What is chronic myeloid leukemia?
Chronic myeloid leukemia is also known as chronic myelogenous leukemia or CML. This is a myeloproliferative disorder, a type of skin cancer that features excess granulocytes in the blood. Granulocytes are immune cells, also known as polymorphonuclear leukocytes. They activate during infection and become the first line of defense when the body needs to fight pathogens. However, in chronic myeloid leukemia, these granulocytes are immature and do not activate properly. Thus, they only take space, create metabolic alterations, and contribute to immune and hematological problems instead of defending the body against disease.
Chronic myeloid leukemia is not rare, and 20% of the diagnosis in adults end up being CML. According to the American Cancer Society, the incidence of this disease has been increasing by 1.8% every year, and it was estimated that 8990 people were being diagnosed with CML in 2019. The condition is characterized to be insidious and slowly progressive, but it is similar to other types of leukemia, and diagnosis is critical to start treatment.
Pathophysiology of chronic myeloid leukemia
Several genetic alterations cause the majority of cancers as they overlap one after another. However, chronic myeloid leukemia is one of the few that does not require many genetic alterations to appear. 90% of cases of chronic myeloid leukemia are triggered by one specific and single mutation, which is known as the Philadelphia chromosome.
This genetic abnormality consists of translocation of genetic content between chromosome 22 and chromosome 9. Part of the genetic information expressed in chromosome 22 sticks to the long arm of chromosome 9. This relocates a gene called ABL, which is an oncogene that becomes activated and triggers the abnormal function of an enzyme called tyrosine protein kinase.
This abnormality is found in the hematopoietic stem cells, which are located in the bone marrow. These stem cells are responsible for the formation of new blood cells, including red blood cells and white blood cells. But chronic myeloid leukemia features an arrestment of polymorphonuclear leukocytes in their immature form by accelerated formation of new cells.
The causes of the chromosomic alteration that gives rise to chronic myeloid leukemia is not known. It does not have an important genetic predisposition, and it appears to be affected by ionizing radiation and environmental agents such as benzene.
Chronic myeloid leukemia symptoms
The majority of cases are diagnosed when the patient is still asymptomatic. These casual findings are discovered after a routine blood test that reveals a high white blood cell count and an enlarged spleen. Symptoms may also appear in later phases of the disease, and the more important are as follows:
1. Fatigue and nonspecific symptoms
They are very common in the early stages of the disease, and usually feature decreased energy and reduced tolerance to exercise.
2. Weight loss
It is not significant and often remains unnoticed for the first stage of the disease. But then, a late-stage features more aggressive signs and symptoms, and weight loss becomes an important concern.
3. Enlargement of abdominal organs
The spleen and liver may become enlarged by the infiltration of white blood cells. This may lead to additional signs and symptoms, such as abdominal pain, early satiety, and weight loss. Splenomegaly is a distinct feature, and it is found in physical examination of around half of the patients diagnosed with CML.
4. Fever
It is a myeloproliferative disease featuring a higher rate of infections. Thus, fever is an important feature, often associated with sweating.
5. Hemorrhagic manifestations
They are only seen in later stages of the disease and the acute subtype of leukemia. In these cases, the bone marrow becomes dysfunctional, and other cell lines become affected, including the number and function of circulating platelets.
In general, we can say that chronic myeloid leukemia is a slow-progressing disease, and the majority of patients are diagnosed in a later phase of the disease. However, there are three primary phases, each one with its own characteristics. The first one is called the chronic phase, the second one is the accelerated phase, and the third one is the blast phase.
During the chronic phase, we have a proliferation of mature cells, and patients may not display severe signs and symptoms. During the accelerated phase, additional genetic abnormalities are causing the disease to become rapidly progressing. And then, in the blast phase, there’s a very rapid proliferation of immature cells, and patients start having severe and often life-threatening health problems.
It is also important to note that the symptoms and the progression of the disease sometimes depend on the age of the patient. Unfortunately, a more aggressive disease usually strikes younger patients diagnosed with chronic myeloid leukemia. They progress to the accelerated and blast phase faster than middle-aged patients and should be treated promptly.
Chronic myeloid leukemia diagnosis and tests
The majority of patients with chronic myeloid leukemia are diagnosed during the chronic phase of the disease. This phase lasts long enough to perceive alterations in blood tests before patients start displaying symptoms. In these cases, patients are expected to go through the accelerated phase and the blast phase of the disease in around 3 to 5 years.
The diagnosis of chronic myeloid leukemia is usually made by analyzing peripheral blood samples and should be confirmed by evaluating the presence of the Philadelphia chromosome in bone marrow samples. It is more common in middle-aged and younger individuals, and it is not so common in older patients.
There’s an extraordinary elevation of white blood cell count, which sometimes surpasses 300,000 cells per microliter. However, a total white blood count of 20,000 cells per microliter is usually enough to suspect a myeloproliferative disease.
Besides blood count, other tests include:
• Peripheral blood smear: It is a more profound analysis of the blood sample through a microscope. It shows precursor cells instead of mature leukocytes and may also show a high number of eosinophils and basophils.
• Bone marrow analysis: It is the final exam to be made in these patients, and cytogenetic studies show chromosomal material of chromosome 9 in the long arm of chromosome 22, which is known as the Philadelphia chromosome.
Chronic myeloid leukemia prognosis
The median survival time of patients with CML after their diagnosis is around 3 to 5 years. However, with the introduction of new drugs and the improvement of the treatment protocols, the median survival time has been increasing through the years. Back in the 1990s, only 31% of patients survived longer than 5 years, and in 2015 this survival rate has reached 69%.
Better prognosis always results from a combination of early diagnosis, early start of therapy, and new targeted drugs that make treatment easier. Bone marrow transplantation is the only way to cure the disease, but the procedure is dangerous and has a very high rate of mortality by itself. Thus, it is not justified in most cases.
The risks of patients with chronic myeloid leukemia can be classified as a good risk with a survival of 5 or more years, an intermediate risk with a survival of 3 or 4 years, and poor-risk, with a survival of 2 years. Each one of these categories also has a percentage of response to treatment, which becomes reduced as the risk becomes higher. One of the ways to calculate the risk is through the Sokal score, which takes into consideration spleen size, age, platelet count, and the percentage of blast cells in the blood.
Among the most important characteristics that dictate a poor prognosis, we have:
- Patients with an older age
- Symptomatic patients unresponsive to medical treatment
- African American patients
- Splenomegaly and hepatomegaly
- CML with a negative Philadelphia chromosome
- Thrombocytopenia, thrombocytosis, anemia, basophilia
Treatment options
Treatment for chronic myeloid leukemia has the main goal of taking care of the signs and symptoms of the patient, preventing and treating infection, and achieving remission of the hematologic abnormalities. For this purpose, a wide variety of medications can be used, and the majority of them are myelosuppressive, which means they are made to inhibit the formation of white blood cells.
One of the best medications for CML is called imatinib mesylate, and it is a tyrosine kinase inhibitor. This agent is actually the first-line treatment when the Philadelphia chromosome is detected and can be used in adult and children, and almost every phase of the disease. It works by decreasing the activity of an enzyme called tyrosine kinase, whose activity becomes exaggerated during chronic myeloid leukemia.
Other treatment agents include interferon alfa and other myelosuppressive agents. In some patients, and depending on the phase of the disease and their age, it will be recommended to undergo allogeneic bone marrow transplantation.
References
Board, P. A. T. E. (2019). Chronic Myelogenous Leukemia Treatment (PDQ®). In PDQ Cancer Information Summaries [Internet]. National Cancer Institute (US).
Faderl, S., Talpaz, M., Estrov, Z., O’Brien, S., Kurzrock, R., & Kantarjian, H. M. (1999). The biology of chronic myeloid leukemia. New England Journal of Medicine, 341(3), 164-172.
Yoshida, C., & Melo, J. V. (2004). Biology of chronic myeloid leukemia and possible therapeutic approaches to imatinib-resistant disease. International journal of hematology, 79(5), 420-433.
National Comprehensive Cancer Network. (2011). NCCN clinical practice guidelines in oncology (NCCN guidelines). Central Nervous System Cancers Version, 2, 19-21.