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The Different Phases Of Chronic Myeloid Leukemia & Their Management

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March 13, 2023

Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.

Chronic myeloid leukemia (CML) is a type of blood cancer that is broken up into several different phases. The treatment options available to you will depend on the phase, as well as several other factors.

The myeloid tissue, called the bone marrow, is the red spongy tissue present inside large bones, like the vertebral column and the hip bones. It produces life-sustaining components of the blood, including red blood cells, white blood cells, and platelets. Rarely, the bone marrow can rev up the production of one or more of these components, which is a recipe for the development of several blood cancers called myeloproliferative neoplasms, one of which is chronic myeloid leukemia (CML).

There are three different types, or phases, of CML. “They’re not sequential,” Dr. Eric Winer, clinical director of adult leukemia at Dana-Farber Cancer Institute, says of the phases. “It’s more common for people to come in with this particular phase of disease. It’s not like people go from chronic phase and then become accelerated phase and then they become blast crisis. Most people, about 90% of people, come in in what’s called chronic phase.”

Chronic Myeloid Leukemia (CML)

CML is a cancer of the white blood cells (WBCs). Specifically, it affects cells called the myeloblasts, which are the parents of mature, infection-fighting WBCs. These cells undergo a genetic mutation due to the formation of the so-called Philadelphia (Ph) chromosome. This mutation allows the myeloblasts to spill immature WBCs into the blood, bone marrow, and spleen. These immature cells are not fit to fight off infections, and their presence in the body causes a host of problems seen in CML patients. The phase of the disease will depend on the number of these immature cells.

RELATED: Understanding Chronic Myeloid Leukemia (CML)

The Philadelphia (Ph) Chromosome:

The Ph chromosome forms when two originally normal chromosomes, 9 and 22 (normal cells have 46 chromosomes in total), break off and fuse together. This fusion brings certain genes together in an unnatural way. In the case of the Ph chromosome, the BCR and ABL1 genes are joined together, forming the abnormal BCR-ABL1 fusion gene. This gene produces a mutant BCR-ABL1 tyrosine kinase, which is a protein (enzyme) that stimulates the CML cells to proliferate in great quantities.

The Three Phases of CML:

CML is classified into three distinct phases, primarily based on the number of immature white blood cells, called blasts, in a patient’s blood and circulation. These are chronic, accelerated, and blast phases. These phases have different treatments and patient outcomes, making them a key part of any CML diagnosis.

Chronic Phase CML

Key information about chronic phase CML is as follows:

  • 90% of patients have chronic phase CML at the time of diagnosis.
  • Their blood and bone marrow have less than 10% blasts.
  • They may have few if any symptoms. If symptoms are present, they disappear with the start of treatment.
  • This phase responds remarkably well to treatment.
  • It can last for years, but if untreated, it will progress to accelerated and blast phases in 3-5 years.
  • All CML cells, regardless of their phase, undergo an acquired genetic mutation due to the formation of the so-called Philadelphia (Ph) chromosome, described below.


Although most patients are symptom-free during the chronic phase, some may experience:

  • Weakness
  • Unintentional weight Loss
  • Fever
  • Shortness of breath
  • Night Sweats
  • Enlarging spleen causing belly fullness and pain
  • Bone pain


At this early stage of the disease, the main therapeutic goal is to improve a patient’s symptoms, if present, destroy the Ph chromosome-containing cells, and prevent the disease from progressing to the accelerated and blast phases. Targeted therapies are often effective during the chronic phase.

Targeted therapies are drugs that target the unique features of the cancer cells. In this way, these therapies can cull cancer cells without causing collateral damage to healthy tissues. For CML, the unique protein product of their BCR-ABL1 mutation, BRC-ABL1 tyrosine kinase can be targeted by drugs called tyrosine kinase inhibitors (TKIs). These oral drugs prevent the tyrosine kinase enzyme from working, killing the CML cells in the process.

Currently, there are 5 TKIs available in the market:

Imatinib is a highly effective treatment for chronic phase CML. Ph chromosome levels, an indicator of CML treatment effectiveness, become undetectable in more than 80% of patients treated with Imatinib. It is a relatively safe drug with few, manageable side effects.

For patients who do not respond to Imatinib or experience too many side effects, the other drugs on the list may be used. Notably, the TKI Ponatinib is used in patients with the T315I mutation, which makes the CML cells unresponsive to the other TKIs.

It is possible that certain chronic phase CML patients will not respond to TKI therapy. In these cases, allogeneic stem cell transplantation could be considered. This procedure replaces the CML-afflicted bone marrow with healthy bone marrow-forming cells harvested from donors. However, this procedure is not harmless and can cause serious, life-threatening complications.

RELATED: How Does a Stem Cell Transplant Work?

Enrollment in a clinical trial is another treatment option for these patients. Clinical trials explore new but unproven potential treatments for diseases. These treatments are not available to patients not in a clinical trial.

Accelerated Phase CML

There are several different definitions and criteria for advanced phase CML. The most oft-used criteria are provided by the World Health Organization (WHO):

  • Between 10-19% of blasts in the blood and bone marrow
  • More than 20% of basophils, a type of white blood cell, within the circulating blood
  • Platelets, which are particles within the blood that help it clot, are either increased or decreased beyond their normal levels
  • Chromosomal abnormalities, such as DNA damage and mutations, in addition to the Philadelphia chromosome
  • Increasing WBC number (more than 1,000 x 109/L) despite therapy

Less commonly used criteria include the MD Anderson Cancer Center and the recently introduced European LeukemiaNet (ELN) criteria.


Patients may experience some of the same symptoms as patients with chronic phase disease. These include weakness, weight loss, fever, night sweats, enlarged spleen, bone pains, and shortness of breath with minimal activities. Accelerated phase patients experience these symptoms more frequently than those with chronic phase CML.


TKIs can be used for accelerated phase CML, although they are usually less successful at controlling this phase than the chronic phase. The disease usually comes back within 2 years on TKIs alone.

Allogenic stem cell transplantation can provide longer relief and is potentially curative. However, this is complicated by the difficulty of finding an appropriate bone marrow donor. As it is an involved, intensive treatment, patients must additionally be “suitable” for a transplant, with a good social support system, financial security, and a complete understanding of the risks of the procedure, which can include death.

TKI therapy is often used as an “induction” therapy for eventual stem cell transplantation. This means that drugs, usually bosutinib, dasatinib, or nilotinib, are used to temporarily control the disease until a transplant can be performed.

Should patients not qualify for transplantation, they could be enrolled in clinical trials.

Blast Phase CML Or Blast Crisis

If the accelerated phase is left untreated, it will eventually transform into blast phase CML.

Like the accelerated phase, there are several sets of criteria for the diagnosis of the blast phase. However, the WHO criteria are most used in clinical practice:

  • More than 20% of blasts in the blood and bone marrow
  • Involvement of tissues and organs besides the blood and bone marrow
  • Bone marrow biopsy showing clumps of blasts within the tissue
  • New chromosomal abnormalities

International Bone Marrow Transplant Registry and ELN criteria are less commonly used in clinical practice in the USA.


Patients with blast phase CML are more likely to experience symptoms than patients with any other phase of the disease. In addition to the symptoms mentioned before, patients may experience:

  • Anemia (low hemoglobin) due to a lack of RBCs
  • Easy bruising and bleeding due to severely reduced platelet numbers
  • Extreme vulnerability to infections due to a lack of normal, infection-fighting WBCs


TKIs can be used as an initial treatment for the blast phase CML. However, they are considerably less effective during this phase and may only work for a few months.

Oftentimes, chemotherapy is combined with TKIs for better disease control. Hydroxyurea is an oral chemotherapy drug that can rapidly reduce the number of WBCs in the blood and reduce the size of an enlarged spleen. If blast phase CML becomes unresponsive to TKIs, then the chemotherapy drug omacetaxine mepesuccinate (brand name: Synribo) may be used. It is given via an injection under the skin every 7 to 14 days. Unlike, TKIs, chemotherapy is indiscriminately toxic (affecting cancer and normal cells alike) and carries its own side effects, such as nausea, vomiting, tiredness, weakness, fever, infections, diarrhea, and low hemoglobin (anemia).

Usually, the purpose of starting a blast phase patient on TKIs is to control their CML at least partially while a stem cell transplant is arranged. Unfortunately, a transplant during this phase is less successful than during the other phases and carries its own risks, as described above. There is some evidence that a transplant is likely to be more successful if imatinib or dasatinib are working.

Ultimately, a patient may progress despite all of the above therapies. For such patients, clinical trials may be the only option.

Key Takeaways

  • Most new cases of CML, 80%-90%, are chronic phase at the time of diagnosis.
  • If left untreated, the chronic phase can progress into accelerated followed by blast phases.
  • Tyrosine kinase inhibitors (TKIs), which block the BCR-ABL1 tyrosine kinase, are the first line of defense against CML and are especially effective in the early phases. They become less effective in more advanced phases.
  • Chemotherapy is often combined with TKIs to increase their therapeutic effect, especially for blast phase CML.
  • Stem cell transplantation is the only cure for CML, but this process is demanding and carries significant side effects.
  • If the patients do not respond to any of the above treatments, they may enroll in clinical trials, which test new and upcoming treatments for efficacy against CML.