CHRONIC LYMPHOCYTIC LEUKEMIA – [Case Study]
INTRODUCTION
Chronic Lymphocytic Leukemia/SML is a mature B cell neoplasm characterized by the progressive accumulation of B-monoclonal lymphocytes. A cell neoplasm characterized by increased cell accumulation. Chronic Lymphocytic Leukemia CLL is considered similar to non-Hodgkin lymphoma SLL (i.e. one disorder with multiple manifestations). The CLL and SLL malignant cells have the same pathological and immune-phenotypic characteristics. The term CLL is used when the disease is mostly found in the blood. When it is mostly nodal, the term SLL is used.
James is a 65 years old man and has been feeling tired the past few months. The patient did not have any personal or family history of cancer, but CLL has been diagnosed based on positive neoplastic cells.
The CLL / SLL will be investigated here for its epidemiology, clinical appearance, pathological symptoms, diagnosis, and differential diagnosis. Cell and molecular biology are discussed separately as well as the treatment of CLL / SLL.
EPIDEMIOLOGY OF CHRONIC LYMPHOCYTIC LEUKEMIA
CLL / SLL, which accounts for approximately 25 to 30% of all United States leukemia in adults in western countries, is the most common leukemia. The disease is more common in males with a ratio of approximately 1.3:1 to 1.7:1 between males and females. There are nearly 6.75 incidences of women and men in the USA and 3.65 cases per 100,000 populations annually. The incidence rates in Europe are 5.87 and 4.01 cases per 100,000 populations per year (SEER, 2018). In Europe, the figures are expected to be 21,040 new CLL / SLL cases, 12,930 for males and 8,110 for females. In the United States by 2020, about 191,000 cases and 61,000 deaths are due to CLL / SLL worldwide annually. Less than 10% of patients with a nodal involvement (i.e. SLL) non-leukemic picture; less than 5% of all non-Hodgkin lymphomas are present (www.uptodate.com, n.d.). CLL / SLL is considered primarily an elderly disease with a median age at diagnosis of about 70 years, but the diagnosis in younger people (e.g. 30 to 39 years of age) is not rare. With rising age, the incidence increases rapidly (SEER, 2018).
CELLULAR & MOLECULAR BACKGROUND FOR THE DEVELOPMENT OF CLL
Cellular Background
The frequency of CLL is significantly affected by geographically. CLL is the most prevalent adult B-cell leukemia of the western world in elderly patients, but less severe in African or Asian patients. Even though there is uncertainty about exactly the cellular origin of CLL, about half of all cases of CLL have unmutated IgV (CLL) genes (Jeon and Cho, 2016, P433). Somatically mutated IgV genes (MCL) are present in the remaining cases. This distinction has a biologic significance and therapeutic importance because it is more severe, and the time between diagnosis and initial treatment is significantly shorter.
To elucidate the pathobiology of the tumor, determining the cellular origin of CLL is important. Only then is it possible to disclose the whole natural course of the disease? The deregulations of gene expression and cellular functions are also important to understand (Jeon and Cho, 2016, P433). A lack or presence of IgV genes, respectively, in a post germinal nucleus, in CLL cellular origin is characterized by uCLL and mCLL of memory B-cells. Nonetheless, a derivative from uCLL (CD5+, CD27-CD38low) traditional native B cells was suggested based on a recent report for unique IgV gene rearrangements. (mCLL) is derived from a distinctive, previously unknown B-cell subset from post germinal centers (CD5+CD27+IgM+B-cell lymphoma[ BC] 6mutIgVHmut).
Source: (Gaidano, Foà and Dalla-Favera, 2012, P343)
Molecular Background
Source: (Ferrer and Montserrat, 2018)
PATIENT INFORMATION
James is a 65-year-old man who has taken laboratory tests and has been told to see his doctor based on initial test results. There have not been acute signs or loss of weight, but in the past few months, he has been feeling more tired. There was no personal or family history for the individual. Physical examination is unremarkable. There is no palpable lymphadenopathy on physical examination.
CLINICAL PRESENTATION AND DIAGNOSIS OF CLL
There are some symptoms and signs seen in James with chronic lymphocytic leukemia (CLL). The initiation is gradual and it is not unusual to find out about CLL when a blood cell count is performed for another cause (Shahjahani et al., 2015, P931). At presentation, 25-50 percent of patients are granulocytes. Enlarged lymph nodes, seen in 75% of James who are symptomatic when diagnosed, are the most common symptoms. Repeated infections including pneumonia, herpes simplex labialis, and herpes zoster may be observed. An enlarged spleen can entail early saturation and/or abdominal discomfort (emedicine.medscape.com, n.d.).
Thrombocytopenia can result in mucocutaneous bleeding and/or petechiae. Tiredness and weakness can be due to anemia; acute hemolytic anemia occurs in 10% of patients with CLL.
The transformation of CLL into an active large B-cell lymphoma is called Richter’s syndrome or transformation of Richter and is seen in approximately 3-10% of the cases (Cancer.org, 2016). Symptoms of fatigue, sweat, muscle loss (i.e. B) or decreased hepatosplenomegaly will frequently occur in patients. Median survival in months remains difficult, with poor prognosis (Kogan, 2018, P515).
Tests used to diagnose and classify leukemia
The full blood count or CBC calculates the different blood cells, including the red blood cells, the white blood cells, the platelets, so you will learn more about other tests. In the case of James, the Flow Cytometry test has been performed. This test is critical for the diagnosis of CLL. It uses a computer that checks for certain substances (markers) in or on cells to classify which cell types they are. This test can be used to determine that CLL cells contain the lymphocytes in a blood sample (Kogan, 2018, P515). CLL cells in the bone marrows or other fluids can also be looked up using Flow cytometry. Prognostic indicators are assessed as an isolated del 13q abnormality detected by FISH and Immunoglobulin.
The chromosome check can be used to analyze cell chromosomes and the DNA without the cells developing in the laboratory.
Fluorescent in situ hybridization (FISH)
They only bind certain parts of certain chromosomes with special fluorescent teeth. FISH is used to look for specific genes or modifications of the chromosome (not changes) (Rahimi et al., 2017). It may also be used in routine samples of blood or bone marrow (Cancer.org, 2016). Since the cells don’t need to develop first in a laboratory, often within a few days, the results can be obtained quicker than cytogenesis (Xu et al., 2017, P430).
Molecular tests
The immunoglobulins are light chains and heavy chains that help your body fight infections. It can help your doctor to know how aggressive your CLL is whether the gene has modified for the heavy chain variable region (IGHV or IgV H) immunoglobulin. The gene is tested in a cDNA sequencing study (Rahimi et al., 2017, P217).
Watch and wait/active surveillance for early-stage CLL
Patients with signs and/or high blood CLL, lymph nodes and spleen often have to be treated immediately after diagnosis. However, no immediate therapy is required for other patients. It is recommended that the disease be carefully monitored without active treatment for these individuals. For patients with early-stage depression and no signs, this is the standard approach. This approach could be difficult to understand and stressful. Patients may, however, discover that their concerns regarding this strategy decrease over time.
During this time, the blood count of the patient is carefully monitored and regular physical examinations are performed. Active treatment would then continue if the CLL shows signs of deterioration. Results of the study show that there is no risk to the early-stage CLL treatment also referred to as active surveillance or watchful waiting. Over the years or even decades, most patients do not develop symptoms and do not need medication. Such patients may only have to be tested every 3 to 6 months if the blood count varies over a few months or years.
IMPORTANCE OF PROGNOSTIC INDICATOR
Numerous studies have strengthened our knowledge of CLL biology over the last 10 to 15 years. Many of those studies have also contributed to the discovery of different prognosis factors to stratify patients into categories of risk (Rodrigues et al., 2016, P346).
- Clinical Makers
The Rai clinical staging method is the first prognostic marker for the clinical management of CLL. Lymphadenopathy and biliopathy (anemia and thrombocytopenia) are used for evaluating five stable classes that can be used to estimate median survival: stage 0, > 150 months; stage I, 101 months; stage II, 71 months. Three classes of patients represent low risk (stage 0), sporadic risk (stage I and II) and high risk (stage III and IV) are stratified. This system was eventually followed by the 1981 Binet inspection system. The possible markers for prognosis also include age, gender, replication of the lymphocyte, the pattern of involvement in bone marrow (Johansson et al. 2010). Only age and lymphocyte replication time were taken into account in the treatment decisions of these prognostic markers. Within the revised recommendations on the diagnosis and treatment of CLL, a lymphocyte doubling duration of fewer than six months is cited as an indicator for treatment (Rodrigues et al., 2016, P346). Although age is not the determinant of when care should be provided for a patient, it can affect the type of treatment, because comorbidity with age can reduce a patient’s toxicity to chemotherapy.
- CD38
CD38 is a glycoprotein trans-mixed in B-cell precursors, B Germ Center and plasma cells with low expression in circulating B-cells, which is usually expressed to high levels. In CLL, it was originally established that a high surface CD38 expression correlated to unmodified IgHV. CD38 positivity threshold was polarized and, while most studies have now used 30%, the expression of CLL in CD38 during the clinical course of the disease was found to be intermittent and variable (Parker and Strout, 2011). Also, 28 percent of patients are experiencing discordance between IgHV mutation and CD38 expression. CD38 cannot, therefore, be used for IgHV mutational status as a valid replacement marker.
- ZAP-70
ZAP-70 is an independent outcome predictor and could be a better time predictor for initiating care as opposed to CD38 and Rassenti et al., 2008, IgHV mutation. ZAP-70, unlike CD38, is relatively stable in expression over time and is calculated in cytometric flow (Poulain et al. 2007). ZAP-70 expression was used as a predictor of aggressive disease, together with CD38 and Ighv mutation status (Morilla et al., 2008), and it has been proposed that these patients may benefit from close surveillance (Rassenti et al., 2008). CD38+ ZAP-70+ unchanged CLL cells are more receptive than their mutated IgHV equivalent from the biológical point of view to B cell receptor stimulation. This leads to the subsequent activation, with the proliferation of CLL cells, of a signal cascade involving LYN, SYK, ERK, and NF-SB. There is a chance of becoming very significant therapeutic indicators for pharmacological activation of these signaling pathways (Parker and Strout, 2011).
- Cytogenetic
Around 80% of individuals with CLL had chromosomal abnormalities within their malignant clone and can be classified into five prognostic groupings accordingly: deletion 13q (mediate survival, 133 months); deletion 11q (median survival, 79 months); trisomy 12 (median survival, 114 months) (Parker and Strout, 2011).
Deletion 13q: The most frequently found cytogenetic abnormality in CLL was ~55 percent of patients with Deletion 13q (Döhner et al., 2015). The existence of a long noncoding RNA, named DLEU2, which contains a microRNA (miR) cluster which expresses miR-15a and miR-16-1, has recently become apparent to researchers in the less deleted chromosome 13q14 region.
Deletion 11q: Removals (Parker and Strout, 2011) are found in about 18% of CLL cases, and are accompanied by a variety of adverse prognosis factors like severe lymphadenopathy, unchanged HIV / AIDS, advanced diagnostic illness, poor treatment response, and shorter progression-free survival. A vital gene ATM at the molecular level is usually located at chromosome 11q23 in the region deleted. This information shows that the current recommendation is for use in patients with 11q documented deletion in regimes involving both fludarabine and cyclophosphamide.
Trisomy 12: They are present in approximately 16% of CLL, and approximately 18% of CLL patients have normal cytogenetic (Parker and Strout, 2011). However, there is no evidence of molecular genetic defects in these risk groups. In trisomy generally, it is often believed that a candidate’s oncogene has a gene-dosage effect on the additional chromosome, but chromosome 12 does not yet recognize such a gene. It is also likely that in patients with trisomy no 12 as well as with normal cytogenetic, molecular mutations of the genes are still unknown. Such results do not affect the treatment of diseases beyond the standard of care as intermediate prognostic indicators.
MODERN THERAPEUTIC APPROACHES
The use of medications to kill cancer cells is a systemic treatment. A sort of medication is used in the bloodstream to enter the whole body’s cancer cells. The hematologist-oncologist usually recommends systemic therapies (www.seattlecca.org, n.d.).
Intravenous (IV) tube in the venous vein with needle or pill or tablet which is swallowed (orally) is normal for systemic therapy. Systemic therapy can also be done as a subcutaneous injection under the skin. The programs for CLL forms of treatments include:
Chemotherapy
Chemotherapy is a drug that destroys fast-growing cells and cancer cells. Chemotherapy may be offered via a vein or in the form of a pill. James’s doctor can use a single drug or you can take a mixture of drugs, depending on his condition (Cancer.Net, 2018).
Immunotherapy
Immunotherapy is a treatment using the immune system of your body to fight cancer. Immunotherapy can promote the identification of cancer cells or the training of cells in an immune system in cancer cell control for his immune system (Cancer.Net, 2018).
Transplant bone marrow or Stem Cell Therapy
A transplant of the bone marrow, also known as stem cell transplant, is used to destroy the stem cells in the bone marrow that produce diseased lymphocytes with strong chemotherapy. Then a donor infuses healthy adult blood stem cells into your blood to your bone and starts building healthy blood cells (Cancer.Net, 2018).
Bone marrow transplantation has become less popular in the treatment of chronic lymphocytic leukemia as new and more successful drug combinations have been created.
Molecular Therapy
Leukemia cells are being screened for certain genes, proteins, changes in chromosomes and leukemia-related factors. Since CLL cells divide very slowly, it is often less useful to display chromosomes than tests to determine other genetic modifications or modifications. In situ, genetic variations are identified by fluorescence testing and another genetic testing, including a polymerase chain reaction (Cancer.Net, 2018). The deletion of the long arm of CLL 13 [ del(13Q)], observed in around half of the patients, is part of the genetic change occurring in CLL.
- An extra copy of chromosome 12 (trisomy 12)
- del(11q)
- del(17p)
- NOTCH1 mutations
- SF3B1 mutations
- TP53 abnormalities
- MYD88 mutations
- IGVH, which may be important whether it is changed or unchanged
Genetic and molecular test results can assess the progression of the disease and can help to identify treatment options.
