Chronic myelogenous leukemia

01Definition and overview

Chronic myeloid leukaemia (CML, also chronic myelogenous or granulocytic leukaemia) is a myeloproliferative neoplasm (MPN): a cancer of the haematopoietic stem cell in which the marrow overproduces myeloid cells that still mature and work, above all neutrophils and their precursors. It is the classic MPN with a single defining lesion; polycythaemia vera, essential thrombocythaemia and primary myelofibrosis are driven by JAK2, CALR or MPL instead.

That lesion is the Philadelphia chromosome (Ph), a short chromosome 22 left by the reciprocal translocation t(9;22)(q34;q11). It joins BCR on chromosome 22 to ABL1 on chromosome 9, and the fusion gene, BCR::ABL1, makes a tyrosine kinase that is always active. The double colon is the current way to write a fusion gene; older texts write BCR-ABL. Without BCR::ABL1 the disease is not CML, however much the blood looks like it.

Untreated, the clone gathers further mutations and stops maturing, so CML runs through phases. The two classifications of 2022 disagree about the middle one:

CML is often confused with chronic lymphocytic leukaemia, but the two share only the word chronic:

02Etiology and pathophysiology

The translocation is acquired in one haematopoietic stem cell; it is not inherited, and CML does not run in families. Usually no cause is found. The one established cause is ionising radiation: CML became commoner among atomic bomb survivors in Japan and after radiotherapy, years after the exposure. It is rare in children and slightly commoner in men.

1. 1

   The translocation

   Chromosomes 9 and 22 break and swap their ends, a reciprocal translocation. BCR breaks in its major breakpoint cluster region, and the fusion transcript is e13a2 or e14a2 (once b2a2 and b3a2) in about 98 per cent of patients.
2. 2

   A kinase without a brake

   ABL1 is a proto-oncogene whose kinase is held shut by a myristoyl group at its start, folded into a pocket of the enzyme. The fusion protein has lost that start, and its BCR part makes the proteins pair up and switch each other on.
3. 3

   Growth without signals

   The kinase drives the RAS–MAPK, PI3K–AKT and JAK–STAT5 pathways: the cells divide more, resist apoptosis, need fewer growth factors and leave the marrow early. They still mature, so the blood fills with neutrophils and their precursors rather than blasts.
4. 4

   Progression

   The kinase also impairs DNA repair. Over years the clone gains more changes (an extra Philadelphia chromosome, trisomy 8, isochromosome 17q, monosomy 7, 3q26.2 rearrangements), stops maturing and becomes an acute leukaemia: myeloid in about three quarters of blast phases, lymphoid in a quarter.

Where BCR breaks sets the size of the protein: p210 in nearly all CML, p190 in most Philadelphia-positive acute lymphoblastic leukaemia (a different disease, treated as an acute leukaemia), and p230 rarely.

Imatinib, dasatinib, nilotinib, bosutinib and ponatinib compete with ATP for the kinase's ATP-binding site. Point mutations in the kinase domain can stop them binding, each sparing some drugs and not others. The most important, T315I, puts a bulky isoleucine at the gatekeeper position at the back of the pocket and blocks all of them except ponatinib. Asciminib binds elsewhere: it sits in the empty myristoyl pocket and locks the kinase shut, as the lost cap would have. It is the first STAMP inhibitor (specifically targeting the ABL myristoyl pocket), works on most ATP-site mutations, T315I included at a higher dose, and the few mutations that resist it leave the ATP-site drugs working.

1. 1960

   A small chromosome

   Peter Nowell and David Hungerford, in Philadelphia, find a small chromosome in CML cells: the first chromosome change tied to a cancer.

2. 1973

   A translocation

   Janet Rowley shows that it comes from an exchange between chromosomes 9 and 22.

3. 1980s

   The fusion gene

   BCR and ABL1 are found at the breakpoints and the fusion protein proves to be a kinase; in 1990 the fusion gene alone gives mice a CML-like disease.

4. 1998 to 2003

   Imatinib

   Brian Druker and colleagues treat the first patients with STI571, later imatinib. It is approved in 2001, and in 2003 a large trial shows it far better than interferon with cytarabine.

5. 2006 to 2013

   More inhibitors

   Dasatinib, nilotinib, bosutinib and ponatinib arrive for resistance and intolerance; the first three later move to first line.

6. 2010

   Stopping

   A French trial shows that about 4 in 10 patients in deep remission stay in remission a year after stopping imatinib.

7. 2022 to 2026

   Asciminib

   The first STAMP inhibitor is licensed in the EU in 2022 after two or more TKIs, in November 2025 for chronic phase at any line, and in April 2026 at a higher dose for T315I when ponatinib has failed or is unsuitable.

03Clinical features

In Europe about 95 per cent of patients are diagnosed in chronic phase, and many have no symptoms: the disease is found on a blood count taken for something else.

• Tiredness, weight loss, night sweats and low-grade fever, from the high turnover of cells.
• Fullness or a dragging ache under the left ribs and early satiety; a splenic infarct gives sudden, sharp pain there.
• Breathlessness and pallor from anaemia, and gout from a high urate.
• Splenomegaly, the main sign, often large; its size in centimetres below the left costal margin is recorded, because it enters the risk score. The liver may be enlarged.
• Bruising and bleeding are uncommon, even with very high platelets.

With a very high white count, usually well above 100 × 10⁹/L, the cells sludge in small vessels, called leucostasis: headache, blurred vision with retinal haemorrhages, confusion, breathlessness and priapism. Leucostasis and priapism are emergencies: the count is lowered the same day with hydroxycarbamide, with leucapheresis when symptoms are severe, and priapism needs a urologist at once.

About 1 in 20 patients in Europe presents in accelerated or blast phase, more where diagnosis comes late: fever, bone pain, worsening anaemia, falling platelets, rising blasts and basophils, and lymph nodes or deposits of blasts in skin or soft tissue (myeloid sarcoma).

The differential diagnosis:

• a leukaemoid reaction to infection, inflammation, a cancer, steroids or G-CSF: mostly mature neutrophils, toxic granulation, no basophilia. The neutrophil alkaline phosphatase score, low in CML, has been replaced by testing for BCR::ABL1;
• the other MPNs, among them polycythaemia vera. CML can present with a high platelet count alone, so an apparent essential thrombocythaemia is always tested for BCR::ABL1;
• BCR::ABL1-negative look-alikes: MDS/MPN with neutrophilia (atypical CML in the ICC and older texts), chronic neutrophilic leukaemia and chronic myelomonocytic leukaemia.

04Diagnosis and management

1. 1

   Count and film

   A full blood count and a film read by a haematologist: the pattern above, with a count of blasts and basophils.
2. 2

   Find the fusion

   BCR::ABL1 by FISH or RT-PCR on blood confirms the diagnosis within days. PCR names the transcript type, which must be known before it can be followed.
3. 3

   The marrow

   An aspirate for the blast count, and a karyotype: it shows the Philadelphia chromosome in about 9 in 10 patients (a variant or hidden rearrangement in the rest) and any extra chromosome changes.
4. 4

   Risk and baseline

   The ELTS score (age, spleen size, blood blasts, platelets) predicts the risk of dying of CML and has replaced the Sokal score. Before a TKI: an ECG with the QT interval, lipids, HbA1c, liver and kidney tests, hepatitis B serology and a review of the patient's drugs.

First-line treatment

Hydroxycarbamide (hydroxyurea) can lower a very high count while the genetics are awaited, with fluids and allopurinol. Every patient in chronic phase then takes a TKI by mouth, usually for many years:

The second-generation TKIs (2GTKIs: dasatinib, nilotinib, bosutinib) and asciminib give faster, deeper responses and somewhat fewer progressions than imatinib, but none has been shown to lengthen survival. In the first-line asciminib trial, 68 per cent reached a major molecular response at 48 weeks, against 49 per cent on other TKIs, the gain clearest over imatinib. A younger patient hoping to stop one day, or a high ELTS score, argues for a more potent drug; other illnesses rule some out:

• lung disease or a past pleural effusion: avoid dasatinib, which caused effusions in 28 per cent against under 1 per cent with imatinib in its main trial;
• diabetes, arterial disease, high cardiovascular risk or past pancreatitis: avoid nilotinib, which over 10 years gave 16.5 per cent of patients a cardiovascular event, against 3.6 per cent with imatinib;
• bowel, liver or kidney disease: avoid bosutinib;
• a long QT interval: care with nilotinib, with potassium and magnesium corrected.

Arterial occlusive events (heart attack, stroke, limb ischaemia) are the most dangerous long-term harm, so blood pressure, lipids, glucose and smoking are treated before and during treatment, above all with nilotinib and ponatinib.

Monitoring and the milestones

The response is measured by quantitative PCR of BCR::ABL1 in blood, converted to the International Scale (IS), on which 100 per cent is the standardised level before treatment. Counts are checked every 2 weeks until normal, and PCR every 3 months until a major molecular response (MMR) is reached and confirmed, then every 4 to 6 months.

about a complete cytogenetic response: no Ph-positive cells in the marrow

1per centabout a complete cytogenetic response: no Ph-positive cells in the marrow

a major molecular response (MR3), after which progression is rare

0.1per centa major molecular response (MR3), after which progression is rare

MR4, a deep molecular response (MR4.5 is 0.0032 per cent)

0.01per centMR4, a deep molecular response (MR4.5 is 0.0032 per cent)

At diagnosis, high-risk chromosome changes or a high ELTS score already count as a warning. The 2025 European recommendations renamed the categories (once optimal, warning and failure) and advise against switching on a single result, or too readily in older patients with other illnesses, in whom a more toxic drug can do more harm than a slow response.

When the response falls short

About 15 to 20 per cent of patients have an unfavourable response to first-line treatment. Missed tablets are a common and often hidden cause of a poor response, so a warning or unfavourable result starts with adherence and interacting drugs, a repeat PCR, and a test for kinase domain mutations. The mutation chooses the next drug: T315I needs ponatinib or asciminib; F317L resists dasatinib but not nilotinib, bosutinib, ponatinib or asciminib; mutations in the myristoyl pocket leave every ATP-site drug working. In a patient in MMR or deeper with side effects, the dose is lowered before the drug is changed, unless the harm is serious (pulmonary hypertension, recurrent effusions, an arterial or venous occlusion), which calls for a switch.

After a 2GTKI fails, the next drug is usually ponatinib or asciminib. After two or more TKIs, 38 per cent reached MMR at 96 weeks on asciminib, against 16 per cent on bosutinib. Ponatinib starts at 45 mg and is cut to 15 mg once BCR::ABL1 is 1 per cent or less, which keeps its effect and lowers its arterial risk; in an earlier trial that started everyone on 45 mg, about 3 in 10 patients in chronic phase had an arterial occlusive event within 5 years. In the EU, ponatinib is licensed for resistance to dasatinib or nilotinib, for intolerance of them when imatinib is not appropriate, or for T315I; asciminib for chronic phase at any line, and for T315I at 200 mg twice daily when ponatinib has failed, is not tolerated or is unsuitable.

Transplantation and advanced phase

Allogeneic stem cell transplantation, the only cure before imatinib, now comes late, because of its death rate and graft-versus-host disease. The donor search starts when the first 2GTKI fails; transplantation is offered for chronic phase resistant to ponatinib or asciminib, intolerance of every TKI, and blast phase. Blast phase is treated as an acute leukaemia: a potent TKI (dasatinib or ponatinib, by the mutation) with AML-type or ALL-type chemotherapy, then a transplant for every fit patient once a second chronic phase is reached.

Treatment-free remission

A patient with a long, deep response can try stopping. About 40 to 50 per cent stay off treatment, and more than 80 per cent of relapses come in the first 6 to 8 months.

• Required: first chronic phase, a motivated patient, a laboratory with reliable, fast IS testing, and agreement to frequent PCR.
• Allowed to stop: first-line treatment (or second line if the switch was for intolerance or a mutation sensitive to another TKI), a typical e13a2 or e14a2 transcript, more than 5 years on a TKI (4 with a 2GTKI), and MR4 or better for more than 2 years.
• Recommended to consider: more than 5 years on a TKI, with MR4 for more than 3 years or MR4.5 for more than 2.

PCR follows every 6 to 8 weeks for 6 months, every 2 months to a year, then every 3 to 6 months for life, because late loss of MMR occurs in up to 14 per cent. The TKI is restarted as soon as MMR is lost, without waiting for confirmation; 90 to 95 per cent regain their deep response, and blast phase after stopping is very rare. About 20 to 30 per cent get a withdrawal syndrome of muscle and joint aches, which usually settles by itself or with an anti-inflammatory drug.

Pregnancy

Men keep taking their TKI while trying for a child. In women, TKIs can harm the fetus from implantation to about week 16: a woman planning a pregnancy ideally reaches a deep response and stops as for treatment-free remission, or, in stable MMR, stops at her first positive test. In pregnancy, interferon alfa is safe and controls the counts, imatinib or nilotinib can be given after week 16 if needed, dasatinib is avoided throughout, and no TKI is taken while breastfeeding. CML found in pregnancy is watched if the count is below about 100 × 10⁹/L and the risk low, or bridged to week 16 with leucapheresis or interferon.

05Epidemiology

CML is uncommon: about 1 new case per 100,000 people a year in a population-based registry covering 20 European countries, with a median age at diagnosis of 56, younger than for most leukaemias. It makes up about 15 per cent of adult leukaemias, is slightly commoner in men and is rare in children. Because treated patients live for decades, the number living with CML keeps rising, and most of the cost of care is the lifelong drugs. That cost has fallen since imatinib became generic, and generic dasatinib and nilotinib followed in the EU in the 2020s; the other TKIs remain expensive.

06Prognosis

Before imatinib, most patients died of blast phase within a few years unless a transplant cured them. In the first large imatinib trial, 83 per cent were alive at 10 years, and most treated patients now die of causes unrelated to CML. In Sweden, patients diagnosed in 2013 were predicted to lose fewer than 3 years of life on average, though a small loss remains at every age.

The outlook is worse with a high ELTS score or high-risk chromosome changes at diagnosis, missed milestones or lost MMR, a resistance mutation (above all T315I or a compound mutation), poor adherence, and blast phase, which is still hard to treat and depends on reaching a second chronic phase and a transplant. Follow-up is for life: PCR, the TKI's side effects (blood pressure, lipids, glucose, heart and lungs), interactions and, in deep remission, the question of stopping.