Differentiating Between Chronic Leukaemia And Acute Leukaemia Biology Essay

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Leukaemia is the name given to a range of diseases that affect the bone marrow or haematological system through direct or indirect effect on white blood cell or white blood cell precursors (eg: B cell precursors) it is a serious disease that compromises the patients and is extremely life threatening , here it will be discussed how to identify the disease mainly from a haematological point of view for 3 types of the disease , other methods will also be discussed when differential diagnosis is required.

Leukaemia being the broad term to refer to these range of cancerous disease it can be broken down into specific types, Chronic or Acute Leukaemia.

Differentiating between Chronic Leukaemia (CL) and Acute Leukaemia(AL)-

AL Has an abrupt onset, whereas CL becomes apparent at a slower rate; AL has an incidence rate similar along all age groups , CL has the highest incidence in adults; CL presents leukocytosis (White blood cell count is high) , AL may or may not present leukocytosis; CL has blood films that present mostly mature white cells (eg: mature neutrophils) , AL blood films present mostly immature white blood cells(eg: monoblast) ;AL presents Anemia(decrease in the normal red blood cell count) neutropenia(very low number of neutrophils in the blood cell count) and Thrombocytopenia (low platelet count in the blood) ,CL is variable in regard to these symptoms;CL presents marked splenomegaly (spleen is enlarged from its normal 5cm to over 15 cm and therefore palpation of the spleen allows identification.) Hepatomegaly ( enlargement of the liver ).

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Here it will be discussed in the terms of two chronic and oneacute leukaemia, each will be discussed in terms of its aetiology, differential diagnosis, epidemiology and possible treatment options (not comprehensive, and, since treatment options are extensive and should be selected with a particular case in mind).

Chronic Myeloid Leukaemia-

Schematic representation of a chromosome translocationAetiology- Also known as Chronic granulocytic leukaemia, is a neoplastic condition (malign carcinoma), it is mainly associated with a translocation (alteration caused by a rearranging of segments in two non-homologous chromosomes) between chromosomes 9 and 22 ( t(9,22) ), this leads to the appearance of an truncated 22 chromosome , known as the Philadelphia chromosome (Ph) . Other factors can affect its atetiology such as radiation "People exposed to high levels of radiation in Hiroshima and Nagasaki at the time of and subsequent to the atomic bomb explosions in 1945 have shown and increased incidence of CML and other hematological disorders"(Mazza 1995 p. 239).Exposure to the known carcinogen ,benzene, shows no effect on the incidence "The meta-analysis indicated consistently a lack of association between benzene exposure and the risk of CML"(Khalade et al 2010)

Diagnosis- The disease can be diagnosed by doing a blood film (blood count and film can be sufficient for the diagnosis) there is a higher granulocyte production , marked increase in leukocyte numbers (leukocytosis) with a higher number of myelocytes and mature neutrophils, Basophils increase and eosinophils increase in roughly 80% of the cases . There is therefore a higher increase in granulocyte lineage related cells.

Provided the blood count and blood film are insufficient for diagnosis a bone marrow analysis can be done in order to detect the t(9,22) translocation in the chromossomes , also genetic analysis can be done to detect the gene that results from the chromosomal translocation (c-abl ,abelson leukaemia gene,present on chromosome 9 and bcr, breakpoint cluster region gene, on chromosome 22 ) , gene translocation referred as the BCR-ABL fusion["(...)Ph Chromossome in at least 90% of the patients with CML. (...) Flourescense in situ hybridization and reverse transcriptase polymerase chain reaction(RT-PCR) confirm the presence of the bcr-abl fusion gene in the majority of the remaining CML patients"](Petruzelli, Schmaier 2003) , in order to diagnose, this is especially beneficial when the t(9,22) translocation wasn't found but other symptoms suggest Chronic Myeloid Leukaemia, Low or absent leukocyte alkaline phosphate score allows to differentiate, along with the genetic markers, between CML and a leukemoid reaction(increase in the white blood cell count associated with another non-cancerous disease or infection) , there is also increased spleen and liver size (splenomegaly and hepatomegaly)as the clonal stem cells seed in them. Other symptoms may be present ["Common findings include fatigue, weight loss, low-grade fever, normocytic, normochromic anemia, night sweats, and spleenomegaly."](Ciesla 2007) and the symptoms will become more apparent as the disease progresses.

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Since haematological findings differ as the disease progresses this is particularly helpful since this allows identification of which particular stage the disease is currently at ,treatment options may differ depending on the stage, therefore the blood smears and bone marrow aspirates can aid in the identification of which phase the disease has progressed to(chronic, accelerated or blast phase):

Findings during Chronic Phase- While processing blood smears there is clear increase in the white blood cell count, presence of blast ,with presence of neutrophils and myelocytes , increased numbers of basophils and eosinophils , with granulocytic precursors present also , there is also mild anemia (reduced red blood cell count) ,thrombocytosis (high platelet count in the blood) is also present during the chronic phase of some patients . Through analysis of the bone marrow aspirate myeloid hyperplasia (change from normal fatty bone marrow in the adult to normal red marrow)["The myeloid-to-erythroid (M:E) ratio is 10:1 and can be as high as 25:1.A normal M:E ratio is 3:1The bone marrow may become fibrotic as disease progresses"](Ciesla 2007) can be present with increased immature basophils , increased megakaryocites and reduced erythrocytes there is also presence of blasts (under 5%). The identification of the disease during chronic phase is the most likely since it can be identified through routine tests such as white blood cell counts that may suggest that a more severe haematological problem is present, after diagnosis immediate action should be taken to prevent it to progress further.

Findings during Accelerated Phase- By blood smear analysis there is a increase in granulocytic precursors (promyelocytes) with an increase in the Blast count , basophils increase further accounting for over 20% of the cells in the smear, anemia becomes more pronounced and there is also chance of persistent thrombocytopenia (low platelet count in the blood). Through analising the bone marrow findings such as fibrosis of the bone marrow tissue , increased presence of blasts (5% to 20%),increased basophils and megakaryocytes. Diagnosis during the Accelerated Phase is less common , but if it occurs immediate action should be taken to attempt to archieve haematological remission and manage to get the patients into an stable Chronic Phase and not allowing the disease to progress further into a Blast crisis, prognosis of the patients relies on accurate approach against the disease with emphasis on what stage the patient is currently at time of treatment.

Findings during Blast Phase-The blood film analysis will show the characteristic increase in Blasts (over 30% must be blast in either the peripheral blood of bone marrow to clinically classify the patient under a blast crisis [Petruzelli, Schmaier 2003]), there is also a increase in promyelocytes, basophils and eosinophils (all granulocytic and granulocytic precursor white blood cells hence the disease also being known as Chronic Granulocytic Leukaemia), there is also occurrence of thrombocytopenia. The disease should be caught before the blast crisis has set in , since most of the patients that enter the blast crisis are less likely to undergo haematological remission, and also the prognosis of patients that enter the blast crisis is not promising , being the phase with the highest mortality rate in the disease therefore disease needs to be caught early to prevent it to progress further and prevent the blast crisis altogether.

Exact diagnosis of this particular type of leukaemia is essential since it can easily progress into Acute Leukaemia(Petruzelli, Schmaier 2003) and early differential treatment can be very effective.

Treatment-To effectively treat CML there is a number of treatments that will be administered during different stages of the disease ,such as the use of myelosuppressive agents, agents capable of inducing bone marrow inhibition which leads to a reduction in the production of blood cells and platelets, during the chronic phase in order to extend the chronic phase as long as possible and aiming to induce clinical remission(the disappearance of the symptoms, will improve the patient`s prognosis or become permanent in which case the patient is cured) , myelosuppressive drugs such as busulfan[ this is also an alkylating agent therefore is associated with inducing second malignancies through long term use(eg: Acute myeloid leukaemia ) therefore it is the less desirable myelosuppressive drug ,despite its potent myelosuppressant properties] , hydroxyurea [this works as an inhibitor of deoxynucleotide synthesis (ribonucleutide reductase inhibitor) and is not associated with second malignancies induction and can be administered instead of busulfan to maintain the chronic phase for longer while having comparable results in the reduction of leukocytosis {"Several studies have shown a survival advantage for patients treated with hydroxyurea rather than busulfan"}(Mazza 1995) therefore it would be more desirable for maintainance of the chronic phase] and interferon-α [protein drug with antiviral and antiproliferative properties , it is administered by subcutaneous injection (injection just below the adipose tissue of the skin ) {"Evidence has been accumulated through clinical trials that suggest that, compared with hydroxyurea or busulfan, IFN-α can increase life expectancy, with a 5-year survival rate of 50% to 59%, compared with 29% to 44% in those treated with hydroxyurea or busulfan."} (Mazza 1995) it is the most effective in comparison with the other myelosuppressors therefore it is preferable provided the patients are willing to comply due to its side effects( depression, neuropathy, flu-like syndrome among others) and since it acts as a CML chrome suppressant it delays progression of the disease and has a reasonable cytogenetic remission rate (decrease in the Ph chromosome positive cells), this can be improved by the adittion of cytarabine as stated by Petruzzelli and Schmaier (2003) "The addition of cytarabine to IFN-α increases the cytogenic remission rate and overall survival of stable phase CML patients compared to IFN-α alone"] , Pherisis ( physical removal of white blood cells or platelets) is another option during the chronic phase, Allogeneic Hematopoietic Stem Cell (HSC) transplant is also desirable since this can effectively cure the disease during the chronic phase, also during the first choice therapy currently would be the use of a Signal Transduction Inhibitor , such as tyrosine kinase inhibitor (eg: imatinib mesylate) this acts by inhibiting the ATP binding site of the bcr-abl fusion gene through competitive inhibition therefore interfering with intracellular factors therefore stoping the proliferation of the leukemic clone, this leads to a dramatic reduction in the cell count of the patients , cytogenetic and clinical remission (disappearance of the Ph chromosome from the cells , and normalisation of symptoms) therefore becoming the preferred treatment method. Graph Showing Age-Adjusted SEER Incidence Rates By Sex Chronic Myeloid Leukemia, All Ages, All Races, 1992-2007 (SEER 13)

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Epidemiology- Incidence of the disease occurs mainly at adolescence to old age, although it can occur at any age cases on children seldom occur, there is also a higher ratio of men affected by the disease ,1.4:1 ratio (Petruzelli, Schmaier 2003)the peak incidence is on patients aged 40-50 (Mazza 1995), Graph on the right provides incidence rate that shows difference in the incidence between male and female patients.

Treatment with myelosupressant drugs (busulfan , hydroxyurea or Interferon-α) or tyrosine kinase inhibitors to archieve remission at the fastest rate possible.

Leukocytosis may be found in routine blood count for minor symptomsGraph:http://seer.cancer.gov/faststats/selections.php?run=runit&output=1&data=1&statistic=1&cancer=90&year=201002&race=1&age=1&subSite=97&series=sex&sex=1;2;3[Accessed 17 October 2010]

Complete physical examination , if spleenomegaly or hepatomegaly present do an ultrasound to asses degree of organomegaly

Patient will either enter clinical remission which can be permanent, undergo temporary remission and remain in a stable chronic or have the disease progress further into an accelerated phase or blast crisis.

Bone marrow aspirate for cytogenetic analysis, and if required for Flourescense in situ hybridisation to verify presence of BRC-ABL gene.

Blood film analysis to asses presence of granulocytic lineage White Blood Cells.

(McCann, Smith et al 2009)

Chronic Lymphocytic Leukaemia-

Aetiology- This disease arises from small lymphocytes of B lineage that readily circulate through bone marrow, spleen and lymph nodes and has numerous aetiological factors that can affect its incidence, genetic factors are present since families affected by CLL have presented a higher incidence rate among themselves, 2 to 3 times the normal incidence rate in relation to the rates of general population for their geographic location (Mazza 1995), the presence of immunodeficiency (eg: by being HIV positive)syndromes is associated with a increased chance of lymphoproliferative disorders ,probably due to the reduced function of the immune system which may result in proliferation of the malignant cell clones. The genetical involvement of the p53 tumour suppressant gene that is affected by the abnormalities of 13q14-23.1 gene , deletion of 11q22.3-23 , 6q21-23 and deletion or mutations of 17q13 (Mazza 1995) this is also involves trisomy 12 , and has chromosomal involvement of chromosomes 11 and 13 also (Ciesla 2007).There is also factors such as carcinogen agents exposure which can increase the rate of incidence , such as benzene ["Our study provides consistent evidence that exposure to benzene at work increases the risk of leukemia with a dose-response pattern. There was some evidence of an increased risk of AML and CLL"](Khalade et al 2010) .

Diagnosis -The first signs that will be present will be those of fatigue and reduced exercise tolerance, there is also fever , bruising and noticeable weight loss; Splenomegaly and hepatomegaly can be present aswell along with the enlargement of the lymph nodes (Lymphadenopathy) carefull examination of these should be done ,splenomegaly and hepatomegaly if not palpable can be assessed through the use of ultrasound to verify and asses the degree of organomegaly , in the case of Lymphadenophaty it can be analised through computer tomography (CT) scan of the thorax to observe if the mediastinal lymph nodes (H) are enlarged (McCann et al 2009).Blood films can aid in the diagnosis process to verify the diagnosis of the disease , there is low count of erythrocytes (anemia) , possibly caused due to the lymphocyte infiltration of the bone marrow (Mazza 1995), cells will be predominantly from B lineage(the norm is T cells), the B lymphocites in the analysis have expressed immunoglobulin (Ig) on their cell surface with single light chains only,κ or λ(McCann et al 2009), lymphocytosis is clearly present on the blood films and have a clear increase in small mature lymphocytes with clumpy nuclear chromatin(when these are viewed on a blood smear since they are easily ruptured they may appear smudged)the malignant cells look the same and share antigenic profiles therefore can difficult the differentiation process, there is also a high nucleus to cytoplasm ratio, cytoplasm is granular and might contain crystal formations, the cells also can present a marker (CD5) in their surface therefore aiding in the diagnosis process, also on some cases where lymphocyte infiltrated bone marrow is affected thrombocytopenia(low platelet count) occurs. It is also worth noting that at early stages there may be no notorious physical findings.

Treatment-For the treatment of the disease alkylating agents can be used (eg:busulfan) , irradiation of the lymph nodes and the spleen can be done in order to reduce discomfort (Ciesla 2007) treatment for this disease should also use a combination of chemotherapeutic agents done with combinations of chemotherapeutic agents,Purine nucleoside analogues are very effective in the management of Chronic Lymphocytic Leukaemia (eg:Fludarabine) being superior to alkylating agents on the short term but not on overall survival (Mazza 1995), and monoclonal antibodies (eg:Rituximab), stem cell transplantation and surgical procedures such as Splenectomy(partial or complete removal of the spleen) can also be used in the management of the disease. Also since the progress of the disease is often slow, if found on an early stage on an elderly patient it may be worth not treating as the patient may live a normal life for a reasonable time(Mazza 1995), treatments for Chronic Lymphocytic Leukaemia are undergoing a fast improvement as different ways of interacting with oncogenes (eg :anti-CD20 monoclonal antibodies like Rituximab and Ofatumubab) .Graph Showing Age-Adjusted SEER Incidence Rates By Age At Diagnosis/Death Chronic Lymphocytic Leukemia, All Races, Both Sexes 1975-2007 (SEER 9)

Epidemiology-The disease is known to affect mainly the middle-aged and the elderly, and as it can be seen in the statistics ,obtained at the USA National Cancer Institute website ,there is a clear trend in the increase in the incidence of the disease as the patients are older (it is also worth noting that there were less than 16 cases for under 20 year olds)therefore there being a clear correlation between old age and incidence rate of Chronic Lymphocytic Leukaemia.

Provided the disease is at early stages the patient may not require any form of treatment, and manage to live for a reasonable amount of time without problems, therefore no treatment is also an option

Analisis to see if certain genetic markers are found (CD5, CD20)

Patient presents with complaints about lack of energy ,decreased exercise tolerance ,fever and/or unexplained weight lossGraph2[http://seer.cancer.gov/faststats/selections.php?run=runit&output=1&data=1&statistic=1&cancer=90&year=201001&race=1&sex=1&subSite=93&series=age&age=15;75;141;160;166](Accessed 20 October 2010)

After Chronic Lymphocytic Leukaemia is confirmed patient can undergo treatment that is most suitable

Analisis and palpation to see if there is splenomegaly and/or hepatomegaly, also asses if there is lymphadenopaty either through palpation or CT scan

Surgical measures may be taken , patient can undergo surgical procedures like splenectomy , irradiation of the spleen and lymph nodes is also a viable treatment.

Combination of chemotherapeutic agents , alkylating agents or use of monoclonal antibodies can be used as treatment.

Assesment of the peripheral blood to observe B precursor presence in the blood sample, anemia may also be present

Acute Myeloid Leukaemia -

Aetiology-Acute Myeloid Leukaemia may be caused due to numerous factors , leukemogen action such as ionising radiation can increase the incidence of AML "Also, patients treated with spinal radiation therapy for ankylosing epondylitis between 1935 and 1954 had a fivefold increased risk of developing AML" (Petruzelli, Schmaier 2003), Benzene is also a known carcinogen and can increase the incidence of AML (Khalade et al 2010) , also as was previously discussed the treatment of some diseases by using alkylating agents (busulfan) can induce AML and myeloproliferative disorders , such as Chronic Myeloid Leukaemia, can progress into AML. Patients that have chromosomal breakage related disorders [down syndrome(trisomy 21) fanconi anemia, bloom syndrome] are also more susceptible to the disease (Petruzelli, Schmaier 2003).

Diagnosis-In order to diagnose AML there are different methods that need to be implemented , as preliminary diagnosis a blood film should be done , in it the blasts must account for over 30% of nucleated cells, blasts can be recognised due to their large size and morphological analisis in the Wright-Giemsa Stained smears , to be considered Acute myeloid leukaemia, to confirm the diagnosis since morphological details may not sufficient in the Wright-Giemsa stained smears (from samples taken from the blood marrow and peripheral blood)to differentiate between AML or Acute Lymphoblastic leukaemia histochemical stains can be used to accurately define and identify lineage specific markers (eg: myeloperoxidase ) .Sometimes a tumour mass (chloroma or cranulocytic sarcoma) may be present (Mazza 1995), other methods of confirming the diagnosis can be through immunophenotyping ,by the use of flow cytometry , by confirming the expression of certain genes (CD 13 , CD33, CD9, CD11b, CD14, CD15, CD33, CD34, CD117) and also the presense of terminal deoxynucleotidyl transferase (TdT) (Mazza 1995) . Cytogenetic karyotyping can also help in the identification ( by demonstrating the translocation t(8;21) , q22;q22 and 16q22) it can also help identify when it may have been caused by exposure to alkylating agents "Abnormalities of chromosomes 5 and 7 (del 5q, del 7q) are commonly seen in alkylating agent-related AML or in elderly patients with de novo AML"(Mazza 1995). The disease is classified into eight morphological subtypes (depending on White blood cell morphology) to aid in diagnosis:

m0- Undifferentiated

m1-Granulocytic, little maturation

m2-Granulocytic, with maturation

m3-Progranulocytic(also hypogranular on the m3 variant)

m4-Monoblastic

m5-Monoblastic and Monocytic

m6-Erythoblastic

m7-Megakaryoblastic

Treatment- As the disease can present multidrug resistance and it is difficult to treat the treatment process can be defined in two stages, induction therapy and postremission therapy. During the induction therapy intravenous application of anthracycline drug daunorubicin plus cytarabine,by intravenous infusion should be administered in order to obtain complete level of haematological remission (less than 5% blasts in bone marrow) (Petruzelli, Schmaier 2003),it has very high levels of toxicity so not all patients respond to it effectively.During the postremisson therapy intensification of induction therapy chemotherapy can be done (high dose cytarabine intravenous infusions) , allogeneic bone marrow transplantation and autologous bone marrow transplantation can be done to effectively complete the postremission therapy and hopefully cure the patient.M:\My Documents\faststats.jpg

Epidemiology: The disease has cases from the neonatal period to old age, with increased incidence as age progresses It is also worth noting that Males have twice the odds of contracting the disease.

Graph 3 http://seer.cancer.gov/faststats/selections.php?run=runit&output=1&data=1&statistic=1&cancer=90&year=201001&race=1&sex=1&subSite=96&series=age&age=15;75;141;160;166 [Accessed 20 October 2010]

Ac

Blood count, more than 30% of nucleated cells are blasts

Induction Therapy - cytarabine intravenous infusions and intravenous daunorubicin

Immunnophenotyping (CD 13, CD 33, CD 117 found) cytogenetic karyotyping (t(8;21) and histochemical analisis of cell lineage must be done

Postremission therapy - high dose cytarabine intravenous infusions, allogeneic bone marrow transplantation and autologous bone marrow transplantation

Acute Myeloid Leukaemia is confirmed and treatment must be immediate

http://globocan.iarc.fr/data/GLOBOCAN_MAP2_607466.png

Conclusion : Leukaemia has many diagnostic methods that can be utilised to identify which type it is, and treatments have been developed to counteract the leukaemia on a specific level (as seen with tyrosine kinase ATP site inhibitor imatinib mesylate)therefore the importance of accurate and early diagnostics have been seen , since the prognosis for patients is better as the disease is diagnosed in an earlier phase, and accurately ,so that disease-specific treatments can be provided and complete remission without relapse occurs. Also epidemiological data suggests that leukaemia can affect us as early as neonatal period until our elderly age therefore there is a lifelong chance that someone may develop leukaemia hence showing the importance of knowing how to identify and treat the disease so that survival rates can increase.

http://globocan.iarc.fr/data/GLOBOCAN_MAP2_74039850.png

Maps taken from [World Health Organization, 2010. Globocan Project 2008[online] Available at: < http://globocan.iarc.fr/> [Accessed 14 October 2010]]

Carlos Andres Mariscal Melgar , 1st year Bsc(Hons)Biomedical Science student.