Leukemia: Types, Risk Factors, Treatment Options & More

Introduction

Leukemia is a cancer of the early blood-forming cells, most often cancer of the white blood cells, and sometimes of other blood cell types. There are several types of leukemia, which are divided based mainly on whether the leukemia is acute or chronic  and whether it starts in myeloid cells or lymphoid cells. Different types of leukemia have different treatment options and outlooks.   

Types of Leukemia

Leukemia types include:

1. Acute Lymphocytic Leukemia (ALL)
2. Chronic Lymphocytic Leukemia (CLL)
3. Acute Myeloid Leukemia (AML)
4. Chronic Myeloid Leukemia (CML)
5. Hairy Cell Leukemia

Definition of Key Terms
Lymphomas (either non-Hodgkin lymphoma or Hodgkin lymphoma) are also cancers which affect the lymphocytes. While leukemia like ALL mainly affects the bone marrow and the blood, lymphomas mainly affect the lymph nodes or other organs (but may also involve the bone marrow). Sometimes it can be hard to tell if a cancer of lymphocytes is leukemia or a lymphoma. Usually, if at least 20% of the bone marrow is made up of cancerous lymphocytes (called lymphoblasts, or just blasts), the disease is considered leukemia. 
Lymphocytes are the main cells that make up lymph tissue, a major part of the immune system. Lymph tissue is found in lymph nodes, the thymus, the spleen, the tonsils and adenoids, and is scattered throughout the digestive and respiratory systems and the bone marrow.
A myeloid stem cell becomes one of three types of mature blood cells (red or white blood cells and platelets).  A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

• B lymphocytes that make antibodies to help fight infection
• T lymphocytes that help B lymphocytes make the antibodies that help fight infection.
• Natural killer cells that attack cancer cells and viruses

Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell. 

1. Acute Lymphocytic Leukemia

Acute lymphocytic (or lymphoblastic) leukemia ALL, starts in the bone marrow and develops from early (immature) forms of lymphocytes.  It progresses quickly, and if not treated, would probably be fatal within a few months.   It is more common in children than in adults. The treatment of ALL in children, result in a good chance for a cure. In adults, the chance of a cure is greatly reduced.
Most often, the leukemia cells invade the blood fairly quickly. They can also sometimes spread to other parts of the body, including the lymph nodes, liver, spleen, central nervous system (brain and spinal cord), and testicles (in males). Some cancers can also start in these organs and then spread to the bone marrow, but these cancers are not leukemia.
In ALL, too many stem cells become lymphoblasts, B lymphocytes, or T lymphocytes. These cells are also called leukemia cells. These leukemia cells are not able to fight infection very well. Also, as the number of leukemia cells increase in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding. 

Etiology of Acute Lymphocytic Leukemia

Acute lymphocytic leukemia occurs when a bone marrow cell develops errors in its DNA. The errors lead to continuous growth and division of the cells without regulation. When this happens, blood cell production becomes abnormal. The bone marrow produces immature cells that develop into leukemic white blood cells called lymphoblasts. These abnormal cells are unable to function properly, and they can build up and crowd out healthy cells.  It’s not clear what causes the DNA mutations that can lead to acute lymphocytic leukemia, but there are findings to show that most cases are not inherited.

Signs and symptoms of acute lymphocytic leukemia

 These may include:

1. Bleeding from the gums
2. Bone pain
3. Fever
4. Frequent infections
5. Frequent or severe nosebleeds
6. Lumps caused by swollen lymph nodes in and around the neck, underarm, abdomen or groin
7. Pale skin
8. Shortness of breath
9. Weakness, fatigue or a general decrease in energy

Risk factors of Acute Lymphocytic Leukemia

Possible risk factors for Childhood ALL include the following:

• Being exposed to x-rays before birth.
• Being exposed to radiation.
• Past treatment with chemotherapy.
• Having certain genetic conditions, such as:
  • Down syndrome.
  • Neurofibromatosis type 1.
  • Bloom syndrome.
  • Fanconi anemia.
  • Constitutional mismatch repair deficiency (mutations in certain genes that stop DNA from repairing itself, which leads to the growth of cancers at an early age).
• Having certain changes in the chromosomes or genes.

For adult ALL

• Previous cancer treatment
• Exposure to radiation
• Genetic disorders eg Down syndrome, are associated with an increased risk of acute lymphocytic leukemia.
• Having a brother or sister with ALL

• Being male
• Being white.
• Being older than 70.

Investigations to Ascertain ALL

• Physical exam and history : Checking for signs of disease, such as infection or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
• Complete blood count (CBC) with differential: 
• Blood chemistry studies  
• Bone marrow aspiration and biopsy 

Tests to ascertain Metastasis

• Chest x-ray 
• Lumbar puncture 
• CT scan (CAT scan)
• MRI (magnetic resonance imaging or nuclear magnetic resonance imaging (NMRI)).

There is no standard staging system for adult ALL. The disease is described as untreated, in remission, or recurrent.

• Untreated adult ALL 

The ALL is newly diagnosed and has not been treated except to relieve signs and symptoms such as fever, bleeding, or pain. In such cases,

• The complete blood count is abnormal
• More than 5% of the cells in the bone marrow are blasts (leukemia cells)
• There are signs and symptoms of leukemia

• Adult ALL in remission 

The ALL has been treated.

• The complete blood count is normal.
• 5% or fewer of the cells in the bone marrow are blasts (leukemia cells).
• There are no signs or symptoms of leukemia other than in the bone marrow.

Recurrent Adult Acute Lymphoblastic Leukemia

Recurrent adult acute lymphoblastic leukemia (ALL) is cancer that has recurred (come back) after going into remission. The ALL may come back in the blood, bone marrow, or other parts of the body. 

Treatment Option Overview

The treatment of childhood ALL is done in 3 phases:

• Remission induction: This is the first phase of treatment. The goal is to kill the leukemia cells in the blood and bone marrow. This puts the leukemia into remission. 
• Consolidation /intensification: This is the second phase of treatment. It begins once the leukemia is in remission. The goal of consolidation/intensification therapy is to kill any leukemia cells that remain in the body and may cause a relapse.
• Maintenance: This is the third phase of treatment. The goal is to kill any remaining leukemia cells that may re-grow and cause a relapse

The treatment of adult ALL usually has two phases.

1. Remission induction therapy: This is the first phase of treatment. The goal is to kill the leukemia cells in the blood and bone marrow. This puts the leukemia into remission.
2. Post-remission therapy: The goal of post-remission therapy is to kill any remaining leukemia cells that may not be active but could begin to re-grow and cause a relapse. This phase is also called remission continuation therapy.

Treatment called central nervous system (CNS) sanctuary therapy is usually given during each phase of therapy. 

Four types of standard treatments are used: 

1. Chemotherapy 
2. Radiation therapy (internal and external radiation)
3. Chemotherapy with stem cell transplant
4. Targeted therapy; Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibody therapy and tyrosine kinase inhibitor therapy are types of targeted therapy used to treat adult ALL

New types of treatment under clinical trials;
Biologic therapy ; It is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy. E.g is Chimeric antigen receptor (CAR) T-cell therapy
CAR T-cell therapy is a type of immunotherapy that changes the patient’s T cells (a type of immune system cell) so they will attack certain proteins on the surface of cancer cells. T cells are taken from the patient and special receptors are added to their surface in the laboratory. The changed cells are called chimeric antigen receptor (CAR) T cells. The CAR T cells are grown in the laboratory and given to the patient by infusion. The CAR T cells multiply in the patient’s blood and attack cancer cells. CAR T-cell therapy is being studied in the treatment of adult ALL that has recurred (come back).

Relapsed Childhood Acute Lymphoblastic Leukemia

Standard treatment of relapsed childhood acute lymphoblastic leukemia (ALL) that comes back in the bone marrow may include the following:

• Combination chemotherapy with or without targeted therapy (bortezomib).
• Stem cell transplant, using stem cells from a donor.

Late effects of cancer treatment may include the following:

• Physical problems, including problems with the heart, blood vessels, liver, or bones, and fertility.
• Changes in mood, feelings, thinking, learning, or memory. Children younger than 4 years who have received radiation therapy to the brain have a higher risk of these effects.
• Second cancers (new types of cancer) or other conditions, such as brain tumors, thyroid cancer, acute myeloid leukemia, and myelodysplastic syndrome.

2. ACUTE MYELOID LEUKEMIA

Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. It usually gets worse quickly if it is not treated. It is the most common type of acute leukemia in adults. AML is also called acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia, and acute non-lymphocytic leukemia. In Adult acute myeloid leukemia:

1. The bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets. 
2. Leukemia may affect red blood cells, white blood cells, and platelets.
3. Smoking, previous chemotherapy treatment and exposure to radiation may affect the risk of adult AML
4. Signs and symptoms of adult AML include fever, feeling tired, and easy bruising or bleeding
5. Tests that examine the blood and bone marrow are used to detect (find) and diagnose adult AML.
6. Certain factors affect prognosis (chance of recovery) and treatment options.

Treatment for adult AML is same with that of adult ALL. Four types of standard treatments are used similar to that of ALL. Other drug therapy Arsenic trioxide and all-trans retinoic acid (ATRA) are anticancer drugs that kill leukemia cells, stop the leukemia cells from dividing, or help the leukemia cells mature into white blood cells are also used.

Risk factors for AML

1. Having a brother or sister, especially a twin, with leukemia
2. Being Hispanic.
3. Being exposed to cigarette smoke or alcohol before birth
4. Personal history of aplastic anemia
5. Family history of AML
6. Past treatment with chemotherapy or radiation therapy
7. Being exposed to ionizing radiation or chemicals such as benzene
8. Having certain syndromes or inherited disorders, such as:
   • Down syndrome
   • Aplastic anemia
   • Fanconi anemia
   • Neurofibromatosis type 1

Signs and symptoms of AML

1. Fever with or without an infection
2. Night sweats
3. Shortness of breath
4. Weakness or feeling tired
5. Easy bruising or bleeding
6. Petechiae (flat, pinpoint spots under the skin caused by bleeding).
7. Pain in the bones or joints
8. Pain or feeling of fullness below the rib
9. Painless lumps in the neck, underarm, stomach, groin, or other parts of the body. In childhood AML, these lumps, called leukemia cutis, may be blue or purple
10. Painless lumps that are sometimes around the eyes. These lumps, called chloromas, are sometimes seen in childhood AML and may be blue-green
11. An eczema -like skin rash

3. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes.  The disease usually gets worse slowly. CLL is one of the most common types of leukemia in adults. It often occurs during or after middle age; it rarely occurs in children.  Leukemia may affect red blood cells, white blood cells, and platelets.
The signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness. Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.

Risk factors for CLL include the following:

• Being middle-aged or older, male, or white
• A family history of CLL or cancer of the lymph system
• Having relatives who are Russian Jews or Eastern European Jews

Signs and symptoms of chronic lymphocytic leukemia

Usually CLL does not cause any signs or symptoms and is found during a routine blood test. Signs and symptoms may be caused by CLL or by other conditions:

• Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin
• Feeling very tired
• Pain or fullness below the ribs
• Fever and infection
• Weight loss for no known reason

Stages of Chronic Lymphocytic Leukemia (CLL)

• The following stages are used for chronic lymphocytic leukemia:

• Stage 0 CLL, there are too many lymphocytes in the blood, but there are no other signs or symptoms of leukemia. Stage 0 CLL is indolent (slow-growing)
• Stage I CLL, there are too many lymphocytes in the blood and the lymph nodes are larger than normal 
• Stage II CLL, there are too many lymphocytes in the blood, the liver or spleen is larger than normal, and the lymph nodes may be larger than normal
• Stage III CLL, there are too many lymphocytes in the blood and too few red blood cells (RBCs). The lymph nodes, liver or spleen may be large than normal
• Stage IV CLL, there are too many lymphocytes and too few platelets.  The lymph nodes, liver or spleen may be large than normal, and there may be too few RBCs

Treatment Options (5 standard treatment options are):

1. Watchful waiting
2. Radiation therapy
3. Chemotherapy
4. Surgery
5. Targeted therapy

1. Watchful Waiting:
This involves close monitoring of the patient without any intervention until signs and symptoms appear. It is also called observation period. During this period, problems caused by the disease such as infection are treated.
2. Radiation therapy 

• External radiation therapy uses a machine outside the body to send radiation toward the cancer
• Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer

The way the radiation therapy is given depends on the type of cancer being treated. External radiation therapy is used to treat chronic lymphocytic leukemia.

3. Chemotherapy  

It involves the use of drugs to kill the cancer cells. Chemotherapy can either be systemic or regional.  The way the chemotherapy is given depends on the type and stage of the cancer being treated.
4. Surgery 
This is done to remove the organ or tissue such as splenectomy, which is surgery to remove the spleen.

5. Targeted therapy 

This therapy uses drugs or other substances to identify and attack specific cancer cells without harming normal cells.
 

4. CHRONIC MYELOGENOUS LEUKEMIA

Chronic myelogenous leukemia (CML or chronic granulocytic leukemia) is a slowly progressing blood and bone marrow disease that usually occurs during or after middle age, and rarely occurs in children. 

1. Chronic myelogenous leukemia is a disease in which the bone marrow makes too many white blood cells
2. Leukemia may affect red blood cells, white blood cells, and platelets
3. Signs and symptoms of chronic myelogenous leukemia include fever, night sweats, and tiredness. 
4. Most people with CML have a gene mutation (change) called the Philadelphia chromosome
5. Tests that examine the blood and bone marrow are used to detect and diagnose chronic myelogenous leukemia.
6. Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

• The patient’s age
• The phase of CML
• The amount of blasts in the blood or bone marrow
• The size of the spleen at diagnosis
• The patient’s general health

Stages of Chronic Myelogenous Leukemia (3)

1. Chronic phase
2. Accelerated phase
3. Blastic phase

In chronic phase CML, fewer than 10% of the cells in the blood and bone marrow are blast cells
In accelerated phase CML, 10% to 19% of the cells in the blood and bone marrow are blast cells
In blastic phase CML, 20% or more of the cells in the blood or bone marrow are blast cells.
When tiredness, fever, and an enlarged spleen occur during the blastic phase, it is called blast crisis.

Treatment Option Overview

• Six types of standard treatment are used for CML:

• Targeted therapy; Tyrosine kinase inhibitors are targeted therapy drugs used to treat chronic myelogenous leukemia. Imatinib mesylate, nilotinib, dasatinib, and ponatinib are tyrosine kinase inhibitors that are used to treat CML.
• Chemotherapy 
• Biologic therapy
• High-dose chemotherapy with stem cell transplant 
• Donor lymphocyte infusion (DLI); Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant. Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.
• Surgery 

• New types of treatment are being tested in clinical trials. 

5. HAIRY CELL LEUKEMIA  

This rare type of leukemia is called hairy cell leukemia because the leukemia cells look “hairy” when viewed under a microscope.
Signs and symptoms of hairy cell leukemia include infections, tiredness, and pain below the ribs. Other general symptoms earlier listed may apply
The treatment options may depend on the following:

• The number of hairy (leukemia) cells and healthy blood cells in the blood and bone marrow
• Whether the spleen is swollen
• Whether there are signs or symptoms of leukemia, such as infection
• Whether the leukemia has recurred after previous treatment

Treatment often results in a long-lasting remission. If the leukemia returns after it has been in remission, retreatment often causes another remission. There is no standard staging system for hairy cell leukemia. Either untreated, relapse or refractory
In untreated hairy cell leukemia, some or all of the following conditions occur:

• Hairy (leukemia) cells are found in the blood and bone marrow
• The number of red blood cells, white blood cells, or platelets may be lower than normal
• The spleen may be larger than normal

Relapsed or Refractory Hairy Cell Leukemia

Relapsed hairy cell leukemia has come back after treatment. Refractory hairy cell leukemia has not responded to treatment. 

Treatment Options

• Five types of standard treatments are used:
  1. Watchful waiting
  2. Chemotherapy; Cladribine and pentostatin are anticancer drugs commonly used to treat hairy cell leukemia. These drugs may increase the risk of other types of cancer, especially Hodgkin lymphoma and non-Hodgkin lymphoma. Long-term follow up for second cancers is very important
  3. Biologic therapy
  4. Surgery
  5. Targeted therapy

New types of treatment are under clinical trials. A clinical trial of chemotherapy and targeted therapy with a monoclonal antibody (rituximab).