is spread to other organs) as well as on the age and general health conditions of the sick person at the time of diagnosis.

Symptoms

In general, chronic lymphocytic leukemia (CLL) does not cause obvious disturbances (symptoms) in the initial phase and, in over half of patients, it is discovered by chance during tests performed for other reasons or because an enlarged lymph node appears in the neck , of the armpits or of the groin. In fact, in about two out of three cases, the assessment (diagnosis) takes place at a stage in which there are still no disturbances (symptoms). When they appear, the most frequent are generalized adenopathy (the lymph nodes appear elastic and are not painful to the touch) and enlargement of the spleen (splenomegaly) and liver (hepatomegaly).

The disorders (symptoms) that develop later are similar to those of other types of leukemia, caused by the invasion of malignant cells in the marrow, at the expense of healthy ones. They can include persistent fatigue, frequent infections, bleeding, unexplained weight loss , early satiety while eating and, less commonly, painless swelling of the lymph nodes in the neck, armpits and groin.

At times, chronic lymphocytic leukemia can also cause the spleen to enlarge so that it puts pressure on the stomach and causes a lack of appetite or signs of "indigestion. Other more noticeable disorders (symptoms) can include severe fatigue, paleness, bone pain," palpitations, night sweats, fever and bruising easily.

If any or even all of the listed disorders should be present, it is good to consult your family doctor as soon as possible because, although chronic lymphatic leukemia is very unlikely to determine them, it is necessary to investigate the causes and treat them.

Causes

The causes of chronic lymphocytic leukemia (CLL) are unclear. At present, there is no evidence to show a relationship between the disease and exposure to radiation, chemicals (benzene), infections or nutrition.

Having observed that among some populations it is less frequent, and remains so even if environmental conditions change, it is assumed that at the base there are family genetic characteristics that can predispose to the disease. Evidence confirmed by "the observation that in the first degree relatives of chronic lymphatic leukemia patients, the frequency is higher than that observed in the general population of the same age and sex. What can be said is that the genetic substrate of CLL consists of" intervention of several genes with different oncogenetic potential.

In recent years, progress has been made in understanding the altered mechanisms underlying the disease. In particular, it was understood that the first interventions that then develop these malignant clones of lymphocytes take place in the stem cell (mother cell, which gives rise to all types of blood cells) and concern the expression of some transcription factors, specific mutations of some important genes, such as NOTCH1, or events that occur in cells that begin to differentiate as B lymphocytes, in particular the B cell receptor (BCR). These changes give the cell the possibility of not undergoing programmed death (apoptosis ), but to survive much longer as an incomplete cell. This condition causes an accumulation of these cells in the blood, lymphatic organs (lymph nodes and spleen) and bone marrow, clinical features of this disease. Genetic studies have also identified recurrent mutations in the genes that regulate the interactions between tumor cells and the medullary microenvironment, required interactions for tumor growth, migration and cell invasion. In any case, chronic lymphatic leukemia is not transmissible and it is not possible to determine precise rules to prevent it.

Risk factors

Like many cancers, chronic lymphocytic leukemia can also be caused by environmental factors that interact with an individual's genetic characteristics. No individual modifiable risk factors have been identified.

Diagnosis

Although chronic lymphatic leukemia (CLL) is often discovered during periodic check-ups (routine tests) carried out for other reasons, to confirm its presence it is important to contact the general practitioner or specialist who, after a careful evaluation of the signs and disorders (symptoms) of the disease, will prescribe the most suitable tests to ascertain (diagnose) it.

Two different types of chronic lymphocytic leukemia have been identified:

      • very slowly progressing, so much so that sometimes years pass before the patient needs treatment
      • fast growing, the most severe form of the disease

To distinguish the two types of chronic lymphocytic leukemia, specific tests are required that assess the level of certain proteins such as ZAP-70 and CD38, which are present in higher concentrations in the fast-growing form.

Blood tests

In case of suspicion of chronic lymphatic leukemia, a blood test is started, the complete blood count. It allows, by taking a small amount of blood from a vein in the arm, to measure the quantity of the different types of cells present in the blood. of CLL, the number of lymphocytes is increased and also the ratio between the various populations of white blood cells (inversion of the leukocyte formula). In addition, a decrease in red blood cells and platelets can be observed. Since the amount of lymphocytes in the blood can also increase in presence of other diseases (viral infections), to confirm the diagnosis of CLL, an analysis called immunophenotypic is carried out, which allows the identification on the membrane of these lymphocytes, of particular proteins absent on normal lymphocytes.

Additional routine tests include LDH (lactic dehydrogenase enzyme) and β2 microglobulin, serum protein electrophoresis and immunoglobulin measurements.

X-rays and diagnostic imaging

In some cases, to rule out the presence of any complications or to check whether the treatments have had an effect, the doctor may prescribe a chest X-ray, an "ultrasound scan, a CT scan (computed tomography), an magnetic resonance. This type of exams. it is also useful for determining how widespread the disease is, assessing the state of the lymph nodes and spleen, and identifying other possible causes of the manifested disorders.

Bone marrow biopsy

To confirm the diagnosis of chronic lymphatic leukemia and check for cancerous cells, the haematologist may order a bone marrow sample. This is usually performed under local anesthesia without the need for hospitalization. It is performed. inserting a needle into a flat bone (usually the pelvis) and aspirating a fragment of bone marrow to be analyzed under a microscope.

Lymph node biopsy

In some cases, the removal and subsequent examination of a swollen lymph gland (lymph node) can help ascertain (diagnose) chronic lymphocytic leukemia. The gland is removed with a small operation performed under local or general anesthesia. Hospitalization is not normally required.

Genetic tests

Blood and bone marrow samples may also be useful in checking for unusual genes in cancer cells:

  • trisomy of chromosome 12
  • deletion of the long arm (q) of chromosome 13 and chromosome 11
  • deletion of the short arm (p) of chromosm 17
  • TP53 gene mutation
  • rearrangement of genes for immunoglobulin heavy chains, this test is important to check for minimal residual disease after therapy

These analyzes help doctors decide if, and at what distance of time, it is appropriate to start a treatment and which is the most suitable. Some therapies planned for chronic lymphocytic leukemia, in fact, do not work as they should in patients who have genetic mutations in cancer cells.

Therapy

The choice of treatment for chronic lymphocytic leukemia largely depends on the condition of the patient at the time of diagnosis.

Chronic lymphatic leukemia is a slow-growing disease, therefore, once the stage in which it is established has been established, the patient does not necessarily need to undergo therapy immediately. At first, in fact, especially if the disease was discovered at a very early stage, only periodic checks may be sufficient. If, on the other hand, the disease is more advanced, the treatment most used and which helps to keep it under control, even for several years, is chemotherapy.

Sometimes, after an apparent disappearance, after several months or a few years the disease reappears and, in this case, it must be treated again.

Initial phase monitoring

Given the absence of symptoms and the slow progression of chronic lymphocytic leukemia, and taking into account the fact that the therapy could cause significant undesirable effects (side effects), treatment in the initial stages would not bring any benefit; medical examinations and blood tests performed they are regularly considered sufficient until the disease worsens.

Chemotherapy - Advanced stage

When the disease progresses, in the presence of anemia and / or thrombocytopenia, splenomegaly, lymphadenitis, progressive increase in lymphocytes, weight loss, fever, asthenia, chemotherapy is started.

Patients are grouped into 3 groups based on physical condition, presence of other pathologies and life expectancy at diagnosis:

    • patients with no other significant diseases: the goal is to achieve complete remission and prolonged survival
    • patients with other diseases affecting life expectancy: a low-toxic, low-dose therapy is carried out on them to control the disease without aggravating the state of health of the patient
    • patients with other major diseases who, therefore, have a "shortened life expectancy": they only receive supportive care

There are several drugs to treat chronic lymphocytic leukemia, but the ones that are mainly prescribed to most patients, in cycles of treatment repeated every 28 days, are:

      • fludarabine, pentostatin and cladribrin, are analogues of purines, usually in the form of tablets, administered individually for the first three to five days for various courses of treatment
      • cyclophosphamide, is an alkylating agent, usually in tablets, administered as fludarabine
      • bendamustine, is placed between the category of alkylating agents and purine analogues. In the event that therapy with these drugs is not possible or is not sufficiently effective, it is possible to try to use other substances such as chlorambucil or prednisolone

Furthermore, in recent years various monoclonal antibodies have become part of the treatments available for chronic lymphatic leukemia, ie biological drugs specifically directed and, with great affinity, on the antigens of cancer cells. They are used alone or in combination with chemotherapy (chemoimmunotherapy):

      • rituximab: it is a chimeric antibody (human and murine), directed against CD20, an antigen present on the membrane of B lymphocytes and has a "cytotoxic action on leukemic cells
      • ofatumumab: acts with greater toxicity than rituximab and is used in patients refractory to fludarabine
      • alemtuzumab: is directed against the CD52 antigen and kills cells through various mechanisms

Treatment with kinase inhibitors

They are B cell receptor (BCR) inhibitors. This receptor is crucial for the development of CLL. The cascade reactions of the events triggered by the activation of BCR induce the cell to differentiate, proliferate, die. These events are facilitated by many enzymes, especially tyrosine kinases, such as phosphoinositil3-kappa (PI3K), the splenic tyrosine kinase ( SYK), Bruton tyrosine kinase (BTK) and phospholipase C gamma2.

The constant activation of BCR seems to be important in the leukemic process; on the basis of these evidences, drugs have been developed aimed precisely at inhibiting some steps of this path:

      • ibrutinib: is a Bruton tyrosine kinase inhibitor, it is used in relapsing or refractory patients. It increases apoptosis in leukemic cells and inhibits their proliferation. It is a well tolerated drug, apart from an increased risk of mucosal bleeding, and atrial fibrillation
      • idelelisib: is a PI3K inhibitor, is used in relapsed or refractory patients and in patients never treated with P53 mutations. It induces apoptosis and reduces the survival of leukemia cells

Several other drugs are currently being studied for use alone or in combination.

Side effects of chemotherapy

In general, chemotherapy is a non-specific treatment for cancer cells, but preferentially affects the latter because it attacks cells that divide faster. For this reason, the drugs used to treat chronic lymphocytic leukemia can cause some significant side effects, including persistent fatigue, general discomfort, increased vulnerability to infection, bruising or bleeding easily, anemia, shortness of breath, weakness, loss or hair thinning, palpitations, allergic reactions. Most of which, in any case, cease with the suspension of the treatment.There are treatments that can mitigate the side effects of chemotherapy, such as the use of growth factors, which stimulate normal cells, and antibiotics to prevent infections.

Stem cell and bone marrow transplant

Bone marrow or hematopoietic stem cell transplantation aims to replace the original diseased bone marrow with the healthy one and, in this way, ensure that the sick person heals completely or, at least, can keep the disease under control for a long time. . Transplantation is usually preceded by high doses of chemotherapy and radiotherapy, both of which are done to eliminate cancer cells and destroy the bone marrow. The allogeneic transplant (cells transplanted from a donor) induces prolonged clinical responses accompanied, in some of the patients, to a negativization of the residual disease, thanks to an immune-mediated effect. However, there may be negative consequences due to infectious complications and the reaction of the transplanted cells against the host organism: the donor's white blood cells attack and destroy the patient's cells. To prevent this complication, drugs are given to the patient before the transplant. suppress the activity of the immune system; or donated stem cells can be treated to remove the white blood cells causing the disorder, with a technique known as T cell depletion.

This treatment, which is in fact the only definitive cure for chronic lymphocytic leukemia, is rarely performed due to its aggressive nature. In fact, most people with chronic lymphocytic leukemia are elderly and the risks of the transplant itself may outweigh. the obtainable benefits.In patients of very advanced age it is preferred to use the non-myeloablative transplant (also called reduced intensity) which is performed without completely destroying the bone marrow.

Stem cell transplantation can be done alone or together with bone marrow transplantation. Stem cells can be taken from the blood, or bone marrow, of the patient himself (autologous transplant) to which they will be re-infused or from a compatible healthy donor, for example, from a brother, sister, parent or person. unrelated to the patient's family who, however, has the same type of tissue as the recipient (allogeneic transplant). Typically, the best candidate for donation is a brother or sister.

Other therapies

When chemotherapy is not effective, or cannot be used, other treatments can be used, sometimes also used to treat some of the complications caused by chronic lymphocytic leukemia:

          • radiotherapy, used to reduce enlargement of lymph nodes or spleen, or for palliative purposes, ie to reduce pain in people with advanced disease that does not respond to other therapies, or to prepare for stem cell transplant
          • surgery, to remove the overly enlarged spleen
          • antibiotic, antifungal and antiviral therapy, to reduce the risk of infections during treatment
          • blood transfusions, in case of severe anemia or haemorrhage
          • replacement therapy with immunoglobulins, transfusion of antibodies to counteract immunodeficiency and thus prevent infections
          • infusion of granulocyte colony-stimulating factor (G-CSF), to help increase the number of white blood cells

Given the invasiveness and high probability of causing undesirable effects of treatments for chronic lymphocytic leukemia, in some cases treatment is refused.In fact, the decision rests only with the patient who, once informed, will be able to consult without haste with the doctor and loved ones and choose whether to undergo treatment or only use pain therapy, at the appropriate time.

Clinical trials

Experimental clinical studies are always in progress with the aim of identifying more effective treatments, seeking personalized therapies, based on the characteristics of leukemic cells and non-tumor tissues that allow their growth (tumor microenvironment). The doctor responsible for the therapy may suggest taking part in a clinical trial, although the drug used may not yet have a marketing authorization from the competent authorities and, therefore, may not be available outside the trials. case, it is to be considered that there are no guarantees regarding the greater efficacy of the treatment offered compared to the therapies available. in which the available therapies are no longer effective and in any case when a potential benefit from the experimental therapy is possible.

Complications

Among the possible complications caused by chronic lymphocytic leukemia:

          • immunodeficiency, consists in the weakening of the defense system of the organism (immune system). It can expose you to a greater risk of infections and can occur either from a lack of healthy white blood cells or from the drugs used to treat the disease.In the presence of an "immunodeficiency, it is necessary to carefully follow the instructions of the attending physician, regularly take the doses of antibiotic prescribed to prevent bacterial infections, maintain good dental and personal hygiene, avoid contact with sick people, even if they have infectious diseases , such as measles or chickenpox, which you have already contracted before. In addition, it is important to report any complaints such as high fever, headache, muscle aches, diarrhea and fatigue, if they last over time, to your doctor. to do physical exercise and for your psychological well-being, it is important to avoid crowded places and public transport at peak times. Furthermore, it is good to make sure that you have had all the vaccinations
          • Richter's syndrome, in one in 20 people with chronic lymphocytic leukemia the disease progresses and becomes very similar to an aggressive form of non-Hodgkin's lymphoma called Richter's syndrome or Richter transformation. It manifests as sudden swelling of the lymph glands, fever, night sweats, unexplained weight loss, abdominal pain
          • autoimmune hemolytic anemia, about one in ten people with chronic lymphocytic leukemia develop a disease, called autoimmune haemolytic anemia, in which the immune system attacks and destroys red blood cells causing severe anemia and weakness (asthenia)

Psychological aspects of chronic lymphocytic leukemia

Discovering that you have chronic lymphocytic leukemia can be very painful emotionally, even more so if the disease has not yet caused problems and you are aware of having to wait years to learn about its evolution and effects. This can cause stress, anxiety and depression. with a counselor or psychologist can help combat these feelings and better cope with the situation by increasing the likelihood of recovery.

Living with

Coping with the diagnosis

It can be very difficult to deal with a diagnosis of chronic lymphocytic leukemia, both from a practical and an emotional point of view. However, the disease generally progresses very slowly and can be effectively treated and kept under control for a very long time.

How does the physical appearance change

Some drugs used for the therapy of chronic lymphocytic leukemia they can cause physical changes that are difficult to accept and that can in some way influence the perception of oneself and the relationship with others. However, the most common effects can be reduced with the help of complementary treatments.

Coping with chronic lymphocytic leukemia in practice

Just as the diagnosis must be faced from an emotional point of view, so too must work to manage the practical aspects of life, from economic issues to family ones, up to strictly personal ones. Who is the diagnosis received communicated to? How can this be explained? It is not necessary to face and solve everything on your own and all at once, and an interview with the doctor or the specialized nurse can help.

Bibliography

Cancer Research UK. Living with Chronic Myeloid Leukaemia (CML) (English)

NHS. Chronic lymphocytic leukaemia (English)

Delgado J, Nadeu F, Colomer D, Campo E. Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies. Haematological 2020;105:2205-2217

Further links

Italian Association for Cancer Research (AIRC). Chronic lymphocytic leukemia

Italian Association of Cancer Patients, Relatives and Friends (AIMaC). Chronic lymphocytic leukemia

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