Chronic Myeloid Leukemia (CML)

What is chronic myeloid leukemia (CML)?

Chronic myeloid leukemia (CML) is a type of cancer (a clonal disorder) that starts in the myeloid cells in the bone marrow. Myeloid cells are immature blood cells that develop into different types of mature blood cells, including red blood cells, white blood cells, and platelets.

CML differs from most of the other myeloproliferative neoplasms in 2 important ways: 1) virtually all untreated patients progress to a phase identical to acute leukemia or also known as blast crisis usually within a period of 3 – 5 years from diagnosis and 2) the acute leukemia of blast crisis may resemble AML or the myeloid blast crisis or ALL, the lymphoid blast crisis. The ability of CML to progress to either acute myeloid or lymphoid leukemia is good evidence that the tumor originates in a multipotent haematopoietic stem cell. Prior to the blast crisis, some patients experienced an accelerated phase by increased resistance to therapy, falling platelet counts and increasing numbers of basophils and blasts. 

The diagnosis of CML is rarely difficult and is assisted by the characteristic presence of the Ph chromosome. This is a somatic mutation that produces a BCR-ABL fusion gene, usually a balanced translocation between chromosome 9, where ABL kinase is encoded, and the breakpoint cluster region (BCR) on chromosome 22 that can be identified by staining of metaphase chromosome preparations. The BCR-ABL kinase activates the RAS, JAK-STAT and PI3 kinase/AKT pathways, the same pathways that are stimulated by hematopoietic growth factors in normal progenitors. As a result, there is an overgrowth of granulocytic and megakaryocytic precursors in the bone marrow. 

Signs and symptoms of CML

Early stages of CML

Many people with CML do not have any symptoms when they are first diagnosed. In the early stages of CML, the abnormal white blood cells may not cause any problems. However, as the disease progresses, the abnormal white blood cells can crowd out the healthy blood cells in the bone marrow. This can lead to a variety of symptoms, including:

  • Fatigue: Fatigue is one of the most common symptoms of CML. It is caused by a shortage of healthy red blood cells.
  • Weight loss: Weight loss can occur due to a variety of factors, including fatigue, loss of appetite, and increased metabolism.
  • Night sweats: Night sweats are another common symptom of CML. They are caused by the body’s attempt to cool down.
  • Fever: Fever can be a sign of infection or inflammation. It can also occur in people with CML due to the release of chemicals from the abnormal white blood cells.
  • Shortness of breath: Shortness of breath can occur due to a shortage of healthy red blood cells or due to pressure on the lungs from an enlarged spleen.

Later stages of CML

As CML progresses, the abnormal white blood cells can accumulate in the organs and tissues of the body. This can lead to a variety of other symptoms, including:

  • Easy bleeding and bruising: Easy bleeding and bruising can occur due to a shortage of platelets. Platelets are responsible for blood clotting.
  • Abdominal fullness: Abdominal fullness can be caused by an enlarged spleen. The spleen is an organ located in the upper left abdomen that helps to filter the blood.
  • Bone pain: Bone pain can be caused by pressure on the nerves from the abnormal white blood cells or by the spread of the disease to the bones.
  • Gout or renal impairment: Is caused by hyperuricemia from excessive purine breakdown may be a problem. 

What causes CML?

The pathogenesis of CML is characterized by the acquisition of the Philadelphia (Ph) chromosome, a cytogenetic abnormality that results in the constitutive activation of the BCR-ABL tyrosine kinase. This oncogene encodes a chimeric protein that is formed by the fusion of the BCR and ABL genes. The BCR-ABL protein has increased tyrosine kinase activity, which leads to uncontrolled growth and proliferation of myeloid cells.

The pathophysiology of CML is complex and involves a variety of cellular and molecular mechanisms. The BCR-ABL protein disrupts normal hematopoietic signaling pathways, leading to increased cell proliferation, decreased apoptosis, and enhanced stem cell self-renewal. It also promotes angiogenesis and increased vascular permeability, which contributes to the development of splenomegaly and other clinical features of CML.

The following are some of the key pathophysiological mechanisms involved in CML:

  • Increased cell proliferation: The BCR-ABL protein activates a variety of signaling pathways that promote cell proliferation, including the RAS/MAPK, JAK/STAT, and PI3K/AKT pathways. This leads to increased expression of cyclin D1 and c-myc, which are key regulators of the cell cycle.
  • Decreased apoptosis: The BCR-ABL protein inhibits apoptosis by upregulating anti-apoptotic proteins such as Bcl-2 and Mcl-1. This allows the abnormal myeloid cells to survive longer than normal.
  • Enhanced stem cell self-renewal: The BCR-ABL protein promotes stem cell self-renewal by activating the Wnt/β-catenin signaling pathway. This leads to an increased pool of abnormal stem cells, which can further contribute to the development and progression of CML.
  • Angiogenesis and increased vascular permeability: The BCR-ABL protein promotes angiogenesis and increased vascular permeability by upregulating the expression of pro-angiogenic factors such as VEGF and MMP-9. This leads to the development of splenomegaly and other clinical features of CML.

In addition to the above mechanisms, the BCR-ABL protein also disrupts the normal function of the immune system. This can lead to a variety of immunological abnormalities, including impaired T cell function, increased B cell activity, and autoimmunity.

The pathophysiological mechanisms involved in CML are complex and not fully understood. However, significant progress has been made in recent years in understanding the role of the BCR-ABL protein in the development and progression of CML. This knowledge has led to the development of more effective and targeted therapies for this disease.

How is CML investigated?

Laboratory investigations play an important role in the diagnosis and monitoring of CML. The following tests are commonly used:

Complete blood count (CBC) with differential

A CBC is a blood test that quantitatively measures the different parameters of red blood cells, white blood cells, and platelets in the blood. 

People with CML often have a high increased white blood cell count. They may also have a decreased red blood cell count and platelet count.

Peripheral blood smear

A peripheral blood smear is a blood test that examines the different types of blood cells under a microscope. This test can help to identify abnormal blood cells, such as leukemic blast cells.

People with CML often have immature myeloid cells (blast cells) in their peripheral blood smear. Leukocytosis with a complete spectrum of myeloid cells. Normochromic, normocytic anemia is usual. NAP score is low as opposed to those during infections.

Image depicting a peripheral blood smear of chronic myeloid leukemia (CML), showcasing leukocytosis with immature granulocytes, basophilia, and eosinophilia
The presence of leukocytosis with immature granulocytes, basophilia, and eosinophilia in a blood smear serves as a telltale sign of CML, a condition characterized by the uncontrolled proliferation of granulocytes in the bone marrow. These abnormal cells, characterized by their increased numbers and immature morphology, are a direct consequence of the Philadelphia (Ph) chromosome translocation, a genetic alteration that leads to the overproduction of the BCR-ABL oncogene.

Bone marrow aspiration and biopsy

A bone marrow aspiration and biopsy are procedures that remove a sample of bone marrow for examination under a microscope. Bone marrow is the soft tissue inside the bones where blood cells are made.

In CML, the bone marrow is usually hypercellular, meaning that it contains more cells than normal. There is also an increased number of myeloblasts in the bone marrow (granulopoietic predominance).

Cytogenetic analysis

Cytogenetic analysis is a laboratory test that examines the chromosomes in cells. This test can identify chromosomal abnormalities, such as the Philadelphia chromosome.

The Philadelphia chromosome is a chromosomal abnormality that is found in the bone marrow cells of almost all people with CML. It is formed when two chromosomes, chromosome 9 and chromosome 22, exchange material.

Fluorescence in situ hybridization (FISH)

FISH is a laboratory test that uses fluorescent probes to identify specific genes or chromosomal sequences. This test can be used to detect the Philadelphia chromosome.

Molecular testing

Molecular testing like quantitative polymerase chain reaction (qPCR) can be used to detect the BCR-ABL gene fusion, which is the genetic abnormality that causes CML. Molecular testing is more sensitive than cytogenetic analysis and FISH, and it can be used to detect CML cells even when the Philadelphia chromosome is not present.

Current treatment and management for CML

The current treatment and management of CML is focused on targeting the BCR-ABL protein with tyrosine kinase inhibitors (TKIs). TKIs are oral medications that block the BCR-ABL protein from signaling, which prevents the leukemia cells from growing and dividing.

There are six TKIs that are currently approved for the treatment of CML:

  • Imatinib (Gleevec)
  • Nilotinib (Tasigna)
  • Dasatinib (Sprycel)
  • Bosutinib (Bosulif)
  • Ponatinib (Iclusig)
  • Asciminib (Scemblix)

Imatinib was the first TKI to be developed for the treatment of CML, and it remains the first-line treatment for most patients. However, some patients may not respond to imatinib, or they may develop resistance to it over time. In these cases, a second- or third-generation TKI may be used.

TKIs have revolutionized the treatment of CML, and they have led to significant improvements in survival rates. In fact, most patients with CML who are treated with TKIs can now expect to live a normal lifespan.

Treatment goals

The primary goal of treatment for CML is to achieve complete molecular remission (CMR). CMR is defined as the absence of detectable BCR-ABL transcripts in the blood.

Achieving CMR is important because it is associated with the best long-term outcomes for patients with CML. Patients who achieve CMR have a very low risk of relapse and progression to the more aggressive blastic phase of CML.

Treatment options

The specific treatment options for CML will depend on the patient’s individual disease characteristics, such as the phase of CML and their response to previous treatments.

For most patients with newly diagnosed chronic phase CML, the first-line treatment is imatinib. Imatinib is a very effective TKI, and it can achieve CMR in up to 90% of patients.

However, some patients may not respond to imatinib, or they may develop resistance to it over time. In these cases, a second- or third-generation TKI may be used.

Second-generation TKIs, such as nilotinib and dasatinib, are more potent than imatinib and can achieve CMR in a higher percentage of patients. Third-generation TKIs, such as ponatinib and asciminib, are even more potent than second-generation TKIs and can be used to treat patients with CML who are resistant to other TKIs.

In addition to TKIs, other treatment options include:

  • Stem cell transplant: A stem cell transplant is a procedure in which the patient’s own stem cells are harvested and then reinfused into the body after high-dose chemotherapy. Stem cell transplants can be curative, but they are associated with significant risks.
  • Chemotherapy: Chemotherapy is a type of medication that kills cancer cells. Chemotherapy is not curative, but it can be used to control the disease in patients who are not responding to TKIs or who are not eligible for a stem cell transplant.

Management of CML

Once a patient with CML has achieved CMR, they need to continue taking their TKI indefinitely. This is because the BCR-ABL gene fusion is still present in the patient’s body, even if they are in remission. If the patient stops taking their TKI, the leukemia cells can return.

In addition to taking their TKI, patients with CML also need to be monitored closely for any signs of relapse. This typically involves regular blood tests and bone marrow biopsies.

New treatments on the horizon

Researchers are constantly developing new treatments for this disorder. One promising area of research is the development of targeted therapies that can kill CML cells without harming normal cells.

Another area of research is the development of immunotherapies that can boost the body’s own immune system to fight CML.

These new treatments are still in the early stages of development, but they have the potential to revolutionize the treatment of this disorder in the future.

Key points of CML


A slower progressing clonal disorder of the hematopoietic stem cells where untreated patients progress to blast crisis stage after 3 – 5 years. 


Peak at 40 – 60 years old

Signs and symptoms

  • Hypermetabolism e.g. weight loss, anorexia or night sweats
  • Splenomegaly
  • Anemia, bruising, epistaxis or menorrhagia
  • Hyperuricemia 


Unveiling the Molecular Mechanism of Chronic Myeloid Leukemia (CML): A Microscopic View of the Philadelphia Chromosome. Image depicting a microscopic view of a chromosome translocation resulting in the formation of the Philadelphia chromosome, a hallmark of CML.

Laboratory investigations

Peripheral blood and bone marrow smear

PBF: Normochromic normocytic anemia and leukocytosis

BMA: Hypercellular with granulopoietic predominance

Other Laboratory investigations

  • NAP score: Low
  • Cytogenetic analysis or qPCR: Presence of Philadelphia chromosome
  • ↑ serum acid

Treatment and management

  • Imatinib – blocks ATP-binding on BCR-ABL fusion protein
  • Stem cell transplantation

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.


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