Chronic Myeloid Leukemia


Definition of Chronic Myeloid Leukemia (CML)

Leukemia is a type of cancer of the blood. There are different forms of leukemia depending on what type of blood cell is affected. “Chronic” describes a gradual or slow progression, and “myeloid” denotes the origin from myeloid cells, which are immature cells that normally become mature red blood cells, white blood cells, or platelets. In chronic myeloid leukemia, the bone marrow produces too many myeloid blood cells which are at various maturation stages including cells known as immature granulocytes, metamyelocyte, and myeloblasts. Platelets and basophils (different myeloid cells responsible, in part, for the allergic response) are also often overproduced at diagnosis.
Excess production of myleloid blood cells in the bone marrow ultimately prevents the normal production of red blood cells, which are important in delivering oxygen to all cells in the body, and can also decrease production of platelets or thrombocytopenia. Platelets play a critical role to stop bleeding.
Patients with chronic myeloid leukemia (CML) may be diagnosed at a routine checkup, or after seeking medical care due to lack of energy and fatigue from anemia, or bleeding, abdominal pain or discomfort, and rarely bruising from insufficient platelets. Enlargement of the spleen, known as splenomegaly, leads to abdominal and left chest discomfort, early satiety, or a change in bowel patterns. Other possible symptoms include fever, shortness of breath and bone pain. At diagnosis, most patients, have a white blood count (the number of white blood cells circulating in the blood) increased above normal.


This guide for patients has been prepared by the Anticancer Fund as a service to patients, to help patients and their relatives better understand the nature of Chronic Myeloid Leukemia (CML) and appreciate the best treatment choices available according to the subtype of CML. We recommend that patients talk to their doctors about the tests or treatments that are needed for their type and stage of disease. The medical information described in this document is based on the clinical practice guidelines of the European Society for Medical Oncology (ESMO) for the management of Chronic Myeloid Leukemia. This guide for patients has been produced in collaboration with ESMO and is disseminated with the permission of ESMO. It has been written by a medical doctor and reviewed by two oncologists from ESMO including the lead author of the clinical practice guidelines for professionals. It has also been reviewed by patients’ representatives from ESMO’s Cancer Patient Working Group.


Is CML frequent?

Compared to breast cancer in women or prostate cancer in men, chronic myeloid leukemia is not common. In the European Union, 1 to 2 cases will be diagnosed among 100,000 people every year. CML is very rare in children. Its frequency increases with age. Median age of patients diagnosed with CML is around 60 years. There are no geographic differences in number of newly diagnosed cases.


What causes CML?

Today, the cause of chronic myeloid leukemia (CML) is known to result from a specific genetic abnormality which occurs in the blood stem cell, however the cause leading to the abnormality is not understood.

This specific abnormality is an abnormal rearrangment of genetic material. Two chromosomes exchange a portion of their genes with genes on the other chromosome. This is known as a translocation. For CML, specifically, genes from chromosomes 9 are swapped with genes from chromosome 22. Translocation of the Abelson murine leukemia gene (ABL) on chromosomes 9 and the breakpoint cluster region (BCR) on chromosome 22 resulting in the Philadelphia chromosome (translocation of chormosomes 9 and 22, t(9;22)) can be detected in 95% of patients with CML either from cells circulating in the blood or in the bone marrow.

The Philadelphia chromosome encodes a dysregulated tyrosine kinase (an enzyme in cells), which results in an abnormal behavior of the cells affected. This includes the formation of immortalized cells, increased cell turnover and proliferation, and abnormal cell maturation.

There are very few known risk factors of CML, which increase the chance of leukemia occurrence, but do not necessarily lead to development of leukemia.

  • Exposure to high-dose radiation can increase the risk of CML. Atomic bomb and nuclear reactor accident survivors as well as radiology technicians prior to 1950 (when protective shielding was first introduced) are at inceased risk of developing CML.
  • The risk of developing CML increases with age but as people get older the risk is still very small. CML also occurs slightly more often in men than in women.

People exposed to pesticides or benzenes as part of their work seem to have a moderate increased risk of developing CML.





How is CML diagnosed?

Chronic myeloid leukemia can be suspected in patients due to symptoms or laboratory abnormalities in patients with and without symptoms (asymptomatic). Symptoms and clinical manifestations may include:

  1. Splenomegaly. Enlargement of the spleen due to its location in the upper left abdomen, results in abdominal discomfort, pain that radiates to the left shoulder, early satiety (inability to eat full meals), a change to bowel habits (due to obstruction of the intestines), occasionally weight gain, and the feeling of a mass extending from under the left chest into the abdomen.
  2. Fatigue. Fatigue is a common symptom due to anemia (a decreased red blood cell count, often measured as hematocrit or low hemoglobin level). Patients who are physically active may not notice the effects of being anemic until it is severe.
  3. Bleeding. Sometimes patients initially present with an elevated platelet count. Conversely, a low platelet count due to replacement of the normal bone marrow cells with leukemic cells can be seen and may result in easy bruising, bleeding from the nose or gums, petechiae (red spots seen on the skin commonly over the shins and ankles), and purpura (groups of petechiae resulting in larger red skin spots).

In patients who have the above symptoms a complete blood count should be done to check the three types of blood cells produced in the bone marrow: 1) white blood cells, 2) red blood cells, and 3) platelets. Occasionally the first suspicion of a possible leukemia may be based on routine laboratory findings alone. In addition, the complete blood count identifies, as part of the white blood cell count, leukemia cells circulating in the blood: An increased number of white blood cells at various stages of maturation, which are proliferating at an abnormal rate, with a disproportionate increase in basophils, are observed in the circulation.

If a diagnosis of CML is suspected based on symptoms and the white blood cell count, a bone marrow biopsy is performed. In the majority of cases the leukemia cells, which are found on the complete blood count, can provide adequate tissue to test for the presence of the Philadelphia chromosome (translocation of chromosomes 9 and 22, described above). The Philadelphia chromosome, t(9;22) can be detected by conventional cytogenetic methods (chromosome banding analysis of marrow cell metaphases) but also by molecular techniques including polymerase chain reaction (PCR), a technique in molecular biology to amplify a single or a few copies of a piece of DNA (deoxyribonucleic acid), and fluorescent in-situ hybridisation (FISH), a cytogenetic technique that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. In these cases, treatment may begin prior to a bone marrow biopsy.

A bone marrow biopsy is an uncomfortable minor procedure lasting fifteen minutes. Local anesthesia (pain-numbing medicine) is used for the procedure and sharp pain is usually not experienced. The procedure allows the pathologist (a doctor trained in diagnosing the disease based on the appearance of cells or tissues in the microscope) to diagnose CML. The pathologist can also determine what type of CML a patient has and further identify the genetic abnormalities of the leukemia by looking closely at the chromosomes. PCR and FISH tests are performed to identify the Philadelphia chromosome.





What is it important to know to get the optimal treatment?

Doctors will need to consider many aspects of both the patient and the leukemia in order to decide on the best treatment.

Relevant information about the patient

  • Personal medical history
  • Results from the clinical examination by the doctor
  • General well-being
  • Typing for bone marrow transplant. Before the development of targeted therapies for CML, first-line therapy was bone marrow transplantation. These days, some patients with CML may require a bone marrow transplant, but usually only if they fail to respond to targeted therapy and their disease progresses. Bone marrow transplant involves using the healthy bone marrow cells of someone else to replace the patient’s own, cancerous bone marrow. To prevent the donor’s immune system from damaging the patient’s body (a condition known as graft-versus-host disease), tissue typing must be performed to determine if a donor and a patient ‘match’. This is determined by the level of resemblance of specific proteins called Human Leukocyte Antigen (HLA), between the patient and donor. Since the process of finding a matching bone marrow may take a few months, it is helpful to know the patient’s type ahead of time. HLA typing of the sisters or brothers who are possible donors should also be performed. If siblings do not ‘match’, unrelated donors will be screened.

Relevant information about the leukemia

  • Staging, prognosis and risk classification

Unlike other cancers, which develop at a single site (such as breast cancer within the breast, or prostate cancer within the prostate) and then spread (metastasise), malignant cells in patients with leukemia are considered to be present throughout the body at diagnosis due to their normal circulation in the bloodstream. For this reason the prognosis is not determined by the extent of spread of the disease. The stage of disease is determined by the “phase” including chronic, accelerated, and blastic phase or blast crisis. The majority of patients are diagnosed in chronic phase. Patients are diagnosed with accelerated phase disease if the percentage of blasts increases to 15-29% in the blood or bone marrow, greater than 20% basophils develop in the blood, platelets either become severely elevated or low (but not as a result of therapy), or a clonal abnormality develops in addition to the Philadelphia chromosome. The most advanced stage of disease is blast crisis which is defined by an increase in bone marrow or peripheral blood blasts to at least 30%.

In peripheral blood or in bone marrow
CCA / Ph+= clonal chromosome abnormalities in Ph + cells
+ Excluding liver and spleen, including lymph nodes, skin, central nervous system (CNS), bone, and lung.

Untreated, patients with chronic phase CML will progress to accelerated phase in 3-5 years. Patients diagnosed with accelerated phase have a median survival of 4 to 6 months without treatment. Survival is further limited if blast crisis occurs with a median survival among untreated patients of 2 to 4 months.

The prognosis of a patient is best predicted by characteristics of the patient (including percentage of basophils as well as spleen size). Multiple scoring systems using patients and disease characteristics have been developed which provide an estimate of likelihood of response to therapy and survival. When using the most up to date, EUTOS risk score, five-year, progression-free survival was significantly better in the low than in the high-risk group (90% vs. 82%), but overall survival was only slightly lower than that of the normal, healthy population.


What are the treatment options?

The treatment should take place only in centres used to treat CML and offering an adequate multidisciplinary infrastructure. Whenever possible, the treatment should be offered in the form of clinical trials.

Treatment of CML is tailored to the individuals based on phase of disease at diagnosis. Unlike solid tumors, surgical resection and radiation therapy do not typically serve a role in the management of CML.


Treatment for chronic phase CML

The aforementioned  t(9;22) mutation results in the mutation of a tyrosine kinase. Today, all patients should first be treated with an inhibitor of this mutated tyrosine kinase, also known as the BCR-ABL tyrosine kinase.  Other agents, including interferon and hydroxyurea have a limited role in first-line therapy. Hydroxyurea is used to rapidly lower disease burden and white blood cell counts. Imatinib is a first generation oral, tyrosine kinase inhibitor which achieves a 8-year overall survival of nearly 90% of patients. Second generation tyrosine kinase inhibitors, such as dasatinib or nilotinib, may also be considered for all patients with CML at diagnosis. Patients should not discontinue (stop taking) imatinib, dasatinib, or nilotinib, unless instructed to as part of a clinical trial or in case of severe side effects. These therapies are used indefinitely as stopping their use has been shown to result in recurrence or progression of CML.

After initiating therapy for CML, patients should be monitored for treatment response assessment. The process of monitoring response to therapy is important to determine if an adequate response is being achieved, or if patients should be transitioned to a higher dose or different therapy. Since therapy is continued indefinitely and relapse occurs upon cessation of therapy in most patients, it is critical that the disease is closely monitored. Continued monitoring over time is needed, even in the setting of an optimal response, in order to detect and treat potential recurrence. Specific response criteria, including optimal, suboptimal, and failure have been established to guide appropriate increase or change of therapy.

Response assessment is based on 3 levels of response: hematologic response, cytogenetic response and molecular response, as described below.

  • Hematologic response
    • Assesment of hematologic response should be performed after the initiation of therapy every 2 weeks to monitor peripheral white blood cell (WBC) and platelet counts.
    • A complete hematologic response (CHR) is the association of
      • a total WBC <10×109/l,
      • a WBC formula with no present immature granulocytes and <5% of basophils,
      • platelets count <450×109/l,
      • and non palpable spleen.
  • Cytogenetic response (CgR)
    • Cytogenetics should be monitored after 3 months, 6 months, 12 months, and 18 months of therapy with a tyrosine kinase inhibitor. Until a complete cytogenetic response (CCgR) is achieved, cytogenetics should be repeated at least every 6 months.
    • A complete cytogenetic response (CCgR)is defined by the inability to detect the Philadelphia chromosome by analyzing the chromosomes metaphases
    • A partial cytogenetic response (PCgR) is defined as presence of 1%–35% positive Philadelphia chromosome metaphases.
  • Molecular response
    • Monitoring of molecular response is done with PCR which quantifies the BCR-ABL/ABL anomalies
    • It should be repeated at least every 3 months until a major molecular remission is achieved
    • Major molecular remission is defined by a PCR result with BCR-ABL/ABL <0.10% on the International Scale.
  • Once both a complete cytogenetic response and a major molecular remission have been achieved, cytogenetic monitoring should be performed every 12 months and molecular monitoring by PCR should be performed every 6 months.

Patients who achieve an optimal response should continue therapy with imatinib or the second generation tyrosine kinase inhibitor they are currently receiving. This group of patients should only discontinue therapy in the setting of a clinical trial.

Patients with only a suboptimal response can be considered for a dose increase in their current tyrosine kinase inhibitor or a change of therapy, if they are receiving imatinib, to a second generation tyrosine kinase inhibitor.

In patients failing to respond to imatinib, the treatment should be changed to a second generation tyrosine kinase inhibitor such as dasatinib or nilotinib. More recently, another second generation tyrosine kinase inhibitor (bosutinib) has been approved in the USA. The tyrosine kinase inhibitor ponatinib is also approved in the USA for the CML forms that have a specific mutation called T315I mutation. A different type of drug, omacetaxine that does not belong to the class of tyrosine kinase inhibitor has also been recently approved in the USA for the treatment of  cases whose CML is resistant to tyrosine kinase inhibitors. A dose increase in imatinib is unlikely to have a beneficial effect on the progressing disease. The ability to achieve a response and the duration of time a response lasts should be considered important factors when patients are being considered for allogeneic bone marrow transplant.

Treatment for accelerated phase or blast crisis CML

In these phases, evidence is more limited to decide which treatment option is the best. Treatment with a tyrosine kinase inhibitor can be initiated in patients who have not already been treated with a tyrosine kinase inhibitor. Change to another tyrosine kinase inhibitor or chemotherapy can be considered for patients who have already been treated with a tyrosine kinase inhibitor. However, those options are effective for only a limited time.

In these patients performing an allogeneic bone marrow transplant remains the most valid option and should be considered. This is the process of transferring someone else’s bone marrow stem cells into the patient. The patient’s white blood cells, red blood cells, and platelets are replaced by the donor’s cells. The donor’s cells will all become part of the patient’s own blood . The donor’s cells can recognise the patient’s cells as foreign since they are new to the patient’s body, resulting in damage to the patient’s own cells (this is known as graft-versus-host disease). GVHD typically involves the donor’s T cells contained in the graft attaching the patient’s skin, gastrointestinal tract (mouth, stomach and intestine), and liver. These tissues express minor histocompatibility antigens for which no match between donor and patient needs to be verified before transplantation, as opposed to major antigens. Expression of these minor antigens result in their recognition as foreign. During the same process the donor’s cells also recognise the patient’s leukemic cells as foreign and will destroy them, which is the main beneficial effect of a bone marrow transplant (this is known as graft-versus-leukemia effect, GVL). Bone marrow stem cell transplants provide an opportunity to eradicate the leukemia completely and cure the patient.

Allogeneic bone marrow transplant is the only established curative therapy for CML in either of these phases of disease. In order to control the pace of disease and to obtain a response prior to transplant, patients should consider a clinical trial, a second generation tyrosine kinase inhibitor, or conventional cytotoxic chemotherapy.

Treatment of resistant disease

The disease can become resistant to treatment with a tyrosine kinase inhibitor. Resistant disease can develop as the patient’s disease progresses resulting from mutations in the BCR-ABL tyrosine kinase. It is important when disease progresses and therapy is either increased in dosage or changed to a different tyrosine kinase inhibitor, that mutations which lead to resistance to therapy with a tyrosine kinase are screened. In rare cases in which compliance or drug metabolism is a question, imatinib drug levels can be assayed from the peripheral blood. If leukemia cells present a specific mutation called T315I mutation, the patient can be treated with one tyrosine kinase inhibitor, ponatinib, which is approved only in the USA for the moment.

Treatment of patients who cannot tolerate tyrosine kinase inhibitors

Patients who develop severe side effects because of first generation tyrosine kinase inhibitors, such as severe rash, severe edema (swelling of the legs), or fluid accumulation on the lungs should be first treated with second generation tyrosine kinase inhibitors. The majority of patients who cannot tolerate first generation tyrosine kinase inhibitors can be successfully treated with second generation tyrosine kinase inhibitors without side effects. To reduce the risk of side effects, the dose of second generation tyrosine kinase inhibitors can be reduced without decreasing efficacy. For patients who cannot tolerate three tyrosine kinase inhibitors, a new therapy, omacetaxine was recently shown to be effective and tolerable. In rare cases, patients who cannot tolerate all tyrosine kinase inhibitors should be considered for a bone marrow transplant from a sibling or unrelated donor.

Managing symptoms of the disease and side effects of the treatment

Leukemia and its treatment can cause severe side effects including diarrhoea, nausea, vomiting, hair loss, lack of energy, appetite, and severe infections. Effective therapies for these side effects exist and patients may expect that some of these problems can be treated.


What happens next?

Today, patients with CML require lifelong treatment with tyrosine kinase inhibitors. Research is ongoing to understand if treatment can be discontinued and which patients may be allowed to discontinue the treatment. No treatment discontinuation is recommended outside clinical trials.

Why and how do I need to be followed up by doctors?

After the treatment has been initiated, doctors will propose a follow-up aiming to:

  • detect possible progression, relapse, or return of leukemia, as soon as possible
  • evaluate adverse effects of the treatment and treat them
  • provide psychological support and information to enhance returning to normal life.

Follow-up visits with the doctor should include:
• History-taking, eliciting of symptoms and physical examination
• Routine evaluation of the complete blood count
• A repeat bone marrow biopsy, only in case of treatment failure, or in case of unexplained thrombocytopenia, or  if a reliable molecular test cannot be obtained.

In general, from the third month of the treatment initiation, cytogenetics will be repeated every 6 months until complete cytogenetic response has been achieved and confirmed, and PCR every 3 months until achievement of major molecular response. Once a complete cytogenetic response has been achieved and confirmed, a cytogenetic test is recommended every 12 months, but it is not necessary if  molecular testing is available and reliable. Once a major molecular response has been achieved and confirmed, a molecular test is recommended at least every six months. If the patient was high risk according to the risk score, or responded subobtimally to the therapy, more frequent monitoring may be advised. Screening for BCR-ABL mutations should be proposed only in the case of treatment failure or suboptimal response.

Returning to normal life

It can be hard to live with the idea that the leukemia can come back. From what is known today, no specific way of decreasing the risk of recurrence exists. As a consequence of the cancer itself and of the treatment, return to normal life may not be easy for some people. Questions related to body-image, sexuality, fatigue, work, emotions or lifestyle may be a concern to you. Discussing these questions with relatives, friends, other patients or doctors may be helpful. Support from patients organisations providing advice e.g. on managing effects of treatments, as well as psycho-oncologist services, or telephone info-lines are available in many countries.

How important is it that I take my medicine?

Only treatments that are taken can actually work. It is very important you take your medication as prescribed.

Studies have shown that patient adherence to medication varies significantly in CML patients. Especially when treated with oral drugs like in CML, it is mostly the patient's own responsibility to take the medicine as prescribed. Non-adherence - either deliberately or unintentionally - can have a significant impact on the success of therapy and the maintenance of response. CML studies have demonstrated a strong correlation between adherence levels, rates of relapse and rates of responses, as well as rate of hospitalisations. Already leaving out 1 in 10 pills has shown to have a significant impact on remission rates.

What if the leukemia progresses or comes back?

If the leukemia progresses, such as changing from chronic to accelerated or blastic phase, it is called disease progression or a relapse . The treatment depends on the age of the patient, prior treatment, and possibility of a bone marrow transplant. Specific recommendations for therapy are discussed for each phase of disease.

After obtaining a response using a second generation tyrosine kinase inhibtor, a bone marrow transplantation is recommended in patients at accelerated or blastic phase and those with a T315I mutation, if a sibling or unrelated donor can be identified as only a bone marrow transplant offers a chance of cure. Patients who relapse following a bone marrow transplant are usually not considered for a second transplant. Instead, donor lymphocyte infusion with a tyrosine kinase inhibitor, or a clinical trial are the preferred options for patients who relapse following a bone marrow transplant.

Should I consider clinical trials?

With the use of current standard therapy, including tyrosine kinase inhibitors, the prognosis of patients diagnosed with CML is favorable. In rare cases, the disease progresses despite the best current therapies. In such cases, the prognosis is poor and alternative therapies including clinical trials should be considered. For this reason, doctors and scientists are exploring new therapies. Promising therapies have to be first tested in clinical trials before they are accepted and given to all patients. These clinical trials provide an opportunity to receive a new therapy before it is generally available. On the other hand, such new therapies also have some risks as the side effects are unknown. Because of these positive and negative aspects of clinical trials, it is very important that you discuss the suitability of a clinical trial with your doctor.

Where can I find a CML patient support group?

Patient advocacy groups can help you get in touch with other patients who have CML, learn more about your disease, identify helpful information, find an experienced doctor for a second opinion, or identify clinical centers that run clinical trials. To find a group in your country, visit the CML Advocates Network group at



Chronic myeloid leukemia


Chronic myelogenous leukemia

Chronic myelocytic leukemia

Chronic granulocytic leukemia


Chronic myelogenous leukaemia

Chronic myeloid leukaemia

Chronic myelocytic leukaemia

Chronic granulocytic leukaemia

Blood cancer


Therapies by type

The following list of treatments is based on what we have found in scientific studies about cancer. More information about the listed therapies can be found under the tab THERAPIES. For registered drugs, radiotherapy and surgical interventions, approval by the authorities is given.

Registered drugs

Anti-cancer drugs with market authorization in the USA or in countries of the European Union. More

Cell-based therapies

Administration to patients of their own or someone else’s manipulated human cells. More

Natural products (excluding registered drugs)

Substances found in nature that usually have a pharmacological or biological activity. More


Controlled consumption of carefully selected foods and beverages with the intent to influence disease outcome.

Clinical trials

A clinical trial is a research study conducted with patients to evaluate whether a new treatment is safe (safety) and whether it works (efficacy). Clinical trials are performed to test the efficacy of drugs but also non-drug treatments such as radiotherapy or surgery and combinations of different treatments. Clinical trials take place in all kinds of hospitals and clinics, but mostly in academic hospitals. They are organized by researchers and doctors.

The Anticancer Fund provides a tool to search for phase III clinical trials by type of cancer and by country. For Belgium, the Netherlands, Switzerland, Luxembourg, France and the UK, the Anticancer Fund provides contacts to get more information about the phase III clinical trials currently ongoing. Discuss the possibilities of participating in one of these clinical trials with your doctor.

The list of the phase III clinical trials for chronic myeloid leukemia is available here.