Soham C. Dihenia
13 August 2022
Introduction:
Leukemia remains a highly prevalent and severe cancer around the world. Globally, there are approximately 2.4 million active cases of leukemia at any given point.33 In 2018, approximately 65,000 leukemia cases were reported in children aged 0-14 globally.38 38,000 of those cases were reported in males.38 Some leukemias target children more heavily. However, most leukemia cases are reported in people above the age of 60. In the United States, approximately 400,000 people are living with or in remission from leukemia.23 Every year, in the United States, approximately 25,000 people die from leukemia.23
Leukemia is a cancer of white blood cells, and there are many types of leukemia dependent on the type of white blood cell affected. White blood cells protect the body from infections and are part of the immune system. Figure 1 shows the different types of white blood cells. The different leukemias are categorized by which of these cell types is affected. For example, Acute Myeloblastic Leukemia comes from myeloblasts. Acute Lymphoblastic Leukemia comes from lymphoblasts.35 Proerythroblasts form erythrocytes, and megakaryoblasts form thrombocytes.
All blood cells are made in the bone marrow. Red blood cells carry oxygen, white blood cells prevent infection, and platelets control bleeding.8 Once the various blood cells are mature, they migrate out of the bone marrow and migrate to different tissues of the body to perform essential functions. In leukemia, DNA of a single cell in the bone marrow mutates and functions abnormally. For example, in Chronic Myeloid Leukemia, a triggering mutation forms the abnormal BCR-ABL chromosome, which leads to the cancer.58 Mutations in a cell can lead to immature cells, commonly referred to as blasts, which multiply uncontrollably in the bone marrow. This prevents production of other cells that are needed for survival because the blasts overcrowd the bone marrow, which can lead to infections and anemia due to lower numbers of white and red blood cells, respectively. As these cells proliferate over time, they spill out from the bone marrow and spread to other body tissues, such as the nervous system, the liver, and other organs. This process is called metastasis.
Leukemia falls into two different categories: acute and chronic. Acute leukemia is when the cancer grows over a period of days to weeks.19 If not treated in time, it can be fatal. A diagnosis of acute leukemia is indicated when 20+% of white blood cells in the bone marrow are blasts. Normally, there should be less than 5% of blasts present in the bone marrow.5 Chronic leukemia is when the cancer grows slowly. This is because it is comprised of mature cells, which proliferate more slowly than immature blast cells.19 Symptoms tend to develop over time and can be much milder than those in acute leukemias, especially in the beginning of the disease course. Chronic leukemias tend to occur in phases due to their gradual growth. For example, Chronic Myeloid Leukemia starts with the chronic phase, which is when there is a slow buildup of mature cancer cells, followed by the accelerated phase, where cell proliferation speeds up and become immature, and eventually reaches the terminal blast phase, where there is an intense proliferation of undifferentiated blasts.56
In order for the doctor to diagnose a patient with leukemia, they consider multiple components: patient history, signs and symptoms, and testing.22 A patient may visit the doctor if they feel the following nonspecific symptoms: fever, persistent weakness, weight loss, swollen lymph nodes (for example, under the neck), bleeding, bone pain, infections, and night sweats.31 These symptoms and signs vary by leukemia type and severity. Once the patient addresses their symptoms, the doctor takes a blood sample from the patient. Then, the doctor conducts a bone marrow biopsy by first applying anesthesia in the area where the biopsy needle will be inserted and then withdraws a sample of bone marrow from the patient. Pressure is applied to stop bleeding and a bandage is put on.13 After the bone marrow biopsy, the sample is sent to a laboratory for analysis. The laboratory identifies whether the blood cells are healthy and normal, as well as the extent of the leukemia, if present. From the blood sample the doctor takes from the patient, the laboratory performs peripheral blood smears, which identify the characteristics of each of the types of red and white blood cells present.12,47 Both peripheral blood smears and bone marrow biopsies also detect abnormal changes in white blood cell types and blasts as well as identify complete blood counts and metastasis. Multiple chemical tests can be employed to identify characteristics that specify a subtype of leukemia. The laboratory sends a report back to the doctor. The doctor considers it in the context of the other lab report findings, the patient’s signs and symptoms, and the patient’s history to make a diagnosis.
This paper aims to illuminate the leukemia diagnostic process and the experiences that leukemia patients undergo when diagnosed with different subtypes of this disease. Given the prevalence of this disease in society, increased awareness of disease management and patient experience can help increase education and empathy among the general public. Furthermore, as medical science advances the understanding of and discerning between cancer subtypes in the same category, such as leukemia, increasing public awareness and education that these subtypes are in fact distinct diseases beyond the general label of leukemia and may improve patient experience and engender greater understanding and empathy of individuals within the social support network of the patient.
Acute Lymphoblastic Leukemia Clinical Vignette:
A 9-year-old white male, who is usually an active tennis player, has felt fatigue over the past 2 to 3 weeks. He has difficulty standing up for long periods of time and has a lot of bone pain. His parents notice bruises that keep growing as days pass by. The patient states that he “does not feel normal” and struggles to perform daily tasks the way he used to. He has felt too tired to play tennis since the symptoms began a few weeks ago. Therefore, he asks his mom to bring him to the doctor.
The doctor conducts a physical exam and palpates lymph nodes on the patient’s neck. The doctor sends a sample of the patient’s blood to the lab, where a blood smear is done. The subsequent report states that the sample has a higher number of white blood cells than expected and a lower number of red blood cells than expected. Next, a bone marrow biopsy is conducted to observe the makeup of the various cells and to gain insight to see what is happening in it. Analysis shows that there are a lot of identical blasts, present, and very few of the variety of normal cells present because the blasts keep multiplying uncontrollably. This causes anemia, abnormal bleeding, and a higher chance of infections. To narrow down the subtype of leukemia, other chemical tests are done, one of these being the myeloperoxidase test, which comes back negative.32,52 Considering all of this information, the doctor diagnoses the patient with Acute Lymphoblastic Leukemia. This means that the patient has to spend more time in hospitals and little to no time at school.
In terms of treatment for the patient, the doctor starts the patient on vincristine. The patient faces side effects, such as hair loss, weight loss, nausea, vomiting, and taste changes. After a month, the patient gets another bone marrow biopsy, which shows that most leukemia cells have diminished. To prevent the leukemia cells from growing, he is given consolidation therapy and has to go through this treatment for the next two years. The drugs given to him include cytarabine, doxorubicin, and etoposide. Side effects of these drugs are similar to those from vincristine. When conducting another bone marrow test, it no longer identifies leukemia cells. However, the patient still continues treatment. The immunotherapy drugs given to him are the same he received during induction.
Although the patient has to continue his treatment, he is gradually able to return to his normal life. The patient and his family members are very grateful to the doctors that helped. The patient is delighted to play tennis, go back to school, and hang out with friends.
Acute Myeloblastic Leukemia Clinical Vignette:
A 60-year-old Asian male, a chef who is always on his feet, has noticed even tiny cuts lead to unusual bleeding and has noticeable bruises over the last two weeks without remembering any injury. He has noticed losing 15 pounds over the last couple of months. He states “I feel like I have become old overnight. I can barely even walk to the kitchen. My body just feels so tired and it has become more difficult to cook meals.” He has felt too weak to stand on his feet and cook since he started experiencing symptoms last week. He calls his son, who lives nearby, to take him to the doctor.
The doctor learns that the patient smokes. The doctor conducts a physical exam and palpates lymph nodes. The doctor also sends a sample of the patient’s blood to the lab, where a blood smear is done. The subsequent report shows various cytopenias. There are fewer red and white blood cells than expected. A bone marrow biopsy is conducted to determine the morphology and the count of the cells in the bone marrow. There are many immature cells, or blasts, present. They keep multiplying uncontrollably.59 Auer rods, or needle-shaped structures in the cytoplasm of these blasts, are observed as well. This analysis leads the laboratory to administer other chemical tests, one of them being the myeloperoxidase test. This comes back positive. After the doctor receives the report, he diagnoses the patient with Acute Myeloblastic Leukemia. The doctor admits the patient into the hospital, where he remains for the beginning of his treatment.
The doctor starts the patient on anthracycline. The patient faces side effects, such as nausea, vomiting, fatigue, and hair loss. The patient gets a bone marrow biopsy after a month. The leukemia is not as diminished as the doctor anticipated, so he decides that the patient should get a different drug regimen, which includes mitoxantrone, etoposide, and cytarabine. The patient faces severe side effects from mitoxantrone, such as back pain, itching, and dizziness, so the doctor told him to stop taking it temporarily. Etoposide and cytarabine bring mild side effects which are similar to those from anthracycline. Another bone marrow biopsy is done after 6 months. It no longer identifies leukemia cells. However, the patient still continues with consolidation therapy for the next several months.
The patient quits smoking and retires from his job as a chef. He still visits the hospital quite often because he does experience side effects from the drugs, such as back pain and dizziness. However, he can do most of his activities in his daily life. He is very grateful to the doctors that helped during the course of his treatment. He is glad to gradually be able to return to his hobbies, such as kayaking, cooking at home, and traveling.
Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia Clinical Vignette:
A 69-year-old white male, who is a retired radiologist, was getting a routine blood test during his annual doctor appointment. When the doctor asks the patient about his physical health, the patient states “I feel great. I run on a regular basis and will continue to do so for as long as my health allows me to.” To the patient’s and the doctor’s surprise, the results of the blood test reveal absolute lymphocytosis. The doctor sends an additional sample so it can be tested by flow cytometry. It detects clonal B-lymphocytes. The doctor diagnoses the patient with Chronic Lymphocytic Leukemia, but since the patient is asymptomatic, the doctor advises a “wait and watch” and advises the patient to look out for certain symptoms.34 The patient has to visit the doctor every three months to see if the leukemia is progressing.
Ten months later, shortly after his third trimonthly visit, the patient has a fever. He also notices that he has been sweating a lot at night. The patient decides to check his weight and unintentionally dropped 15 pounds over the last two months. A few days later, while going on his run, he feels out of breath and has to stop. He tries running again the next day but experiences the same. He recognizes the symptoms that the doctor told him to look out for. The doctor tells the patient that he is experiencing “B Cell symptoms'' from the CLL. The doctor also palpates lymph nodes under the patient’s neck and notices lymphadenopathy and splenomegaly. The doctor takes a sample of the patient’s blood for analysis. The report shows mild blood hyperviscosity and even higher absolute lymphocytosis. The peripheral smear also shows that the cells are spreading in the peripheral blood. Once the report is sent back to the doctor, the doctor and the patient agree that the patient needs to begin treatment for the leukemia because the disease is now active. The doctor admits him to the hospital.
The doctor starts the patient on ibrutinib. Ibrutinib brings side effects, such as diarrhea, fatigue, and minor bleeding.46 A bone marrow biopsy is done three months later. It still shows a lot of mature B cells. The doctor decides to put the patient on rituximab and ofatumumab. Side effects that the patient faces from both drugs include back pain, dry mouth, and fever. After another bone marrow biopsy, it shows less mature B cells than before, but there are still many present, so the patient continues on those same drugs, but with a higher dosage. Although the leukemia cells are disappearing, the patient’s spleen is very large and needs treatment. The doctor decides to put the patient on radiation therapy while continuing on the immunotherapy drugs. While the process of radiation is painless, the patient notices skin changes in the treated area, which is a side effect. Three months later, a bone marrow biopsy is done and no longer detects leukemia cells. A blood sample is also taken from the patient and is sent to the laboratory for a peripheral blood smear. The complete blood count is now in normal limits. However, the patient continues with consolidation therapy. He is put on zanubritinib. The patient faces side effects, such as blurred vision and headaches.
The patient continues with consolidation therapy. Because of the side effects from the immunotherapy drugs, the patient is not able to go out on runs. Instead, he decides to play golf. He also writes about his treatment experience after recovery and publishes it. He and his wife are very grateful to all of the doctors that helped.
Chronic Myeloid Leukemia Clinical Vignette:
A 53-year-old Hispanic male, who works at a nuclear power plant, was getting a routine blood test during his annual doctor appointment. When the doctor asks questions about his physical health, the patient states “I do feel very sweaty during work and need to take more frequent breaks because I feel very tired, but otherwise, I feel fine. I think this may be because I work longer shifts.” The doctor takes note of this, telling the patient to keep an eye on how he feels. The results from the patient’s blood test indicate various cytopenias. The doctor wants to follow up with a bone marrow biopsy, which is conducted a few days later. It shows a lot more mature granulocytes than expected, such as neutrophils, basophils, and eosinophils. The neutrophils were cytochemically abnormal as they had low Neutrophil Alkaline Phosphatase levels. The BCR-ABL test is administered to narrow down the type of leukemia that is present, if any. This test comes positive. A few days later, the report is sent to the doctor, who diagnoses the patient with Chronic Myeloid Leukemia. The doctor admits him to the hospital so he can begin treatment.
The patient is diagnosed during the chronic phase, which means that his prognosis is very favorable. In terms of treatment, the patient starts on imatinib. The patient faces side effects, such as stomach pain, frequent headaches, and diarrhea. A bone marrow biopsy is done after two months. The leukemia is not as diminished as the doctor anticipated, so he puts the patient on erlotinib. He is also put on gefitinib. The side effects of both drugs are similar to that of imatinib. Another bone marrow biopsy is done after a month. There are less leukemia cells than there were from the last biopsy. The patient continues on the same drugs with a higher dosage. He faces the same side effects. When another bone marrow biopsy is conducted after two months, it no longer identifies leukemia cells. However, the patient still continues with consolidation therapy. He takes erlotinib and gefitinib and faces the same side effects.
The patient decides to leave the nuclear power plant and become a writer. He also resumes daily activities that he did before being diagnosed with CML, such as attending parties, visiting family, reading books, and watching live football games. He even wrote about his treatment experience after recovery. His family and he are very grateful to the doctors that helped.
Conclusion:
Leukemia remains a big problem in today’s world. Although leukemia cases have gone up 110% in the past 20 years51, the survival rate has quadrupled from 14% in white people (only data available at the time) in the 1960s to 66.4% for all races in the 2010s because of the advances in treatment.23 Scientists and researchers continue to find more effective treatment and a possible cure for leukemia. In addition to advances in therapeutics, medical science has better delineated the different characteristics among cancers within the same category. This paper provides a microcosmic example of how one category of cancer, leukemia, contains multiple different diseases. While these subtypes of leukemia may have overlapping characteristics, they are in fact separate diseases with specific causes and different appropriate treatments.17 The clinical vignette style employed by this paper aids in delineating between and educating the public on the variety of diseases within the leukemia family. This style serves as a model for the continued augmentation of public awareness and understanding of the increasing subcategorization of, and delineation between, cancer subtypes once believed to be the same disease. As advances in medical science further characterize and discern between cancer subtypes within the same category, medical professionals should drive further efforts to educate the public about the nuances of these diseases.
Figure 1:
25
Glossary:
Accelerated Phase: The accelerated phase is the second phase in Chronic Myeloid Leukemia after the chronic phase. The number of immature blast cells have risen and are difficult to manage in treatment. Neutrophil differentiation becomes impaired. A patient’s prognosis becomes generally poor if they reach this stage.54
Acute Lymphoblastic Leukemia (ALL): Acute Lymphoblastic Leukemia is the most common childhood cancer. It is more common in white and Latinx populations as well as males. Mutations occur in the immature B or T cells, which are both lymphocytes.1
Acute Myeloblastic Leukemia (AML): Acute Myeloblastic Leukemia, also referred to as Acute Myeloid Leukemia, Acute Myelocytic Leukemia, or Acute Myelogenous Leukemia, is a cancer more common in adults. The average age for a person diagnosed with this leukemia is 65. There are associations with environmental factors that cause this leukemia, such as chemicals, radiation, tobacco, and chemotherapy.4
Anemia: Anemia is when there are fewer-than-normal erythrocytes, or red blood cells, present in the body. Because leukemia cells rapidly grow, they leave little room for these oxygen-rich blood cells. Reduction of these cells causes fatigue and pallor.5
Anthracycline: Anthracycline is a chemotherapy regimen that damages DNA in cancer cells, which prevents those cells from growing.20
Basophils: Basophils are a type of granulocyte that play a role in inflammation. The role of basophils in the immune system is to defend the body from allergens and pathogens and prevent blood clots.10
BCR-ABL: BCR-ABL is also known as the Philadelphia chromosome. The BCR-ABL mutation is the swapping of the pieces of chromosome 9 and chromosome 22. This essentially connects a tyrosine kinase with cell proliferation, which increases cellular proliferation. If the BCR-ABL test comes positive, then the patient has Chronic Myeloid Leukemia.11
Blast Phase: The blast phase comes after the accelerated phase in Chronic Myeloid Leukemia. This is when blasts overcrowd the bone marrow and spread beyond the bone marrow. At this point, the leukemia is similar to Acute Lymphoblastic Leukemia.54
Blood Hyperviscosity: Blood hyperviscosity is increased thickness of blood which prevents it from flowing properly. It can occur from having a high concentration of cells in the blood.50
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL): Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) is the most common adult leukemia in Western countries. It is more common in men and white people. The median age of diagnosis is 70. CLL is when the disease is in the peripheral blood, whereas SLL is when the disease is primarily in the lymph nodes.14,15
Chronic Myeloid Leukemia (CML): Chronic Myeloid Leukemia, also referred to as Chronic Myelogenous Leukemia, is a rare cancer which only occurs in 1 out of 100,000 people. Slightly more males than females have this leukemia. The only known risk factor to this leukemia is exposure to ionizing radiation. There was a higher incidence of this cancer among the survivors of the Hiroshima and Nagasaki bombings.16
Chronic Phase: The chronic phase is the earliest phase in Chronic Myeloid Leukemia. In the chronic phase, mature leukemia cells slowly start to build up. Patients are mostly asymptomatic and often find out that they have CML from routine blood tests. 85% of CML patients are diagnosed in this phase.54
Consolidation Therapy: Consolidation therapy destroys any remaining leukemia cells and prevents relapse after induction therapy.55 This phase can last for several months. Examples of consolidation include radiation therapy, stem cell transplants, or using drugs similar to or the same as those used during induction.
Cytarabine: Cytarabine is a chemotherapy regimen that stops cancer cells from making and repairing DNA.18
Cytopenias: Leukemia causes cytopenias, or lower-than-normal blood cell counts. Red blood cells and platelets are usually lower when leukemia cells are present. White blood cells can either increase or decrease.9 For example, neutropenia is the decrease in neutrophils. Thrombocytopenia is the decrease in thrombocytes, or platelets. Anemia is the decrease in erythrocytes.
Doxorubicin: Doxorubicin is a chemotherapy regimen that blocks enzymes that cancer cells need to grow.21
Eosinophils: Eosinophils are a type of granulocyte involved in inflammation that is usually responsible for fighting off infections.40
Erlotinib: Erlotinib is a Tyrosine Kinase Inhibitor that blocks the proteins that encourage the cancer to grow.
Erythrocytes: Erythrocytes are red blood cells made in the bone marrow. They contain a protein called hemoglobin, which transports oxygen to the tissues of the body and transports carbon dioxide away from the tissues of the body.41
Etoposide: Etoposide is a chemotherapy regimen that prevents cancer cells from growing and spreading to other parts of the body.22
Flow Cytometry: Flow cytometry is a technique that analyzes and detects physical and chemical characteristics of cells. During flow cytometry, a sample of cells or particles is suspended in fluid and injected into a flow cytometry machine. It can identify the type of cancer to diagnose a specific type of leukemia based on the presence or absence of protein markers on a cell’s surface.24
Gefitinib: Gefitinib is a Tyrosine Kinase Inhibitor that blocks the substances that allow cancer cells to multiply.
Granulocytes: Granulocytes are a type of white blood cell that is part of the immune system. The three types of granulocytes include basophils, eosinophils, and neutrophils.42,59
Ibrutinib: Ibrutinib is a systemic therapy (targeting the entire body) that stops the spread of cancer cells and blocks the abnormal protein that allows cancer cells to multiply.46
Imatinib: Imatinib is a Tyrosine Kinase Inhibitor that prevents the growth of cancer cells.28
Induction: Induction is the first phase of leukemia treatment. It reduces the leukemia as much as possible. Chemotherapy and targeted therapy are commonly used during this phase.30,55
Inflammation: Inflammation is when chemicals and/or the body’s white blood cells enter the blood or tissues to fight off infections or injury.29 The two types of inflammation are acute inflammation and chronic inflammation. In acute inflammation, the body immediately sends inflammatory cells to the injury. In chronic inflammation, the body sends inflammatory cells inappropriately if the immune system becomes dysregulated. Acute inflammation can become chronic inflammation if the body cannot get rid of the substance causing the injury or if the immune system becomes oversensitive to the body’s overall health.27 Chronic inflammation is what can damage DNA and cause cancer because of the continuous flow of inflammatory cells.
Lymphadenopathy: Lymphadenopathy is the swelling of lymph nodes.
Lymphoblast: The lymphoblast is an immature white blood cell that becomes a lymphocyte, which then becomes an agranulocyte.25
Lymphocytosis: Lymphocytosis means that there are an abnormally high number of lymphocytes in the blood. This is normal after an infection.
Mitoxantrone: Mitoxantrone is a chemotherapy regimen that stops cancer cells from growing and spreading to other parts of the body.36
Myeloblast: The myeloblast is an immature white blood cell that eventually matures to become a granulocyte. This cell becomes malignantly transformed in Acute Myeloblastic Leukemia.43
Myeloperoxidase: Myeloperoxidase is an enzyme produced by myeloid lineage cells. A blood sample is administered to see if this enzyme is present. The blood sample can be used to evaluate infection and inflammation. A positive test in the correct clinical context is indicative of Acute Myeloblastic Leukemia.
Neutrophils: Neutrophils are a type of granulocyte. Neutrophils destroy germs and prevent infections. A low number of neutrophils can prevent the body from fighting off bacteria, therefore worsening infection. In Chronic Myeloid Leukemia, neutrophils are cytochemically abnormal because they have low Neutrophil Alkaline Phosphatase levels.39,44
Neutropenia: Neutropenia is when there is an abnormally low level of neutrophils in the body. Neutropenia can cause life-threatening infections in the body and can increase the risk of other conditions. Symptoms of neutropenia include nausea and fatigue. Causes of neutropenia include, but are not limited to, leukemia, chemotherapy, and vitamin deficiency.39,45
Ofatumumab: Ofatumumab is a monoclonal antibody (an infection fighter) that treats CLL and various lymphomas with a combination of chlorambucil, a chemotherapy regimen.37
Radiation Therapy: Radiation therapy is treatment with high-energy rays that destroy cancer cells. While not commonly used for leukemia, it can be used adjuvantly with other treatments, such as chemotherapy or before surgery.48
Remission: Remission indicates a partial or complete absence of cancer. Leukemia remission is characterized by fewer than 5% of blast cells. Blood counts should be within normal limits, and there should be minimal signs and symptoms of leukemia.
Rituximab: Rituximab is a monoclonal antibody (an infection fighter) that treats CLL and various lymphomas with a combination of fludarabine, a chemotherapy regimen.49
Splenomegaly: Splenomegaly is the enlargement of the spleen. In Chronic Lymphocytic Leukemia, the spleen tends to be nontender, or painless, when touched.
Stem Cell Transplantation: A stem cell transplantation is the process of transferring healthy stem cells from a healthy bone marrow to a patient’s affected bone marrow. The transplanted healthy stem cells replicate and produce normal blood cells. It can be autologous, which means the patient’s own stem cells are used; allogenic, which is when stem cells come from a donor; or syngeneic, which can be from an identical twin.26
Thrombocytopenia: Thrombocytopenia is a condition when there are fewer-than-normal platelets, which prevents effective blood clotting. Therefore, when a patient has thrombocytopenia, they can frequently bleed or easily bruise. An enlarged spleen is another symptom of thrombocytopenia.53
Tyrosine Kinase Inhibitors: Tyrosine Kinase Inhibitors are pharmaceutical drugs that essentially turn off tyrosine kinases, so they do not increase cell proliferation as in the case of Chronic Myeloid Leukemia.56
Vincristine: Vincristine is a chemotherapy regimen commonly used during induction treatment. It stops cancer from separating into two new cells.57
Zanubritinib: Zanubritinib is a chemotherapy drug that destroys cancer cells.60
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