It is important to note that cancer start immediately the cell within the body tries to develop out of control. Therefore, the cells can spread to other sections of the body, making the whole body to become cancerous. Chronic myeloid leukemia (CML), may be considered as a paradigm in the current ontology. CML is commonly referred to as chronic myelogenous leukemia. CML is a type of cancer that begins when some blood-forming cell of the bone marrow. For the case of CML, the genetic adjustments take place an initial (immature) stage of the myeloid cells: these cells are the ones responsible for making red blood cell, platelet and other types of white blood cell. The myeloid cells do not make up the lymphocytes. Usually, these adjustments of the change forms result in an abnormal gene known as BCR-ABL, which changes the cell to a CML cell. The genetic fusion in the BCR-ABL leads to the formation of protein with unusual tyrosine kinase element which is regarded as a pathogenic factor contributing to the existence of this disease (Miao et al. pg 53). As for the leukemia cell grow gradually within the bone marrow and spreading into the blood.
Meanwhile, the cell also spreads to other sections of the body, including the liver and spleen: research has shown that CML is a common leukemia and can often change to fast-growing acute leukemia which is challenging to treat. But what is leukemia?: this is a type of cancer which also starts within the blood-forming cell existing in the bone marrow. Whenever one of the cells remodels and become a leukemia cell, it does not grow the way it should. In most occasions, it does divide into the new cell as a quicker rate- these leukemia cells do not die as expected, but instead continue to build up in the bone marrow. For the case of acute, chronic leukemia, the cell mature partially, such cell may appear to be normal, but in the real sense, they are not.
These cells do not fight bacteria and microorganisms within the body as white blood cells. Studies have shown that leukemia cells tend to live longer compared to other functional cells. They cause abnormal crowding of the bone marrow resulting in severe problems. The result is the crowding out of the cells. At a given stage, the leukemia cells get out of the bone marrow and spread into the body bloodstream, causing the white blood cells (WBCs) to increase in their number. However, the leukemia cells can spill to other vital body organs and adversely affect the general functioning of the body.
Most importantly, unlike the other types of cancer that begins in the respective organs of the body, leukemia starts from the bone marrow and spills over the entire parts of the body system. Not all chronic leukemia is similar. Determining the specific type of leukemia assists professional healthcare providers to protect each patient’s prognosis and recommends the best treatment plans (Miao et al. pg 17).
The epidemiology and etiology
The CML is the disorder of myeloproliferation that is affecting the stem of hematopoietic cells. It is occurring within all various groups of ages though, predominantly it is the disease of the adults, which accounts for 20% leukemia within the adults. The data about the lack is very reliable, especially with the countries that are poor with their resources, the extrapolation of the data available suggest about the CML affecting the patients above 100,000 in total worldwide every year and represent the significant burden of health within the global. Therefore, the CML incidences have been approximated at 1 to 2 on every 100,000 of the population yearly.
Consequently, there have always been 10 to 12 cases about the CML (Eichhorst et al. pg 78). The age which is median for the leukemia presentation remains at between 45 and 55 years that account to 20% of adults being affected by the disease. According to the effect of leukemia, the people who are usually affected most are the males as compared to the females with the ratio of 2:1.
Pathology of Chronic Myelocytic Leukemia (CML)
The breakthrough in the pathogenesis e of CML was the Nowell’s landmark invention of the Ph chromosome and its links to the illness. The Ph chromosome is a result of the reciprocal transferring occurring between the elongated chromosomes of nine and twenty-two. The t(9;22)(q34;q11) frequently adds up three component of the ABL gene from the chromosome forming section of the BCR gene on the chromosome; the result is a hybrid BCR-ABL gene that is reproduced into a chimeric BCR-ABL messenger of the RNA. This ABL gene comprises of 11 exons, and the first exon constitutes two variants, namely 1a and 1b. This gene inscribes an endless expressed, a non-receptor tyrosine kinase with an approximate molar mass of 145KD. The isoforms of the ABL genes are usually derived for the explicit spilling of the initial exon. The breakpoint stage of the ABL gene can happen in a section which is largest the 300kilobase, but often before exon 2. The ABL exons that are 2 to 1 are put in the part of the BCR sections. The main breakpoint cluster section (M-bar) of the BCR gene existing in the chromosome (22) is situated between the exon 12 and 16 and often extends to about 3.5kb. The fusion of the two components, namely: b2a2 and b3a2, are formed and each translated into a chimeric protein commonly known as 210kD. In 95% BCR-ABL present in the CML, chance are the leukemic cells can comprise of b2a2 or b3a2 transcripts, and the remaining percentage (5%) can result in alternative spilling events which result in the expression of both the fusion elements (Eichhorst et al. pg 78). The prognosis and treatment for CML patients and similar to patients with b2a2 and b3a2 transcripts, with higher amounts of platelets for patients with b3a2 transcripts.
The BCR-ABL protein
The leukemogenic potential of the BCR-ABL takes place due to the fact that the tyrosine kinase activities of the ABL protein are usually controlled within the activated combination of the oncoprotein. It is important to note that the ABL proteins are non-receptor tyrosine kinase which plays a vital role when it comes on signal transfer and control of cell growth (). There exist two isoforms within the ABL, namely: isoform 1a and isoform 1b, these isoforms are often sown at the higher level of hematopoietic progenitor cell activities. Moreover, the isoforms are situated at the glycine residue of the N-sections. Failure of the myristoylation process to occur in the ABL encourages the events of the tyrosine kinase (Zhao et al. pg 23). At the lower part of the myristoylation site- that is the N-terminal component of the ABL, exists three SRC homology domains, which are: SH3, SH2, and SH1. The SH2 and SH3 do control the function of the tyrosine kinase of ABL, whereas the SH1 exhibits the activities of the tyrosine kinase. Often, the SH3 hurts the functions of the tyrosine kinase. – in other words, the removal of the SH3 enhances the activities of the tyrosine kinase. The deformations of the functional capability of SH2 reduce phosphotyrosine binding and equally decrease the transformation abilities of the ABL (Rinaldi et al. 37). Mainly, the C-section of the ABL comprises of the DNA binding domain, localized nuclear signals as well as a binding site for reactions. Usually, the disorganization of the ABL protein through genetic fusions is responsible for the up monitoring of the tyrosine kinase activities.
The unregulated functions of the tyrosine kinase of the BCR-ABL are also as a result of the misalignment of the alien in the following constituents of the BCR. This N-terminal coiled-coil feature of the BCR enhances the dimerization process and improves the activity of the BCR-ABL tyrosine kinase activities, thus enabling the combining of the F-actin to the ABL. Usually, the serine-threonine kinase section of the BCR enhances the signaling of the different routes enhanced by the BCR-ABL tyrosine kinase. The BCR also comprises of the SH2 binding parts which encourage fusion of the ABL to the higher amino acid and subsequent sections of the ABL. The presence of the BCR in the neighboring SH3 and SH2 domains results in the ABL becoming a useful active site for tyrosine phosphokinase.
Signaling routes/ways for the BCR-ABL
The anatomy of the BCR-ABL enable many protein interactions to take place-such communications comprises of diverse intracellular signaling routes. Most importantly many domains present in the BCR-ABL are crucial when it comes to binding of the adapter protein as well as receptor-bound proteins. The elements such as CBL, SRC, and SHC, homology protein are involved in the control of the cell proliferation as well as differentiation, which serves a vital role for signal pathways during the pathogeneses process of the CML. The signaling incidences of the RAS are noted well grouped and therefore may constitute the nitrogen-activated protein kinases, for instance, the JUN kinase and so forth. The activation of the SHC protein-which combines the SH2 and SH3 segments of the BCR-ABL can also commence the signal transformation of the RAS signaling routes. Besides, the signal transducer and transcripts activate of the JAK/STAT5 routes are directly linked to the BCR-ABL, and is always independent of the RAS signaling routes. Such pathways often result in uncontrolled regulations of the apoptotic proteins which in turn results in pro-myogenic as well as anti-apoptotic signals. Several research and studies have examined the signaling pathways of the BCR-ABL. In this view, we can note that the unregulated kinase functions of the BCR-ABL does result in the cell proliferation and reduced adherence of the leukemic cell within the bone marrow stroma.
Stages of Chronic Myeloid Leukemia
The phases of The CML are categorized into three components. Physicians and clinicians do keenly observe these stages of the disease. It is important to note that the stages are usually based primarily on the number of immature white blasts blood cells present within the bone marrow (Rinaldi et al. 49). Several groups of researchers have come up with different suggestions that define and explain the stages of the CML. Although not all doctors conform to the cutoff points of the phases of the CML, the World Health Organization (WHO) predicts that necessary measures should be put in place to address the challenges that come with this particular disease. The phases of CML include:
Generally, many patients (constituting about 85%) are diagnosed with CML at the chronic stage; this phase is also commonly referred to as a stable stage. Usually, the patient at the chronic stage typically has lesser amounts of blasts within the bone marrow or blood- approximately less than 10% of the total blast. At this phase, the patient often has mild signs and symptoms and can respond to planned treatments. The signs and symptoms at this phase include but not limited to: fatigue, weight losses, abdominal fullness, paints within the joints and left hip and so forth. Nevertheless, the majority of the patient are in a better position to live a usual life and cannot be significantly affected by this health condition. This phase is considered stable given that it can for a considerable amount of time and depending on elements, for instance, diagnosis as well as treatment techniques employed.
Majority of patients are considered to be in the accelerated phase of CML when:
Patients whose CML condition is at the accelerated stage have symptoms which include but not limited to: fever, loss of appetite and even weight loss. Most importantly, the accelerated phase does not respond effectively and efficiently to the treatment and medications as the chronic stage of the CML. At this phase (accelerated phase) it is quite challenging to manage the situation, and treatment options are usually ineffective as compared to chronic CML stage.
Blast phase (acute phase/blast crisis)
Research and analysis of the blood sample of the patient at the blast phase indicate that they exist a total of more than 20% of blasts. Most critically, more significant cluster are often seen in the bone marrow. Such blasts often spill to the other body organs and tissues that neighbor the bone marrow. The other notable features of the cluster phase include the development of leukemia near the bone marrow, bone marrow biopsy among others. These blast cells are usually high concentration within the bloodstreams. Some of the patients at this phase include fever, poor appetite, and weight loss. This stage is often regarded as acute leukemia.
It is important to state that reduction does occur whenever there is an enhanced response to treatments and medications, that is the blood and bone marrow cells tend to come to normal. The number of detectable abnormal cells determines the different levels of remissions to be employed. Furthermore, the relapses may occur in individual patients whenever the leukemia cells reappear within a given period of reduction.
Signs and symptoms of CML
The symptoms of the disease are generally related to the CML cells expansion and consist of the losses in weight, malaise and also the discomfort which results from the splenomegaly. The leukocytosis is a feature which is common within the chronic phase and the white blood cells count (WBC), may so be high for example 1000x 10^9/L that lead to the instances of the signs and the symptoms for hyperviscosities like the priapism, hemorrhage, tinnitus, the accidents by cerebrovascular, stupor and confusion. After about 3-5 years, the patients who have failed to undergo the treatment with the CML-CP progress inevitably to the CML-BP which is the aggressive form to acute leukemia and is very refractory on chemotherapy and is fatal.
The transformation risk of CML-BP has been estimated to occur between 3% and 4% every year. The chronic myeloid leukemia of AP has been characterized with the arrest for increasing maturation which heralds the transformation of CML-BP. Many patients are having the CML usually remain within the AP for about 4-6 months before they proceed to the BP. The classic definition criteria of CML-BP demonstrates about 30 percent of blasts within blood in the periphery, the bone marrow, and availability to the blastic special medullary foci (Hwang et al. 117). Clinical experiences by several patients who are having the CML-BP show the signs and symptoms that relate to the increased burden of tumor, including difficulty in control of white blood cells count previously, with the stable medication doses and the marked signs of constitution, for example, sweat at night, fever, malaise, anorexia and loss of weight. It also has the symptoms of pain in the bone, the infarcts of splenic that result from massive splenomegaly and the increased risk to bleeding and infections.
The Laboratory and Pathological Features
The findings within the laboratory for CML includes the leukocytosis that has a remarkable shift in the left, eosinophilia and basophilic. The count of platelets can either be low or high while the observation of mild anemia becomes to be universal. The phosphate of alkaline leukocyte activity is usually reduced, even though the functions of the phagocytes remain normal. There could also be the observation of minimum values within the myeloid agnogenic metaplasia, while the activity can increase with the remission of clinic, infection and within the onset for BP. Bone marrow for the patients having the CML are devoid of the fats and also notorious with hypercellular.
The primary biologic defect for CML is the maturation of discordant whereby the slight delay to the maturation of cells within it are found in the compartment of myeloid resulting to the increase in mass of myeloid. The stages for the maturation of myeloid are usually present in the predominance of the myelocytes. In the chronic phase, the sum for the promyelocytes and myeloblasts accounts to 10% less as compared to the cellularity of bone marrow. The reduction of the apoptosis for the myeloid cells results in an enlargement of the compartment, also an adherence to the defective in immature cells of CML to the marrow stromal cells.
Treatment options of CML
The human recombinant interferon of Alfa has indicated the significance of immunomodulatory and antitumor activity for the treatment of the CML. The significant responses have been reported on the use of cytogenetic responses, (MCGRs), the Ph chromosomes of positive cells that are also published in the patient’s ranging up to 40% and the complete reaction of cytogenetic (CCGRs) which is 0% of Ph chromosomes in positive cells for up to 25%. The CCGR achievements have been associated with the survival improvement whereby, 78% for the affected people who were achieving the CCGR remain life for ten years, and therefore, this establishes the achievement CCGR of the goal of therapy in an era of interferon alfa. Approximately, about 30% CCGR patients also were having the disease which was undetectable with PCR (Complete Molecular Remission). Instead, none of the patients indicated the relapse after the follow up for about ten years, and hence it could be treated. About 40-60% of people who are under CCGR have the presence to the minimum residual diseases within a little point and also not been relapsed for 10 years. It is, therefore, attributed with the interferon of alfa induced modulation of immune, for instance, the occurrence of the specific cytotoxic T lymphocytes for the PR1, which is the peptide being derived from the proteinase 3 and is also being overexpressed within the cells of CML.
The Transplant of the Stem Cell
This has been the treatment which is very important, especially, for the patients who are having the CML for example, the young people with identical HLA siblings. The evidence currently suggests such that the exposure of the affected person before the imatinib does not affect the outcome of the result. The data indicate that post mortality of SCT that occur within the first year should be between 10% and 20% (Hwang et al. pg 22). This takes place even to the patients who had attended the transplantation due to certain conditions that are optimal. Additionally, it is only one and third of the one-half patients who could be having the suitably matched HLA sibling and also the stringent criteria for inclusion, for example, age, the status about performance and adequately functional organ that can preclude, especially the possibility for the SCT into the broader patient proportion.
The rate of disease-free to survival within the long term range after the MUD SCT in the younger patients in early stage of CP for the disease is about 57% as compared to the 67% of the patients who receive the graft from the matched HLA siblings. In the recent years, there has always been incorporation about the lower molecular matching which has resulted to the decrease in the rate about the graft versus host to the diseases and therefore, improves causes and the improvement of probability for survival in the long term with the patients who are undergoing the treatment of MUD SCT. The condition of reduced intensity is used as the means for making the SCT available on the broader number to the patients that could otherwise be very ineligible by the SCT standard. The approach takes the advantage towards the capability of harbored T cells inside graft for the elimination of the cells of CML (the graft versus the effect of leukemia) which is opposed to obtaining the effect through the use of cytotoxic ablative chemotherapy. The strategy results in the increase in tolerability and the morbidity decrease and significant rate of mortality. Therefore, the successful frequent management of relapse should be done with the lymphocyte of the donor infusion for about 70% to the patients who usually relapse with CP, especially, when they have been administered during the period of relapse by the molecular. Consequently, the imatinib may also be for post-relapse of SCT which sets and induces the CCGR within the patients exceeding 40% and have been treated by CP.
The Tyrosine Kinase Inhibitor Therapy
This is a kind of therapy being targeted. These drugs usually target the BCR-ABL of abnormal protein which assists in the growth of CML cells. The drugs prevent the protein in BCR-BCL so that the signals are not sent which may result in the formation of too much number of CML cells. The immunotherapy, the interferon is the substance made naturally by the system of immune. The pegylated interferon is the form in which the drug acts. It can be the option to the patients who cannot tolerate the tyrosine kinase inhibitor therapy.
During the diagnosis process, the doctor takes the history of medicine which helps him/her to perform an exam physically while it is also done for the evaluation of other illnesses. For instance, the doctor can check the size of the patient’s spleen. The correct size of the spleen cannot be felt normally, while the spleen which has been enlarged is detected towards the side of the left above the abdomen and also below the rib cages. In the CML, spleen becomes larger in volume since more white blood cells occupy it. The test for the gene: the test is performed to check for Philadelphia chromosomes or BCR-ABL genes. The test has been used for the confirmation of the CML diagnosis. For example, if an individual lacks Philadelphia chromosomes and BCR-ABL genes; therefore, the person does not have the CML.
The imatinib is the inhibitor which is selective for BCR-ABL tyrosine kinase resulting from the translocation of the chromosome. It is very useful to the patients that their leukemia cells are carrying the translocation and hence, the identification by translocation becomes very critical in prior for the decision of using the imatinib as the therapy towards this particular disease. Even though about 90% of the CML cases usually demonstrate the translocation, therefore, the CML can still be confused with certain diseases which are myeloproliferative thereby making the prior testing of the disease before treatment to be very critical.
Prognostic factors for chronic myeloid leukemia and risk assessments
The adverse prognostic factors are associated with less survival time. Together with the stages of CML, there exist many factors that are crucial when it comes to the analysis if the survival rates of this disease. The main adverse prognostic factors include accelerated phase or cluster stage, elongated spleen, damages in the areas of the bone marrow, increased levels of basophils and eosinophil within the bloodstreams, a higher or very low rates of the platelet counts and multiple chromosome adjustments in the CML cells. A majority of the above-mentioned factors are incorporated into the Sokal system which often gives us a score to project the prognosis. Notably, the system takes into consideration an individual’s age, the percentage of the blasts within the bloodstream and size and shape of the spleen as well as the number of platelets. The ELTS score is the prognostic score that predicts the probability of treating a patient with CML as well as related death cases. Possibly, these patients are treated using imatinib. That’s notwithstanding, the Euro scores do indicate the levels of risks of different groups. As evident in research, the Sokal and Euro models are helpful when it comes to the development of drug needed to treats patients with CML.
Consequently, the Hasford and Sokal scores are based on possible risk factors, as for such it is possible to categorize the risk assessments scores into three, namely, low, intermediate and high-risk people. Physician and doctors can use this assessment to ascertain the treatment options and equally guide their decisions when treating CML patients. CML drug therapies do rely on these risk groups.
From the discussions, CML is a severe disease that has continued to affect a majority of individuals not only in the United States but also other nations. Enough said, Chronic myeloid leukemia (CML), may be considered as a paradigm in the current oncology, bearing in mind the fact that it is cancer that begins in the bone marrow and spreads to other essential organs of the body. The understanding of the pathology of CML allows doctors and physicians to come up with the best treatment options for patients. Meanwhile, the phases of CML are crucial as they also enable the patient to understand their conditions and seek appropriate medical assistance whenever necessary. The prognostic factors of CML equally assist in the determination of the survival rates of the disease, What is interesting is that fact that a patient has several options to choose from during his or her treatment plan. And as for such, the risk associated with the illness is mostly reduced.
Eichhorst, B., et al. “Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.” Annals of Oncology 26.suppl_5 (2015): v78-v84.
Hwang, Andrew, et al. “Cystic acne due to imatinib therapy for chronic myelocytic leukemia.” Journal of Oncology Pharmacy Practice (2018): 1078155218761799.
Miao, Weili, Lei Guo, and Yinsheng Wang. “Imatinib-induced Changes in Protein Expression and ATP-binding Affinities of Kinases in Chronic Myelocytic Leukemia Cells.” Analytical chemistry (2019).
Rinaldi, I., et al. “323P Association between duration of hydroxyurea administration before matinib mesylate to the achievement of major molecular response (MMR) in chronic phase of chronic myelocytic leukemia: A review on P-glycoprotein.” Annals of Oncology 28.suppl_10 (2017): mdx664-006
Zhao, Lifen, et al. “Upregulation of miR-181c inhibits chemoresistance by targeting ST8SIA4 in chronic myelocytic leukemia.” Oncotarget 7.37 (2016): 60074.