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HAEMATOLOGICAL NEOPLASM
ADVANCES IN THE LABORATORY DIAGNOSIS OF HAEMATOLOGICAL
NEOPLASM
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Abstract
The study aims at reviewing haematological neoplasm as a subject, its causes, symptoms, and
prevention. It will also discuss the current advances in the laboratory diagnosis of
haematological neoplasm. This is to help understand wider and better how this disease gets to
the body and its ability while in the human body.
Medicine Net (2016) defines ‘haematology’ as the diagnosis, prevention, and
treatment of diseases related to blood and the bone marrow and that of the vascular system
and blood clotting. To them, the study of haematology is as important as it affects the study
of many diseases that run in the blood stream. Mandal (2014) on the other hand, puts it that
neoplasm is derived from two geek works, ‘neo’, meaning new and ‘plasm’, meaning
formation. She, therefore, uses a reference from oncologist Willis to define neoplasm as ‘‘an
abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the
normal tissues, and persistent in the same excessive manner after cessation of the stimulus
which evoked the change.’’ Haematological neoplasm is, therefore, a form of cancer of the
blood that starts its journey of attack in the cells found in the blood forming tissues like the
bone marrow and the cells of body immunity. Categorically, the disease may include
leukaemia, multiple myelomas, myelodysplastic syndromes, and lymphomas. From the study
researches, chromosomal translocation is said to be the common cause of haematological
neoplasm. Further research, as indicated by Rayur (2012), indicates that the disease is rare in
children but common in the elderly due to the increase in myeloma with age, mostly affecting
those with over 65 years of age. However, notably, within the last decade, the prevention and
treatment of the curable diseases under this category has significantly advanced (Bain &
Haferlach, 2010).
The signs and symptoms of Haematological neoplasm, as listed in an article written
by Cleeland & Williams (2014) include; damage to the bone marrow, anaemia, frequent
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sickness due to weak white blood cells, general body weakness, fever, fatigue, chills, nausea
and night sweats among other symptoms. The main haematological neoplasms include but
not limited to; multiple myeloma, non-Hodgkin’s lymphoma, Hodgkin’s disease and
myeloproliferative disorder and Chronic lymphocytic leukaemia (Cleeland & Williams,
2014).
A diagrammatic representation of Haematological Malignancies (Rayur, 2012).
Rayur (2012) also notes some of the symptoms of haematological malignancies to be
persistent low grade fever, unusual pain resistant to the common therapies, fatigue,
unexplained fractures, the occurrence of a typical infection, night sweats, difficulty in
breathing and significant weight loss among others (Rayur, 2012).
In order to discover the presence of haematological neoplasm, one needs to undergo a
thorough assessment which aims at evaluating the most targeted organs like the heart and the
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liver. The evaluation should be able to achieve a balance of general condition for the presence
of other diseases in the body that is accompanied by this disease, which includes; heart failure
and diabetes among other diseases. To an extreme extent, memory loss, nutritional disorder,
and depression may be observed. After the assessment, and it a case that the results are
positive, treatment always commences immediately. The multidisciplinary teams discuss
one’s treatment protocol. Treatment applications like therapeutics procedure based on the
resultant diagnosis, medical, staging and social context are applied. At this stage, care during
chemotherapy is very important in regulating the blood cells count thus preventing either a
rise or a drop in the blood cells (Lloyd-Thomas, Wright, Lister, & Hinds, 1988).
According to a research done by Craig & Foon, (2008) haematological neoplasm does
not just attack anyone anyhow. There are certain risk factors that if avoided can reduce the
occurrence of this disease drastically. Such risk factors include; the experience of
chemotherapy and radiotherapy, accidental exposure to radiation or even worse is the
exposure to certain toxic chemicals like fertilizers used everywhere for faming activities and
to increase yield, chemical pesticides, and herbicides that may have hydrocarbons and
benzene compounds. The occurrence of leukaemia, for instance, is majorly contributed by
such risk factors. The biology behind these chemical toxins is that they cause human genes
transformation. When these disorders like leukaemia attack the human body, they always
affect the functioning of the currently present blood cells and the production of more blood
cells thus resulting in low blood cells count and low immunity. It has been reported that most
of these haematological neoplasms always starts their development and spread at the bone
marrow, an alternative organ for blood formation and production. At the bone marrow, there
is always a continued production of three major blood cells; the red blood cells, white blood
cells, and the blood platelets. When the neoplasm attacks, it results in the formation of a
strange and abnormal blood cell. The abnormally big sized cell normally affects the
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functioning of the other blood cells thus putting the body at a risk of being attacked by any
other disease (Craig & Foon, 2008).
Bone Marrow Specimens from Three Patients with Primary Mediastinal Germ-Cell Tumours
and Hematologic Neoplasia ((Nichols, Roth, Heerema, Griep, & Tricot, 1990)
The improvement in innovation and technology has been at the lead in helping control
and manage haematological neoplasm. Over the past one decade, there has been a
tremendous research work to curb this disease group. The great work is what has led to the
development of new techniques that targets both the genetic and the molecular side of
haematological neoplasm. Inasmuch as there has not been any cure on the cancerous diseases,
some of the recently developed techniques aim at improving the comfortability of the
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infected thus increasing the chances of survival and the time. What remains a question to be
asked is how the patients feel in cases of prolonged therapy. There is needed to keep on
exploring much more techniques that will not only prolong the patient’s survival but also
make them feel comfortable. This will be possible if further study of each agent is done. With
the improvement in innovation and technology towards the assessment and treatment of
haematological neoplasm without one having to visit their doctor. A software has been
developed, that has a special assessment questionnaire. When a patient starts having some of
these symptoms, what they do is that they answer the questionnaire appropriately and
sincerely. If the symptoms are very straight and direct, a possible disease is identified.
Immediate test then follows. If the results are positive, treatment immediately commences. If
a possible disease cannot be identified, then the patient is left with an option of performing a
wide test where every possibility is taken into consideration. The advantage of this kind of
questionnaire is that it saves on the patient’s energy, time and cost of testing every possibility
(Rodriguez-Abreu, Bordoni, & Zucca, 2007).
Because of the wide range of the haematological neoplasm, identification of a single
most appropriate disease among them is always slow, tedious, costly and at the same time
difficult, notes Nichols, Roth, Heerema, Griep, & Tricot (1990). One approach to
identification of the specific disease is the use of the Myeloproliferative Neoplasm Symptom
Assessment Form (MPN-SAF). The symptom items in this form were selected from the ones
most endorsed at the international standard level and samples of previously and currently
infected patients with specifically myeloproliferative neoplasm. Cleeland and Williams
(2014) explains that the final MPN-SAF has ten symptoms expected from a
myeloproliferative neoplasm. Its ratings are done in the range of zero to ten where zero
indicates absence, and ten represents strongly present. The assessment must always be done
frequently in order to note the difference after the start of the treatment.
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Advances in the Treatment of Haematological Neoplasm
Haematological neoplasm treatment has been revolutionized by the introduction of
the monoclonal antibody therapy. This has been made possible by improving the patient’s
condition and survival. The global technological improvements are what has driven the sector
to identifying better techniques of treatment thus advancing its treatment. The treatment has
now become diverse and broader. The introduction of the Imunoconjugates (ICs) is what has
made a positive impact in the improvement of the treatment of this disease. It is an
advancement that is basically grouped into three; radioimmunoconjugates, also known as the
radionuclide, immunotoxins, also known as the protein toxins, and the small molecule drug,
also known as the antibody drug conjugates. Before any therapeutic efficacy, it is important
that a proper and accurate optimization of the individual components of the Imunoconjugates
is done. A recent study conducted by Maria Corinna Palanca-Wessels and Oliver W. Press
(2014) indicates that with the introduction of the ICs, treatment of lymphoma has made a
great achievement in both multi-agent and monotherapy regimens. The Imunoconjugates
comprises a spectacular group of therapeutics that are promising in the management and
treatment of haematological neoplasm (Shah, Mehta, Salmon, & Stallard, 2001).
The most challenging part in the treatment of any type of cancer is the difficulty in
the administration of a significant dose of tumouricidal agents that help eradicate the diseases
found in the human system while at the same time having minimal effects on the normal body
tissues. The tumour target delivery can be the most effective method of increasing the
quantity of cytotoxic agent that can be safely administered. The development of a therapy
with an ability to settle to a malignant cell, based on the surface receptors, was realized with
the coming up of the monoclonal antibody therapy. This kind of therapy, although it took
over twenty years to get approved, is able to counter deal with most of the haematological
diseases. The superiority of this kind of therapy has of course not been an overnight
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achievement. For instance, the realization that immunoglobulins of murine origin had a high
immunogenic effect while at the same time being able to get neutralized by the same tumour
immune surveillance system led to immediate tampering with the functionality of antibodies
such as the ‘magic bullets.’ The impediment has largely been overcome by the efforts in
place that create fully human antibodies. In order to ensure a specific delivery and lethal
preload of the cancer cells, the Imunoconjugates must harness the targeting function of the
antibodies. This would depend on the availability of a covalently attached effector moiety for
the therapeutic purposes. As mentioned earlier, it is this effector that subdivides the
Imunoconjugates into three categories, that is, radioimmunoconjugates (RICs), antibody Drug
Conjugates (ADCs), and Immunotoxins (ITs) as shown in the figure below;
Cleeland, C. S., & Williams, L. A. (2014)
The Structure and Mechanism of Action of Imunoconjugates
From the diagram on the previous page, an imunoconjugate consists of an effector
molecule, linker, and a monoclonal antibody. In addition, the diagram also shows how the
three sub-groups of immunoconjugates are specially linked to different effector molecules.
An immunotoxin contains a protein toxin while the radioimmunoconjugate contains a
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radionuclide. An antibody drug conjugate, on the other hand, carries a tiny drug molecule.
Considering the mechanism of action of imunoconjugates, all imunoconjugates has the ability
to recognize and bind to a cognate tumour receptor or antigen. For the case of immunotoxins
and antibody drug conjugate, there is a need for internalization through a receptor mediated
endocytosis in order for it to enter into the target cells. This is followed by a subsequent
release of the effector moiety from the imunoconjugate, which takes place through the
conditional cleavage of the protease degradation of the antibody within the lysosomal
compartment or the antibody. The released drug, what is referred to as the toxin, diffuses into
the cytoplasm thus inhibiting the growth of the tumour by disrupting the antibody drug
conjugates (ADCs), causing damage to the DNA or ensuring that protein synthesis has been
inhibited (Safdar & Armstrong, 2011).
As previously stated, an imunoconjugate consists of three groups; the effector
molecule, the target antibody and the linker that joins the effector molecule to the target
antibody. Each group plays a vital role towards the success of this kind of therapeutic
activity. During the selection of an antibody and an antigen (receptor), several factors have to
be considered for its success. An ideal antigen should be expressed at a high level of
neoplastic cells. It should be located at the cell surface and its location must have as minimal
shedding into its surrounding as possible. The best antibody, on the other hand, should have
the ability to penetrate homogenously and quickly to the tumour tissue and be rapidly cleared
from the systemic circulation. This should mean encountering as minimal binding to the
receptors present as possible. It should not possess an intrinsic antitumor activity as this is
done by the effector molecule. Such targets investigated and proven to be ideal include;
CD79b, CD22, CD19, CD 30 and CD33 (for the internalizing receptors) and CD45 and CD20
(for the stable receptors (Bernstein, 1997).
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To enhance the efficacy of an imunoconjugate, judicious conjugation, modification
and selection of the effector molecules is what is needed. A potent effector is important
because the cell delivery is limited to the number of surface bounded imunoconjugates. It is
said that most effector molecules are usually too toxic that using them without conjugation
would mean a failure to get them delivered to the target. To counteract that, synthetic
derivatives of the natural compounds have commonly been used. For the case of
radioimmunoconjugates, the ionizing radiation affects not only the bound cells but also the
neighbouring cells. The use of the alpha-emitting radionuclides that has shorter path lengths
and higher energy than the common beta-emitting radionuclides is still under investigation.
Studies have shown the application ability of protein engineering to remove the immunogenic
sequences from immunotoxins that can generate neutralizing antibodies. To counter the
problem of toxicity of the target cell tissues, modification of a drug to a membraneimpermeable form is required. It works by reducing the toxicity stemming from a not specific
uptake of unconjugated effector, or alternatively, a premature diffusion and release out of the
target cell (Descatha, Jenabian, Conso, & Ameille, 2005).
Li & Zhong (2016) notes that the position of the effector molecules within the
antibody and the total number being conjugated can affect antigen binding, clearing,
tolerability, potency and sometimes its aggregation. Advances in the technology of linking
the antibody and the antigen is what has accelerated the development of potent
imunoconjugates. An unstable linker would be one that leads to a non-specific distribution or
even rapid clearance which is accompanied by either reduced potency or intolerable toxicity.
An ideal linker is one with the ability to prevent the release of premature effectors in the
circulation while at the same time allow its liberation in the tumour. The antibody drug
conjugates and the immunotoxins are internalized by the receptor –mediated endocytosis,
then, transferred to the lysosome. The release of the cytotoxic agent is done conditionally by
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the cleavable linkers. In order for the cytotoxic agent to be released, there has to be an acid
(hydrazine linkage), reducing environment (disulphide bond), and a lysosomal enzyme
(peptide bond) available within the endocytic compartment. Difficulties that come with the
production of heterogeneous species by traditional chemical conjugation can be overcome by
the recombinant DNA technology introduction or modification of the amino acid residues so
that it can be able to control conjugation sites.
Illustration by (Cleeland & Williams, 2014)
Radioimmunotherapy (RIT)
Although not very much utilized in the treatment of haematological neoplasm,
Radioimmunotherapy has proven its effectiveness in many cases. Inside this technique, the
widest clinical experience has been the one involving the RICs that contain beta particles
with an isotope emission of (131I or 90yttrium 90Y). This kind of isotope has an added
advantage of favourable emission profiles, stable antibody attachment, and its availability.
Earlier studies prove that isotope 131I, with a label monoclonal anti CD20, was in the 1990s
applied in the treatment of haematological neoplasm. The method worked because of the
production of a ‘crossfire effect’ on nearby cancer affected cells. The method could not be
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able to restrict the production of toxicities in its neighbouring normal tissues. Comparing it
with the alpha particles, the alpha particles has a short path length, they exhibit less
dependence on energy in order to be able to kill a cell. They, in addition, has a higher linear
energy transfer that results in greater cytotoxicity. This suggests that the alpha particles could
have been the best to use. However, its utilization in the treatment of haematological
neoplasm has not been possible because; they have a short half-life, are limited in availability
and they have more difficult radiolabelling in chemistry. That is why they still are not being
used in the modern health organizations (Sepkowitz, 2005).
Various studies on radioimunotherapy have been ongoing in order to advance it. Such
studies have included studies on setting a Haematopoietic Stem Cell Transplantation (HSCT).
By this trial, the scientists are hoping to improve the durability of responses to such
treatment. A study done earlier on indicated that using a myeloblative dose of 131I–anti-CD20
RICs, which is approximately five times higher than that of the conventional RIT, followed
by an autologous Haematopoietic Stem Cell Transplantation gave an objective remission in
about 85% to 95% of the patients infected with multiple relapses. It also indicated a durability
of 10 to 20 years remission to about 45% of the infected patients that were involved in the
study. This study, together with many ongoing studies has indicated that RIT is the best
method that the world currently has. Unfortunately, this technique has not been embraced.
The antibody drug conjugate, being the latest, is the one currently being used worldwide in
the treatment of haematological neoplasms (Cavallo, 2015).
In conclusion, there has been a tremendous witnessing of the advances in the
laboratory diagnosis of haematological neoplasm. Although some have not been embraced,
the ones in place have proven to be better than the ones that previously existed. Application
of ICs in the treatment of haematological neoplasm, especially RIT, has been very effective
even though it is being under-utilized in the modern treatment clinics. There is a lot of
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ongoing research in the health sector aiming at making better the diagnosis of haematological
neoplasm. With such advances, the patients with haematological neoplasm are able to survive
for a much longer time.
HAEMATOLOGICAL NEOPLASM
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