Chronic myeloid leukaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

CML is defined by BCR::ABL1, usually the Philadelphia chromosome t(9;22). Many adults are diagnosed incidentally with neutrophilia, myelocytes and metamyelocytes, basophilia and thrombocytosis. Symptoms include fatigue, sweats, weight loss, abdominal fullness and early satiety from splenomegaly. Gout and priapism reflect high cell turnover or extreme counts. A leucocyte alkaline phosphatase score is historical and not diagnostic. Confirm the fusion directly and exclude an acute leukaemia or another myeloproliferative neoplasm when blast percentage, fibrosis or molecular findings are atypical.

At baseline perform FBC and film, marrow aspirate and trephine, conventional cytogenetics and quantitative BCR::ABL1 RT-PCR. Marrow determines chronic versus blast phase and detects additional chromosomal abnormalities; current classifications have simplified the former accelerated-phase category, but rising blasts, basophils, cytopenias and clonal evolution remain warning features. Calculate an ELTS or current validated risk score. Record standard e13a2 or e14a2 transcript, or design personalised monitoring for an atypical transcript. Check renal, liver, cardiovascular and metabolic baseline before TKI selection.

For newly diagnosed chronic phase, imatinib 400 mg daily, dasatinib 100 mg daily or nilotinib 300 mg twice daily are evidence-based options under NICE. Explain exact administration: imatinib with a meal and water; nilotinib with no food for at least 2 hours before and 1 hour after. Review acid suppression with dasatinib because gastric pH alters absorption, and screen every medicine for CYP3A interactions. Manage early cytopenia with SmPC interruption and reductions rather than abandoning therapy. Hydroxycarbamide can temporarily control a very high symptomatic count while confirmation or TKI access is arranged but should stop once definitive therapy controls disease.

Molecular monitoring is the core outcome. Use quantitative RT-PCR on the International Scale at 3, 6 and 12 months and at least every 3 months until major molecular response, BCR::ABL1 at or below 0.1%, is confirmed. Current international 2025 landmarks label 10% at 3 months, 1% at 6 months and 0.1% at 12 months as favourable. A result above 10% at 3 months should be confirmed within 1–3 months. Interpret trajectory, dose interruptions and adherence before declaring resistance. Loss of a previous response or a rising pattern prompts earlier repeat, marrow cytogenetics and kinase-domain mutation analysis.

When response is inadequate, first check that tablets are actually taken at the correct time and dose and that interactions or intolerance have not reduced exposure. Test BCR::ABL1 kinase-domain mutations with an accredited assay and choose a TKI active against the mutation while respecting comorbidity. T315I resists imatinib, dasatinib, nilotinib and bosutinib and can support ponatinib under NICE criteria. Allogeneic transplant is now uncommon in chronic phase but remains important for blast phase, multi-TKI resistance or intolerable disease with poor options. Blast phase needs AML- or ALL-type therapy according to lineage plus an active TKI, aiming for a second chronic phase before transplant.

Treatment-free remission is not casual discontinuation. Eligible patients have first chronic phase, reliable standard molecular monitoring, several years of TKI treatment and sustained deep molecular response, commonly MR4 or deeper for at least 2 years, under the centre criteria. Discuss that approximately half restart treatment. Current international guidance uses PCR every 6–8 weeks for 6 months, every 2 months during months 6–12 and every 3–6 months thereafter; restart if major molecular response is lost. Late molecular recurrence occurs, so monitoring continues indefinitely.

Pregnancy requires joint CML and maternal-medicine planning; use the dedicated medicine and monitoring pathway below rather than abrupt unmonitored TKI cessation.

Key points

Suspect CML from persistent neutrophilia with left shift, basophilia, thrombocytosis and splenomegaly; confirm BCR::ABL1 rather than diagnosing from count pattern alone.
First-line confirmation uses peripheral-blood BCR::ABL1 FISH or RT-PCR, while baseline marrow morphology and conventional karyotype establish phase and additional chromosomal abnormalities.
Record the exact BCR::ABL1 transcript type and baseline International Scale result so subsequent quantitative RT-PCR uses a valid marker.
Imatinib, dasatinib and nilotinib are NICE-supported first-line options for untreated adult chronic-phase Philadelphia-positive CML; choose from molecular goal and comorbidity, not potency alone.
Monitor BCR::ABL1 on the International Scale at least every 3 months until major molecular response is achieved and confirmed; stable deep responders can later move to 4–6-month intervals.
Favourable molecular landmarks are BCR::ABL1 at or below 10% at 3 months, 1% at 6 months and 0.1% at 12 months, but confirm trends and check adherence before switching on one result.
Rising transcript or milestone failure requires dose and interaction review, marrow cytogenetics and BCR::ABL1 kinase-domain mutation testing before selecting the next TKI.
Treatment-free remission is a monitored specialist strategy for selected chronic-phase patients with prolonged TKI exposure and sustained deep molecular response; restart promptly if major molecular response is lost.
Pregnancy or conception requires a pre-agreed specialist TKI interruption and monitoring plan.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Philadelphia chromosome

An acquired reciprocal t(9;22) translocation creates BCR::ABL1 in a haematopoietic stem cell, producing constitutive tyrosine kinase signalling.

Additional clonal evolution

Secondary chromosomal abnormalities and kinase-domain mutations emerge under disease progression or treatment selection and can drive resistance or blast transformation.

Limited environmental association

High-dose ionising radiation modestly increases risk, but most patients have no preventable exposure or inherited cause and family screening is unnecessary.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Constitutive kinase activity
BCR::ABL1 activates proliferative, survival and adhesion pathways, expanding granulocytic cells while retaining maturation during chronic phase.
2
Marrow and splenic expansion
Excess myeloid production causes neutrophilia, basophilia and thrombocytosis, with extramedullary haematopoiesis producing splenomegaly and early satiety.
3
Progressive genomic instability
Untreated or resistant clones acquire further lesions, lose differentiation and progress to myeloid or lymphoid blast phase resembling acute leukaemia.
4
TKI-dependent suppression
Tyrosine kinase inhibitors usually control rather than eradicate the founding stem-cell clone, so adherence and molecular surveillance remain central even when blood counts normalise.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Typical chronic phase

Persistent neutrophilia with full granulocytic maturation, basophilia, thrombocytosis and splenomegaly is characteristic but still requires BCR::ABL1 confirmation.

Progression pattern

New anaemia or thrombocytopenia, rising blasts or basophils, clonal abnormalities and enlarging spleen despite therapy suggests resistant or blast-phase disease.

Molecular warning

Failure to achieve expected transcript decline, a confirmed rise or loss of major molecular response may precede haematological relapse.

Drug-specific toxicity

Pleural dyspnoea, arterial ischaemia, QT symptoms, metabolic deterioration, oedema or severe diarrhoea should be linked to the selected TKI rather than treated generically.

Red flags requiring action

New cytopenias, rising blasts or basophils, rapidly enlarging spleen, constitutional decline or extramedullary mass suggests accelerated biology or blast phase rather than simple TKI intolerance.
Dyspnoea, hypoxaemia, confusion, retinal haemorrhage or priapism with extreme leukocytosis requires emergency leucostasis assessment and cytoreduction.
A rising BCR::ABL1 trend, loss of major molecular response or loss of complete haematological response requires adherence, interaction and resistance assessment rather than waiting for the next routine sample.
Chest pain, focal neurology, limb ischaemia, pleural effusion or pulmonary hypertension may reflect TKI-specific serious toxicity and should change treatment promptly.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: FBC, film and blood BCR::ABL1First stepFirst line
Why
Identify a compatible myeloid pattern and demonstrate the defining fusion promptly.
Interpretation and limitations
RT-PCR identifies transcript and FISH detects rearranged cells; neither replaces baseline marrow phase and cytogenetic assessment.
02
Reference-standard baseline marrow and karyotype
Why
Establish phase, morphology and additional chromosomal abnormalities.
Interpretation and limitations
Record blast and basophil percentages, fibrosis and clonal evolution; use cytogenetics again at suspected resistance or progression rather than for routine molecular monitoring.
03
Quantitative BCR::ABL1 International Scale
Why
Measure treatment response and identify molecular recurrence.
Interpretation and limitations
Compare serial results at 3, 6 and 12 months and beyond. Confirm an unexpected rise, review adherence and dose interruptions and act on kinetics, not one isolated decimal.
04
BCR::ABL1 kinase-domain mutation analysis
Why
Select an active later-line TKI when resistance or progression is suspected.
Interpretation and limitations
Use at a confirmed inadequate or lost response, not routinely in stable deep remission; T315I has specific treatment implications and blast phase requires full reassessment.
05
TKI comorbidity baseline
Why
Choose the medicine least likely to amplify existing organ risk.
Interpretation and limitations
Assess ECG, cardiovascular disease, blood pressure, lipids, glucose, lung and pleural disease, renal and liver function and all interacting medicines before selection.
06
Pregnancy and reproductive assessment
Why
Prevent fetal exposure and plan a monitored interruption or alternative.
Interpretation and limitations
Document pregnancy status and goals before therapy or treatment-free attempts and involve maternal medicine promptly for conception or unplanned exposure.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Reactive neutrophilia

Infection, inflammation, smoking or steroids cause mature neutrophilia and toxic change without a BCR::ABL1 clone; basophilia and persistent left shift strengthen CML suspicion.

Other myeloproliferative neoplasm

Polycythaemia vera, essential thrombocythaemia and primary myelofibrosis usually carry JAK2, CALR or MPL rather than BCR::ABL1 and have different marrow morphology.

Chronic neutrophilic leukaemia

Persistent mature neutrophilia with CSF3R mutation and absent BCR::ABL1 defines a rarer myeloid neoplasm with a different prognosis and treatment.

Leukaemoid malignancy response

Metastatic cancer and severe infection can produce dramatic leukocytosis; integrated film, marrow, cytogenetic and molecular findings prevent false CML diagnosis.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspected CMLConfirm fusion and establish phaseFirst stepPersistent myeloid leukocytosis, basophilia or splenomegaly suggests a clonal myeloproliferative disorder.

1Send FBC, expert film, blood BCR::ABL1 testing, lysis and organ baseline and assess leucostasis symptoms.
2Perform marrow morphology, trephine and conventional karyotype and record transcript type and quantitative baseline.
3First lineClassify phase and ELTS risk and select a first-line TKI using comorbidity, reproductive goals and treatment aim.

02Molecular follow-upMeasure response on one scaleTKI has started or changed in chronic-phase CML.

1Check counts frequently to haematological response and quantitative BCR::ABL1 at least every 3 months until major molecular response is confirmed.
2Compare with 3-, 6- and 12-month landmarks and previous trajectory, including interruptions, adherence and interactions.
3Continue and space to 4–6 months when stable, or repeat early and investigate mutation and cytogenetics for an unfavourable or rising result.

03Inadequate responseExplain failure before switchingA landmark is missed, transcript rises or a previous response is lost.

1Confirm the result and review adherence, dose, administration, adverse effects and interacting or acid-suppressing medicines.
2Obtain marrow cytogenetics and accredited BCR::ABL1 mutation analysis when resistance criteria are met.
3Select an active TKI from mutation and comorbidity, and refer early for transplant assessment in advanced phase or multi-TKI resistance.

04Treatment-free remissionStop only inside intensive surveillanceA motivated chronic-phase patient has sustained deep response and meets specialist eligibility criteria.

1Confirm treatment duration, stable MR4 or deeper, standard transcript, reliable PCR access, adherence and understanding of restart criteria.
2Stop under the CML service and monitor PCR every 6–8 weeks initially, then at the defined lifelong intervals.
3Restart a TKI promptly if major molecular response is lost and monitor frequently until the prior response is regained.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

First-generation BCR::ABL1 inhibitor and NICE-supported first-line option with long-term efficacy and safety experience.

Imatinib

Give 400 mg orally once daily with a meal and a large glass of water for chronic-phase CML; the SmPC dose is 600 mg once daily for accelerated phase or blast crisis, integrated with specialist phase-directed therapy.

Monitor FBC, liver, renal function, oedema, weight, cramps and gastrointestinal effects; review CYP3A interactions and dose interruption criteria. Avoid during pregnancy unless specialist life-saving benefit outweighs risk, use effective contraception and stop breastfeeding.

Potent first-line or later-line TKI with activity against many imatinib-resistant BCR::ABL1 mutations, but not T315I.

Dasatinib

Give 100 mg orally once daily for chronic-phase CML; use 140 mg once daily for accelerated or blast phase when selected, with dose interruption or reduction according to cytopenia and toxicity.

Avoid or use cautiously with pleural effusion, pulmonary arterial hypertension or major bleeding risk. Do not combine with proton-pump inhibitors or H2 antagonists without specialist review, assess CYP3A interactions and avoid pregnancy and breastfeeding.

NICE-supported first-line potent TKI that can produce rapid deep molecular responses when vascular and metabolic risk is acceptable.

Nilotinib

For newly diagnosed chronic-phase CML give 300 mg orally twice daily approximately 12 hours apart, with no food for at least 2 hours before and 1 hour after each dose.

Obtain ECG and correct potassium and magnesium; avoid long-QT and strong CYP3A interactions. Monitor arterial disease, glucose, lipids, pancreas and liver. Food markedly increases exposure. Avoid pregnancy and breastfeeding.

Short bridge for very high symptomatic counts or lysis risk while BCR::ABL1 confirmation and TKI initiation are organised.

Hydroxycarbamide

For temporary symptomatic cytoreduction use a specialist dose commonly 20–40 mg/kg/day orally, adjusted rapidly to FBC, renal function and the time that definitive TKI control begins.

It does not replace a TKI and should be withdrawn as definitive control develops. Monitor counts and lysis chemistry, adjust in renal impairment, use safe handling and avoid pregnancy unless a specialist emergency benefit outweighs fetal risk.

Non-teratogenic cytoreductive option when CML counts need treatment during pregnancy and TKI exposure is being avoided.

Interferon alfa in pregnancy

Use the exact haematology and maternal-medicine product and subcutaneous schedule, commonly starting with a low dose several times weekly and titrating to blood-count control and tolerability; pegylated formulations require product-specific pregnancy review.

Monitor flu-like symptoms, mood, liver, thyroid, autoimmune and blood-count effects. It may not achieve rapid deep molecular control, so coordinate with leukapheresis or postpartum TKI restart where clinically required.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Blast-phase transformation

Myeloid or lymphoid acute transformation causes marrow failure, extramedullary disease and poor survival without rapid TKI-active salvage and transplant.

Treatment resistance

Non-adherence, inadequate exposure, BCR::ABL1 kinase mutations and additional chromosomal abnormalities can produce failure or loss of response.

TKI organ toxicity

Pleural, pulmonary, arterial, metabolic, cardiac, hepatic and renal harms differ between agents and may dominate choice in long-term survivors.

Reproductive and pregnancy harm

TKIs are potentially teratogenic and enter breast milk, requiring planned interruption, specialist monitoring and alternative cytoreduction when pregnancy occurs.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Check FBC every 2 weeks until complete haematological response or more often with cytopenia, then space according to stability and each TKI SmPC.
Measure BCR::ABL1 International Scale at least every 3 months until major molecular response is achieved and confirmed; use 4–6-month intervals only after stable response.
At every result review tablets, food timing, acid suppression, CYP3A interactions, interruptions and adverse effects before attributing a molecular rise to resistant disease.
Use agent-specific surveillance: pleural and pulmonary symptoms for dasatinib; ECG, electrolytes, vascular, glucose and lipids for nilotinib; oedema, renal and liver effects for imatinib.
During treatment-free remission use the intensive PCR schedule indefinitely and restart promptly at loss of major molecular response; monitor 4–6 weekly until response is regained.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

The fusion defines disease

A CML-like blood count without BCR::ABL1 is another myeloid disorder. Conversely, an atypical transcript needs a personalised assay or routine follow-up can appear falsely negative.

Comorbidity directs choice

Pleural, arterial, metabolic and adherence hazards can matter more across decades than a simple first- or second-generation TKI label.

Trend before switch

A single delayed milestone after dose interruption differs from a confirmed rising transcript with full exposure. Current guidance incorporates kinetics and comorbidity into switching.

Stopping increases monitoring

Treatment-free remission replaces daily tablets with frequent lifelong molecular surveillance; success depends on rapid access to results and willingness to restart.

11Common pitfallsFrequent interpretation and management errors.

01
Do not diagnose CML from neutrophilia or a historical leucocyte alkaline phosphatase score without demonstrating BCR::ABL1.
02
Do not omit baseline marrow karyotype because blood PCR is positive; phase and additional chromosomal abnormalities affect prognosis.
03
Do not choose nilotinib without vascular, metabolic, QT and food-timing assessment or dasatinib without pulmonary and acid-suppression review.
04
Do not switch TKI on one unexpected PCR result before confirming it and checking adherence, interruption and interactions.
05
Do not treat blast phase by simply increasing a chronic-phase TKI; add lineage-directed acute-leukaemia treatment and transplant assessment.
06
Do not allow an unmonitored patient to stop a TKI for pregnancy or treatment-free remission without a rapid molecular and specialist plan.