Module 6

Acute Lymphocytic Leukemia

Objectives

1. Discuss functions and properties of blood to include:

a. Three general functions (Workbook 6-7)

b. Components of blood including plasma and formed elements

(Workbook 6-8, 6-9)

c. Five primary types of WBCs and their function (Workbook 6-10,

6-11)

d. Describe hematopoiesis. Identify myeloid and lymphoid cell line and

list cells that develop from each line (Workbook 6-12).

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2. Define the following terms (Leukemia case study pgs. 1-5): pus,
petechiae, thrombocytes (from CBC link on pg. 1 case study), blasts
(Workbook 6-13 and CBC results link on pg. 1 case study), anemia,
thrombocytopenia, blood-brain barrier, meninges, upper lobe infiltrate
(from chest x-ray results, link on pg. 4 case study), pneumonia, remission.

3. Discuss a CBC. Include in your definition an explanation of the following

components of a CBC: WBC, RBC, Hb, Hct, platelets, and WBC
differential (CBC link from Leukemia case study pg. 1).

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4. Discuss the diagnostic testing discussed in the case study including: throat
culture, bone marrow aspirate, lumbar puncture, and chest x-ray.
(Leukemia case study pgs. 2-5).
a. Define the principle of the test.
b. Describe when the test is indicated.
c. Describe how the test is performed.
d. Summarize the diseases that can be diagnosed by the test.

5. Discuss a gram stain (Leukemia case study gram stain link from pg. 4).
a. Define the two groups of bacteria differentiated by a gram stain.

b. Discuss why the gram stain is an important first step in the

identification of a pathogen.

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6. Discuss leukemia (Leukemia case study pg. 2 and associated links, Work-
books pg. 6-14):

a. Define leukemia

b. List common symptoms of leukemia

c. List the 4 major types of leukemia.. List key features of each type .

d. Discuss causes of leukemia

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7. Review the following treatments for leukemia: chemotherapy,
transfusion, radiation, bone marrow transplant. (Leukemia Case Study
pgs 3, 5).
a. Define the principle of the treatment.
b. Describe how the treatment is given.
c. Discuss the benefits and side effects of treatment.

8. Describe targeted therapies for cancer treatment to include: (Workbook

6-17-6-20).

A. Gleevec

B. CAR T-cell treatment

C. Monoclonal Antibodies

1. Define antigen, antibody, and epitope

2. Describe the development and use of monoclonal antibodies in

treating cancers

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9. Discuss the role of the following health care professionals in diagnosing
and/or treating a patient with leukemia (Case Study Professionals):
a. Physician to include the following physician specialties: pediatrcian,
oncologist, radiation oncologist, pathologist, and radiologist.

b. Medical laboratory scientist

c. Registered nurse

d. Radiology technician

e. Respiratory therapist

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 Functions of Blood

More than likely you take your amazing blood for granted. We typically don’t
worry about our blood unless we’re bleeding, but components of the blood are
continually working for our benefit. Blood has three main functions:

1. Transportation. Think of blood vessels as the highways running through-

out the body, and blood as the vehicle running through those highways.
Blood transports oxygen from the lungs to the tissues, and then picks up
carbon dioxide and wastes from the tissues for elimination from the body.

2. Regulation. The blood is key in main-

taining homeostasis of all of the fluids
in the body. Proteins in the blood help
regulate fluid balance through osmosis,
keeping essential fluids in the blood-
stream. When protein levels are low in
the bloodstream (for example in liver
disease, malnutrition, or severe burns),
an individual has fluid retention. The
fluid often accumulates in the
abdominal cavity, a condition called as-
cites.

Blood is also important in distributing

heat in the body and regulating body
temperature. If you’re out in a snow-
storm, blood will shunt heat to the essential organs, away from your ex-
tremities (hands and feet). Vessels in the extremities vasoconstrict, and
hands and feet will be cold and may turn blue. The body’s main goal is to
keep you alive and you can live without your extremities. When you’re
hot, vessels close to the surface vasodilate, giving off heat. After a hard
workout, your face may be red and your skin warm.

3. Protection. The blood literally has an army of cells and proteins that help
protect us from infection. Blood also contains clot-forming proteins that
prevent bleeding.

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 Components of Blood
You have probably had your blood drawn for testing. As the blood settles, it
will separate into its heavier and lighter components. Blood is composed of
formed elements and plasma.

Formed elements consist of cells and cell fragments. Cells are further
divided into red blood cells (RBCs) and white blood cells (WBCs). Plate-
lets are cell fragments that break off from a large cell in the bone marrow, a
megakaryocyte. Formed elements make up an average of 45% of the blood.
This number varies per individual and corresponds to the individual’s hemato-
crit, the percent of blood occupied by red blood cells. Because RBCs are the
heaviest of the formed elements, they settle to the bottom of the tube. WBCs
and platelets settle just above the RBCs in what is known as the buffy coat.

The liquid portion of the blood is called plasma and is primarily water
(91.5%). The remaining solutes in plasma (8.5%) are primarily proteins (7%)
which help regulate fluid balance in the body. Nutrients, wastes, electrolytes,
and gasses make up the remainder of the plasma.

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Red blood cells are responsible for transporting oxygen to the tissues where
they pick up carbon dioxide and carry it back to the lungs. White blood cells
primary function is to provide protection against foreign invaders. Platelets
aid in hemostasis (or stopping bleeding) by forming platelet plugs. This is
similar to putting Kleenex in your nose to stop a nosebleed. Platelets also re-
lease chemicals that help with blood clotting.

There are 4.8-5.4 million RBCs/ mm3(which is about one drop of blood).
They are by far the most numerous of the formed elements. Platelets follow
with 150,000-400,000/mm3. White blood cells are the fewest in number aver-
aging 5,000-10,000/mm3. WBCs are divided into five different classes. These
different classes of WBCs all have different defensive functions which will be
discussed on the following page.

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 White Blood Cells

There are five primary types of white blood cells, or leukocytes. Some
white blood cells contain chemical granules giving them a granular appear-
ance. The presence or absence of these granules separates the WBCs into two
major divisions, granular and agranular leukocytes.

Laboratorians study and count circulating types of white blood cells in a

test called a WBC Differential. The types and numbers of circulating WBCs
give important diagnostic information about the condition of the patient. We’ll
explain these five different types and their functions below.

Granular Lymphocytes
Neutrophils. Of the granular lymphocytes, 60-70% are neutrophils in the
circulating bloodstream. You can pick out a neutrophil by the many segments
in its nucleus (sometimes called a polymorphonucleocyte or PMN). This cell
is a powerful phagocyte and can engulf foreign bacteria. When a patient has a
bacterial infection, the neutrophil count is often high.

Eosinophils. These cells are easy to pick out under a microscope because
their granules stain bright red-orange. Only 2-4% of circulating WBCs are
Eosinophils. Remember that we’re looking at cells in the bloodstream, so
we’re not accounting for the number hanging out in the tissues. Eosinophils
are elevated with allergies or inflammation. These cells have the amazing
capacity of attacking a parasitic worm, so if a patient has a parasite infection,
their eosinophil count will likely be high.

Basophils. These cells are rare in the bloodstream, 0.5-1%, because they hang
out mainly in the tissues. With their large blue-black granules, they’re easy to
pick out. These cells play a key role in the inflammatory response.

Agranular Lymphocytes
Lymphocytes. These cells have a clear blue cytoplasm and are key in the
body’s immune defense. Lymphocytes are further divided into B cells and T
cells. When activated, B cells will divide into plasma cells which make anti-
bodies. When activated, T cells can directly attack a cell infected with a virus
or cancer, among other things. Lymphocytes comprise 20-25% of circulating
WBCs and may be slightly elevated in viral infections.

Monocytes. These cells are mainly found in the tissues where they become
macrophages, another powerful phagocyte. Only 3-8% of circulating WBCs
are monocytes.

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Types of White Blood Cells

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 Hematopoiesis
Blood Cell Formation

Blood cells are continually formed in the bone marrow through a process
called hematopoiesis. Cells begin their development in the red bone marrow.
Notice that all cell development starts from one pluripotent (multipotential)
stem cell. Under the influence of different cytokines (cellular messengers),
this cell can develop into any of the cell lines. Also notice that there are two
main divisions at this point, myeloid stem cells or lymphoid stem cells. From
the myeloid line develop several types of cells. Megakaryocytes are large
cells that remain in the bone marrow. Cell fragments called thrombocytes or
platelets break off from the megakaryocyte and assist with hemostasis.
Erythrocytes (red blood cells), mast cells (important in inflammation) and
myeloblasts also develop from the myeloid line. From the myeloblast come
the granular WBCs: basophils, neutrophils, and eosinophils. Monocytes
which become macrophages in the tissue also develop from a myeloblast.
Lymphocytes and natural killer (NK) cells come from the lymphoid stem
cell line. NK cells play a role in attacking cancers and foreign pathogens.
Lymphocytes father divide into T and B lymphocytes. Each have a different
role in our body’s defense. When a B cell is activated it becomes a plasma
cell which make antibodies, important specific weapons against a pathogen.

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Early cells in the developmental line
are called blasts. In a blood sample,
typically only mature WBCs are
seen. In this case study, many early
cell types including blasts are seen
in the blood stream indicating a
problem in blood cell formation.
Many blasts in two peripheral blood
smears can be seen in the photos to
the right.

Below are four peripheral blood

smears.
Top left: Lymphocytes
Top right: Neutrophils
Bottom left: Eosinophil
Bottom right: Atypical lympho-
cytes; red blood cells and platelets
can also be seen.
Blasts in a peripheral blood smear
Image courtesy of T-Photo/Shutterstock

Image courtesy of T-Photo/Shutterstock

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 Leukemias

Blood cancers or leukemias stem from either the myeloid or lymphoid line. In
the case study we have a child with Acute Lymphocytic Leukemia. This is a
leukemia of rapid onset, with cancerous cells from the lymphoid cell line.
Chronic leukemias typically have a slower onset. A broad classification of
leukemias demonstrates cancers developing from both lines with either an
acute or chronic onset. Each type of leukemia has many other subdivisions.

Acute lymphocytic leukemia (ALL). This type of leukemia is predominantly

found in children. There are many lymphoblasts (immature cells). The five
year survival rate for individuals under 20 is 89%. If this leukemia is found in
an individual over 20 years of age, the five year survival rate drops to 38%.

Acute myelocytic leukemia (AML). This leukemia affects both adults in

children. The predominant cell type are myeloblasts. The five year survival
rate for individuals 20 and older is 26%.

Chronic lymphocytic leukemia (CLL). This leukemia is found primarily in

the elderly. Bone marrow or blood samples show many small, round lympho-
cytes. The five year survival rate for individuals over 20 is 86%.

Chronic myelocytic leukemia (CML). This leukemia shows many immature

to mature cells from the myeloid line. This leukemia occurs due to a translo-
cation in chromosomes 9 and 22. Translocations occur one chromosome
breaks, and the broken piece then fuses onto another chromosome. This trans-
locations creates a BCR-ABL gene which causes the production of an abnor-
mal enzyme, tyrosine kinase. This enzyme causes WBC’s to grown out of
control. The new chromosome is called the Philadelphia chromosome. This
type of leukemia is rate in children. Fifty percent of cases are adults over 64
years of age. The five year survival rate depends on the phase of the disease.

Lymphoblasts from a smear from a

patient with Acute lymphocytic Translocation of chromosomes
leukemia 9 and 22.
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 Review Questions

1. Which of the following WBCs are phago-

cytes?
A, Basophils
B. Eosinophils
C. Lymphocyte
D. Macrophage
© DENNIS KUNKEL MICROSCOPY/Science
E. Neutrophil Source
F. A and C
G. D and E

2. Match parts of the blood with their principle function.

_____ Carry O2 and CO2 A. Platelets
_____ Assist in prevention of bleeding B. Plasma
_____ Carry nutrients, waste, hormones, and enzymes C. RBCs
______Defense of the body D. WBCs

3. All blood cells start as a ______________ _________ ___________.

4. Early cells in the developmental line are called ___________.

5. These cells are elevated in allergies and inflammation and can be easily
identified by their bright orange-red granules _________________.

6. Sally Jordan was brought to the ER with an appendicitis. Because this typ-
ically indicates there is a bacterial infection, which WBC would you expect
to be elevated? ________________.

7. Lymphocytes may be slightly elevated in a ___________ infection.

8. These cells leave the bloodstream and become powerful phagocytes in the
tissue _________________.

9. These cells have large, blue-black granules and play a big role in the in-
flammatory response ______________.

10. Platelets are cell fragments that break off from a large cell in the bone
marrow called a ________________.

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11. Match the type of leukemia with a description of one of it’s distinguishing
characteristics.

Acute lymphocytic leukemia_______ A. Philadelphia chromosome

Acute myelocytic leukemia ________ B. Primarily in children

Chromic lymphocytic leukemia______ C. Predominant cell type are

myeloblasts

Chronic myelocytic leukemia ________ D. Primarily in the elderly

[Link] develop into _________ and __________.

13. An activated B cell becomes a _________ __________ which produces

__________.

[Link] is the predominant cell type found in the bone marrow or blood in
acute lymphocytic leukemia?
A. Lymphoblasts
B. Mature lymphocytes
C. Myeloblasts
D. Neutrophils

[Link] white cell growth enzyme is produced

from the Philadelphia chromosome?
A. Acid Phosphatase
B. Creatine Kinase
C. Lactate dehydrogenase
D. Tyrosine kinase

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 Targeted Therapies for Cancer

Unlike chemotherapy, which targets all rapidly dividing cells in the

body, targeted therapies are specific for targets that are involved in
the growth and spread of the cancer.

An example of a targeted therapy is imatinib mesylate (Gleevec), a

drug which targets the growth enzyme, tyrosine kinase, made by
the BCR-ABL gene in chronic myelocytic leukemia. This drug has
been called a silver bullet...magic! A five year study showed that af-
ter treatment of Gleevec for 60 months, 98% of patients had a com-
plete hematologic response (all blood cell counts have returned to
normal). Before Gleevec only 30% of patients with CML survived
5 years. The survival rate now is at least 89% (Pray, 2008).

Chimeric antigen receptor (CAR) T-cell treatment

Remember that leukocytes develop into B and T-cells. We’ve
learned that an activated B cell becomes a plasma cell that makes
Abs. T-cells perform cell-to-cell combat, and when activated can
directly kill a cancer cell. This revolutionary new treatment isolates
T cells from the patient. These cells are engineered by adding a
man-made receptor called a chimeric antigen receptor or CAR.
This helps the cells better identify cancer cells. The cells are grown
and multiplied into million of cell in a lab and then given to the pa-
tient by infusion. A cool thing is that once the CAR T cells start to
bind to the cancer cells, they increase so that even more cancer cells
can be destroyed. While there are a few CAR T-cell therapies cur-
rently approved, many others are now in clinical trials.
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6-18
 Targeted Therapies for Cancer
Monoclonal Antibodies

Cancer cells may display certain antigens not normally expressed by cells of
the body. For example, some cancer antigens are only expressed in embryonic
cells. If a cancer cell expresses a specific antigen, then there is the potential to
manufacture an antibody specific for that antigen, thus providing a specific
weapon to fight a specific cancer. An antigen (Ag) is a protein on a cell that
helps identify the cell. Antibodies are proteins that can bind to an antigen and
cause cell destruction. This is one of the methods that our bodies use to fight
foreign pathogens; our cells create antibodies as a weapon. The image below
depicts an antigen-antibody reaction. Antigen binding sites are known as
epitopes. This image depicts three different epitopes on each cell. Specific
antibodies for each antigenic epitope are depicted

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Monoclonal antibodies (mAbs) are antibodies that are manufactured that are
specific for a given antigen. To produce mAbs, the antigen is isolated and in-
jected into a mouse. Lymphocytic B cells (cells that produce Abs) are isolated
from the spleen of the mouse. These B cells are then fused to immortal cancer
cells (cells that will live forever). These hybridized cells are grown in culture
and produce a specific Ab for the Ag in question. These Abs are called mono-
clonal because the clone of cells produce one very specific Ab. If these Abs
are specific for a cancer Ag, they will directly bind to and kill the cancer cells.
This is called targeted therapy. Cool, right?

While mAbs have different trade names, you can tell them from their scientific
name which ends in “mab.” In Feb of 2021 the FDA approved treatment of
Covid-19 with mAbs for patients 65 and older that target the spike viral pro-
tein. The two approved drugs are bamlanivimab and etesevimab (notice the
mab at the end of the name). mAbs are also used for diagnostic testing inclu-
ing pregnancy tests and rapid strep tests.

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 Case Questions
1. What symptoms did Noah exhibit?

2. Are Noah's symptoms consistent with a Strep infection?

3. Which health professional is responsible for performing Noah's laboratory

tests?

4. What abnormalities were present in the laboratory tests?

5. Which health professional would Noah's pediatrician be most likely to

consult with?

6. Define leukemia.

7. What is the difference between chronic and acute leukemia? How do the
symptoms differ?

8. What are the four most common types of leukemia? In which age groups is
each most predominantly found?

9. What are common symptoms of leukemia?

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10. What tests help a physician diagnose leukemia?

11. What is a bone marrow procedure?

12. What abnormality in Noah's bone marrow smear was suggestive of a

Leukemia?

13. What is ALL?

14. What does the word "acute" mean when talking about ALL?

15. What are the 5 common symptoms of ALL that are talked about in this
video?

16. Chemotherapy is the first line of treatment for ALL. What treatments
would follow if chemotherapy fails?

17. ALL is the most common cancer in young children. What is the
approximate cure rate in children?

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18. What is a spinal tap or lumbar puncture?

19. Why is a lumbar puncture performed?

20. What is cerebral spinal fluid?

21. What chemicals or constituents can be measured from the cerebral spinal
fluid?

22. What is chemotherapy? How is it given? What are some of the side
effects of chemotherapy?

23. Why did Noah develop a fever?

24. Why would the physician order a chest x-ray?

25. What is a chest x-ray?

26. What abnormalities can be detected from a chest x-ray?

27. What health care professional is responsible for gram stain and culture
testing?

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28. A gram stain differentiates bacteria into what two classes?

29. Why would an immunocompromised patient be more susceptible to

disease?

30. What is pneumonia? What are some causes of pneumonia?

31. What is the difference between Noah's initial and final chest x-ray?

32. Which health care professionals worked together to diagnose and treat
Noah's pneumonia? Define each role.

33. Do Noah's CBC and bone marrow aspirate results indicate he is making
progress? Base your answer on specific results.

34. What is radiation therapy?

35. What evidence can be noted in the CBC and bone marrow results to
indicate Noah is in remission?

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[Link] is bone marrow and what is its purpose?

37. How is bone marrow transplanted?

38. What are possible sources for transplanted cells?

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American Society of Clinical Oncology (July, 2021). Types of Cancer.
Retrieved July 5, 2021 from [Link]

Pray, L.2008). Gleevec: the Breakthrough in cancer Treatment. Nature

Education 1(1):37

U.S. Food & Drug Administration (Feb, 2021). Coronavirus (COVID-19)

Update: FDA Authorizes Monoclonal Antibodies for Treatment of
COVID-19. Retrieved July 2 2021 from [Link]
events/press-announcements/coronavirus-covid-19-update-fda-authorizes-
monoclonal-antibodies-treatment-covid-19-0

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