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Understanding leukemia

Chronic myeloid leukemia (CML)

CML is one of the most hopeful stories in modern cancer care. A few decades ago it was considered a grave illness; today it is controlled with daily tablets, and most people live an almost normal lifespan. This topic explains the cause of CML, its phases, its treatment and how results are monitored.

Last updated: ~6 min read
Blood smear in chronic myeloid leukemia: a great many white blood cells at different stages of maturity among red blood cells
Figure 1.Blood smear in CML: because of a chromosome change in one cell, the marrow produces large numbers of white blood cells at every stage of maturity.

01Short answer

Chronic myeloid leukemia (CML) is a usually slow-growing leukemia in which myeloid cells, especially granulocytes, multiply excessively in the bone marrow. Its cause is almost always the same: a swap between chromosomes 9 and 22 creates the Philadelphia chromosome and the BCR::ABL1 fusion gene. This gene makes an enzyme — a tyrosine kinase — that stays permanently “switched on”. CML is often found with no symptoms, on a routine blood test; sometimes there is tiredness, weight loss, night sweats and an enlarged spleen. In the US the median age at diagnosis is 67. The main treatment is tyrosine kinase inhibitors (TKIs), which block BCR::ABL1 — daily tablets. With TKIs, 10-year overall survival exceeds 90%, and some people can stop treatment under medical supervision after a long, deep remission.

02Simple explanation

In CML, the marrow makes far too many white blood cells — mostly neutrophils and their precursors. Unlike in acute leukemia, many of these cells can mature and work for a while. That is why the disease usually develops slowly and may cause no symptoms for a long time.

The cause is a chromosome “swap” in one cell: pieces of chromosomes 9 and 22 trade places. The shortened chromosome 22 is called the Philadelphia chromosome. In the process two genes fuse, creating BCR::ABL1. This change is not inherited and is not passed on to family members.

The BCR::ABL1 protein is like a car with its accelerator stuck down: it constantly sends the cell a “divide, multiply” signal. As a result, the white cell count rises a lot, the spleen grows, and you may feel heaviness or fullness under the left ribs.

In the late 1990s, scientists created a drug that blocks this protein — imatinib. It became one of the first targeted drugs in cancer treatment. Today there are several such drugs, called tyrosine kinase inhibitors (TKIs). They are taken as tablets once or twice a day.

How well treatment works is tracked with a sensitive test (PCR) that measures the level of BCR::ABL1 in the blood. The goal is to bring this level as low as possible. Most people who take their TKI regularly work, raise families and travel — CML often becomes a chronic condition managed for many years.

03Scientific explanation

The Philadelphia chromosome — t(9;22)(q34;q11) — is found in more than 95% of CML cases; in the rest, BCR::ABL1 arises through cryptic or complex rearrangements and is detected by molecular methods. BCR::ABL1 is a constitutively active tyrosine kinase: by permanently activating signalling pathways such as RAS/MAPK, PI3K/AKT and JAK/STAT, it increases proliferation, reduces apoptosis and weakens how cells are held in the marrow. BCR::ABL1-negative “CML-like” cases are assessed as separate diseases (for example chronic myelomonocytic leukemia or atypical CML).

Three phases are traditionally described: chronic (most diagnoses), accelerated and blast phase. Blast phase is defined by blasts ≥20% (WHO, ICC) or ≥30% in some systems (ELN), or by blast deposits outside the marrow, and it behaves like an acute leukemia (myeloid or lymphoid). In the TKI era, WHO 2022 dropped the accelerated phase as a separate category, emphasising high-risk features of progression instead, while ICC 2022 keeps it. According to the NCI, an enlarged spleen is the most common physical finding at diagnosis.

In chronic phase, any BCR::ABL1 inhibitor can be chosen as first treatment: imatinib, second-generation TKIs (dasatinib, nilotinib, bosutinib) or asciminib, an allosteric inhibitor that binds the ABL1 myristoyl pocket. According to the NCI, 10-year event-free and overall survival with these drugs exceed 90%, and median survival is projected to approach normal life expectancy for most people. The choice takes into account side-effect profiles, other conditions, drug interactions and cost. The T315I mutation causes resistance to imatinib, dasatinib, nilotinib and bosutinib; in that case, options such as ponatinib or asciminib, and sometimes an allogeneic transplant, are considered.

Response is measured by the BCR::ABL1 transcript level on the International Scale (IS): ≤10% at 3 months (early molecular response), ≤0.1% (major molecular response, MMR) and deeper responses (MR4 ≤0.01%, MR4.5 ≤0.0032%). According to the NCI, people who have taken a TKI for more than 3–5 years and reached a deep molecular response (MR4.5) are the best candidates to consider stopping; about half have a molecular relapse after stopping, but almost all respond again to their previous TKI. Close PCR monitoring after stopping is essential; some people report muscle and joint pain (a “withdrawal syndrome”).

04What happens in the body?

One chromosome change — one cause

CML is one of the few diseases whose cause is almost the same in everyone. Chromosomes 9 and 22 swap pieces, creating the BCR::ABL1 gene. The diagnosis is confirmed by finding this change in the blood or marrow with cytogenetics, FISH or PCR.

Two glowing chromosomes on a dark background, one long and one short; teal and orange pieces trade places between them, and a small warm point of light glows on the short chromosome.
Figure 2.Chromosomes 9 and 22 swap pieces: the shortened chromosome 22 — the Philadelphia chromosome — carries BCR::ABL1.

Phases: why early diagnosis matters

In the great majority of people, CML is found in the chronic phase — the stage that is easiest to treat. Without treatment, the disease can move over years into more aggressive phases. TKIs prevent this very effectively.

TKIs: targeted tablets

A TKI sits in the “active pocket” of the BCR::ABL1 protein and blocks its signal. The leukemia cells stop multiplying, and normal blood formation recovers. Taking the medicine every day as prescribed is one of the most important factors for good results.

Close-up of a folded protein: a small, teal-glowing drug molecule fits precisely into its pocket, and the orange signal waves coming from the protein fade away.
Figure 3.A tyrosine kinase inhibitor sits in the active pocket of the BCR::ABL1 protein and switches off its signal.

Monitoring and treatment-free remission

PCR tests are usually done every 3 months in the first years. Some people who stay in a deep response for a long time may try stopping their TKI under medical supervision — this is called treatment-free remission. This decision should only be made with your hematologist and with close monitoring.

05CML: how we block one faulty gene

The cause and the treatment of CML are links in one chain.

Chromosome swap — t(9;22) creates the Philadelphia chromosome.1Chromosome swapt(9;22) creates the Philadelphia chromosome.
An enzyme stuck “on” — The BCR::ABL1 tyrosine kinase signals growth.2An enzyme stuck “on”The BCR::ABL1 tyrosine kinase signals growth.
Too many white cells — Granulocytes rise in the blood; the spleen grows.3Too many white cellsGranulocytes rise in the blood; the spleen grows.
The TKI blocks it — A tablet closes the protein’s active pocket.4The TKI blocks itA tablet closes the protein’s active pocket.
A daily tabletLong-term control for most people.
PCR monitoringBCR::ABL1 levels are measured regularly.
Near-normal lifespan10-year survival above 90%.

06Molecular response milestones in CML (BCR::ABL1, International Scale)

ResponseBCR::ABL1 levelIn plain words
Early molecular response≤10% at 3 monthsTreatment has got off to a good start
Major molecular response (MMR)≤0.1%About a 1,000-fold fall from baseline; a sign of good long-term results
Deep molecular response (MR4)≤0.01%A very low, barely detectable level
Deep molecular response (MR4.5)≤0.0032%If sustained for a long time, stopping treatment can be discussed

* Targets and time frames may vary between international guidelines. Results should be measured in a laboratory standardised to the IS. Discuss your own results with your hematologist.

07Key terms

CML
Chronic myeloid leukemia — a usually slow leukemia caused by BCR::ABL1.
Philadelphia chromosome
A shortened chromosome 22 formed by t(9;22).
BCR::ABL1
A fusion gene that makes a permanently active tyrosine kinase.
Tyrosine kinase
An enzyme that passes signals inside a cell.
TKI
Tyrosine kinase inhibitor — a targeted drug that blocks BCR::ABL1.
Chronic phase
The earliest and most treatable stage of CML.
Blast phase
The stage in which CML behaves like an acute leukemia.
MMR
Major molecular response — BCR::ABL1 ≤0.1% (IS).
Treatment-free remission
A deep response that continues after stopping the TKI.
Spleen
An organ under the left ribs that filters blood; often enlarged in CML.

08Key points

  • CML is a usually slow-growing myeloid leukemia.
  • Its cause is almost always the Philadelphia chromosome and the BCR::ABL1 gene.
  • It is often found with no symptoms, on a routine blood test.
  • The main treatment is tyrosine kinase inhibitors — daily tablets.
  • Response is tracked by measuring BCR::ABL1 with PCR.
  • With TKIs, 10-year survival exceeds 90%.
  • Some people can stop treatment under supervision after a long, deep remission.
  • Taking the medicine regularly is very important for results.

09Frequently asked questions

Will I have to take TKIs for life?

Many people take them for many years. But some who stay in a deep molecular response for a long time may try stopping under their hematologist’s supervision. This is only possible when certain criteria are met and with frequent PCR monitoring.

What happens if I miss a dose?

An occasional missed dose is usually not dangerous, but missing doses regularly can make treatment less effective and raise the risk of resistance. Ask your doctor or pharmacist what to do if you miss one — do not take two doses at once.

What are the side effects of TKIs?

They depend on the drug: tiredness, muscle cramps, diarrhea, nausea, rash, swelling and others. Some drugs can affect the heart, blood vessels or lungs. Side effects can often be managed, or reduced by switching to another TKI.

Do other medicines and foods affect TKIs?

Yes, some do. Certain medicines, herbal supplements and foods such as grapefruit can change the level of a TKI in the blood. Check with your doctor or pharmacist before starting any new medicine or supplement.

Can I have children with CML?

Many people with CML have become parents. But TKIs can harm an unborn baby, so family planning should be discussed with your hematologist in advance. Your doctor can adjust the treatment plan accordingly.

Can CML turn into acute leukemia?

Without treatment, CML can progress to blast phase over time. TKIs have greatly reduced this risk, and blast phase is rare in people who take their treatment regularly. Regular PCR monitoring helps spot any change early.

10Questions for your doctor

Take these questions to your appointment. The ones you save are collected on the “My questions” page and stay on this device only.

  1. Which phase is my CML in?

  2. Which TKI has been chosen, and why?

  3. How often will we check my BCR::ABL1 level, and what are our targets?

  4. Which foods and medicines can interact with my TKI?

My questions

12Sources

  1. National Cancer Institute (NCI). Chronic Myeloid Leukemia Treatment (PDQ®) — Health Professional Version
  2. National Cancer Institute (NCI). Chronic Myeloid Leukemia Treatment (PDQ®) — Patient Version
  3. National Cancer Institute (NCI), SEER. Cancer Stat Facts: Chronic Myeloid Leukemia (CML)
  4. American Cancer Society. What Is Chronic Myeloid Leukemia?
  5. American Cancer Society. Phases of Chronic Myeloid Leukemia
  6. NHS. Chronic myeloid leukaemia — Symptoms
  7. NHS. Treatment for chronic myeloid leukaemia
  8. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: Philadelphia chromosome
  9. National Cancer Institute (NCI). Targeted Therapy to Treat Cancer
  10. National Human Genome Research Institute. Translocation
  11. Leukemia (Nature) — WHO 5th edition. WHO Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms
Medical disclaimerThis information is for educational purposes only and does not replace medical advice.
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