Chronic Myeloid Leukaemia (CML)

A Review of the British Society for Haematology 2020 Guidelines

Introduction to CML

Chronic Myeloid Leukaemia (CML) is a type of cancer that affects the blood and bone marrow. It's characterized by the presence of the Philadelphia (Ph) chromosome, leading to the BCR-ABL1 fusion gene.

The management of CML has significantly evolved, with Tyrosine Kinase Inhibitors (TKIs) transforming it into a chronic, manageable condition for most patients. These guidelines from the British Society for Haematology (BSH) provide healthcare professionals with clear guidance on diagnosis and management.

Diagnosis of CML

While CML can be suspected from peripheral blood findings and BCR-ABL1 positivity, a bone marrow (BM) aspirate is recommended for full karyotype analysis and morphological investigation to confirm disease phase.

Essential Investigations:

  • Peripheral blood count and film
  • Bone marrow aspirate (for morphology and cytogenetics)
  • Karyotyping (to detect Ph chromosome and Additional Cytogenetic Abnormalities - ACAs)
  • BCR-ABL1 detection (FISH or RT-PCR if karyotype is Ph-negative)
  • Determination of BCR-ABL1 transcript type (e.g., e13a2, e14a2) for molecular monitoring

BM trephine biopsy is not routinely required. BCR-ABL1 kinase domain (KD) mutation analysis is not typically needed at diagnosis in chronic phase.

Prognostic Scoring:

Calculate a prognostic score (Sokal or ELTS) to inform prognosis. ELTS is preferred and is the only score of value in children.

ELTS Score Risk Groups:

Risk Group ELTS Score
Low-risk<1.5680
Intermediate-risk≥1.5680 to ≤2.2185
High-risk>2.2185

Key Diagnostic Recommendations:

  • Perform BM aspirate for full karyotype and to confirm disease phase (Grade 2B).
  • Establish fusion type for molecular monitoring (Grade 1B).
  • Calculate ELTS score to inform prognosis (Grade 2B).

Primary Therapy for Chronic Phase (CP)

Four TKIs are licensed for newly diagnosed patients: Imatinib, Bosutinib, Dasatinib, and Nilotinib. Most patients have a realistic prospect of normal life expectancy.

First-Line Treatment:

Imatinib is recommended for the majority of adults and children in CP (Grade 1A).

When to Consider a 2nd Generation TKI (2GTKI) Upfront (Grade 2B):

Baseline Assessments (Grade 2B):

First-Line TKI Choice by Pre-existing Medical Condition:

Adapted from BSH Guidelines (Table II, Smith et al., 2020). Co-morbidities should be assessed (Grade 2B).

Hypertension
Bosutinib: Low Risk, Dasatinib: Low Risk, Imatinib: No Contra, Nilotinib: Low Risk
Ischaemic heart disease
Bosutinib: Low Risk, Dasatinib: Low Risk, Imatinib: No Contra, Nilotinib: Avoid
Cerebrovascular thrombosis
Bosutinib: Low Risk, Dasatinib: Low Risk, Imatinib: No Contra, Nilotinib: Avoid
Peripheral arterial occlusive disease
Bosutinib: Low Risk, Dasatinib: Low Risk, Imatinib: No Contra, Nilotinib: Avoid
Prolonged QT interval
Bosutinib: Intermediate*, Dasatinib: Intermediate*, Imatinib: No Contra, Nilotinib: Avoid*
Congestive cardiac failure
Bosutinib: Low Risk, Dasatinib: Intermediate, Imatinib: Low Risk, Nilotinib: Low Risk
Diabetes mellitus
Bosutinib: No Contra, Dasatinib: No Contra, Imatinib: No Contra, Nilotinib: Intermediate
Gastrointestinal bleeding
Bosutinib: Low Risk, Dasatinib: Low Risk, Imatinib: Low Risk†, Nilotinib: No Contra
Pulmonary hypertension
Bosutinib: No Contra, Dasatinib: Avoid, Imatinib: No Contra, Nilotinib: No Contra
Chronic pulmonary disease
Bosutinib: No Contra, Dasatinib: Intermediate, Imatinib: No Contra, Nilotinib: No Contra
Pancreatitis
Bosutinib: Low Risk, Dasatinib: Low Risk, Imatinib: No Contra, Nilotinib: Avoid
Abnormal liver function
Bosutinib: Intermediate, Dasatinib: Low Risk, Imatinib: Low Risk, Nilotinib: Intermediate

Key: No Contra No contra-indication; Low/Intermediate Risk Low/Intermediate risk of exacerbation; Avoid Avoid if possible. *Some evidence all 2GTKI prolong QT. †Imatinib associated with GAVE.

Response Criteria and Monitoring

Molecular monitoring by RT-qPCR is the strongest predictor of outcome. Results should be expressed on the International Scale (IS) and indicate Molecular Response (MR) level.

International Scale (IS) for BCR-ABL1:

  • 100% IS: Standardized baseline
  • 10% IS: MR1
  • 1% IS: MR2 (corresponds to Complete Cytogenetic Response - CCyR)
  • 0.1% IS: MR3 (Major Molecular Response - MMR)
  • 0.01% IS: MR4 (Deep Molecular Response - DMR)
  • 0.001% IS: MR5 (DMR)

Monitoring Frequency (Grade 1B):

  • Every 3 months until stable MMR (<0.1% IS, MR3) sustained for 1 year.
  • Thereafter, every 3-6 months.
  • More frequent if concerns (compliance, resistance, TFR attempt).

Key Monitoring Recommendations:

  • Molecular monitoring by RT-qPCR, expressed on IS and by MR level (Grade 1A).
  • Labs should be accredited and participate in EQA schemes, optimized to detect MR4-5 (Grade 1B).
  • BCR-ABL1 KD mutational analysis for ELN treatment failure or 'warning' (Grade 1B).

First-Line TKI Response Milestones (Adapted from Table V, Smith et al., 2020):

BCR-ABL1 (IS) >10%
3 Months: Consider TKI switch*
6 Months: Failure: Switch TKI
12 Months: Failure: Switch TKI
>12 Months: Failure: Switch TKI
BCR-ABL1 (IS) 1-10%
3 Months: Continue same TKI
6 Months: Consider TKI switch*
12 Months: Failure: Switch TKI
>12 Months: Failure: Switch TKI
BCR-ABL1 (IS) 0.1-1% (MR2)
3 Months: Continue same TKI
6 Months: Continue same TKI
12 Months: Consider TKI switch*
>12 Months: Consider TKI switch*
BCR-ABL1 (IS) <0.1% (MR3/MMR)
3 Months: Continue same TKI
6 Months: Continue same TKI
12 Months: Continue same TKI
>12 Months: Continue same TKI
BCR-ABL1 (IS) <0.01% (MR4/DMR)
3 Months: Continue same TKI
6 Months: Continue same TKI
12 Months: Continue same TKI
>12 Months: Consider TFR†

Key: Optimal; Suboptimal (Consider change)*; Failure (Change therapy); Optimal for TFR†.
*Careful assessment needed. †See TFR section.

Management of Resistance or Intolerance

Patients may discontinue first-line therapy due to resistance/failure or intolerance.

Key Recommendations:

  • Change to an alternative TKI if treatment failure on first-line therapy (Grade 1A).
  • Choice of second-line TKI guided by BCR-ABL1 KD mutation analysis (Grade 1B). (See Table IV in Smith et al. for specific mutations).
  • Dose escalation of imatinib (e.g., 600mg) reasonable for ELN 'warning' criteria with good tolerance and no mutation (Grade 2B).
  • In absence of specific mutations, co-morbidities and side effect profiles guide 2GTKI choice (Grade 2B).

Patients intolerant to imatinib often have better responses to 2GTKIs than those with resistance. Low cross-intolerance for non-haematological side effects.

Management of Advanced Phase Disease (AP/BC)

5-10% of patients present in de novo Accelerated Phase (AP) or Blast Crisis (BC). TKI therapy has reduced progression to AP/BC. ELN criteria for AP/BC are recommended.

Treatment Approach (Simplified from Fig 2, Smith et al., 2020):

ACCELERATED PHASE (AP)

De Novo AP: Dasatinib 140mg OD or Imatinib 600-800mg daily.
AP arising from CP on TKI: Perform mutation analysis. If on Imatinib, consider 2GTKI. If on Nilotinib, consider Dasatinib/Bosutinib/Ponatinib. If on Dasatinib, consider Nilotinib/Ponatinib.
↓
If T315I Mutation Detected: Switch to Ponatinib. Consider alloSCT, investigational agent/IFN.
↓
Monitoring: As for CP CML (aim for MR3/MMR).
If failure to achieve optimal response: Consider KD mutation analysis, alternative TKI, alloSCT.
(AlloSCT recommended for most transplant-eligible AP patients if suboptimal response. Exception: AP at presentation achieving optimal responses).

BLAST CRISIS (BC)

De Novo BC: Perform mutation analysis. Consider Dasatinib 140mg or Imatinib 800mg daily. Current UK practice often favours FLAG-Ida + TKI.
BC arising from CP on TKI: Perform mutation analysis. Switch TKI based on prior TKI and mutations (similar logic to AP). For CNS disease, consider Dasatinib.
↓
Myeloid BC:
  1. FLAG-Ida + TKI.
  2. Rarely TKI monotherapy (if no/partial response, proceed to intensive remission induction).
Lymphoid BC:
  1. FLAG-Ida or other intensive ALL therapy (e.g., UKALL) + TKI + IT therapy.
  2. Trial of TKI + vincristine & prednisolone for transplant-ineligible.
↓
AIM: Remission / 2nd CP & alloSCT if suitable candidate.
(All responding, transplant-eligible patients in BC CML should proceed to alloSCT).

Key Advanced Phase Recommendations:

  • De novo AP CML: Ideally treat with 2GTKI or consider alloSCT if suboptimal response (Grade 1B).
  • All responding, transplant-eligible BC CML patients: Proceed to alloSCT (Grade 1B).

Side Effects of TKIs & Management

Side effects are common but often manageable with dose reduction, suspension, or switching TKI (little cross-intolerance).

General Management:

  • Dose interruption or reduction, slow titration back to dose maintaining MMR.
  • Switch TKI if intolerable side effects persist.

Cardiovascular & Respiratory:

  • Assess CVD risk (e.g. QRisk3); offer statin if 10-yr risk >10%.
  • Monitor and treat hypertension. Suspend TKI if BP >180/110 mmHg.
  • Investigate breathlessness thoroughly (pleural effusions common with Dasatinib, PAH rare).
  • ECGs for bosutinib/nilotinib at baseline or if clinically indicated.

Monitoring for TKI Toxicity (Simplified from Table IX, Smith et al.):

Frequency depends on TKI and clinical context. This is a general guide.

  • FBC, Biochemistry (renal, liver, bone): At least 3-monthly.
  • Lipid profile, HbA1c, TFTs, Amylase: Clinical indication.
  • BNP (for Dasatinib): 12-monthly or clinical indication.
  • ABL1 Kinase Domain Mutation: At warning or failure of response.
  • Blood Pressure: At least 3-monthly.
  • ECG, Echocardiogram, Chest X-ray: Clinical indication.

Key Side Effect Management Recommendations:

  • Most side effects managed by dose interruption/reduction (Grade 1A).
  • Switch TKI for intolerable side effects due to little cross-intolerance (Grade 1A).
  • Offer secondary prevention for prior CVD events; assess CVD risk for all (Grade 1B).
  • Monitor and treat BP (Grade 2A). Investigate breathlessness thoroughly (Grade 1A).

Allogeneic Stem Cell Transplantation (AlloSCT)

Outcomes for alloSCT in CP CML have improved, but it's generally reserved for specific situations due to TKI efficacy.

Role in Chronic Phase (CP):

  • Consider for patients resistant to or intolerant of at least one 2GTKI.
  • A trial of a 3GTKI (e.g., ponatinib, if available and appropriate) is reasonable before alloSCT.
  • For intolerant patients, multiple TKI attempts may be justifiable before alloSCT (see flowchart).

Role in Advanced Phase (AP/BC):

  • AP: Recommended for most eligible patients progressing to AP, or those presenting in AP with suboptimal TKI response.
  • BC: All responding, eligible patients should proceed to alloSCT. Aim for CP2 pre-transplant.
  • Post-transplant TKIs may be needed, especially after RIC or for AP/BC history.
  • Monitor molecularly post-transplant; intervene with DLI/TKI for MRD/relapse.

AlloSCT for Intolerant CP Patients (Simplified from Fig 3, Smith et al.):

First Line TKI (Imatinib, Nilotinib, Dasatinib) -> INTOLERANCE (Persistent Grade 2/3 toxicity) -> Switch
➔
Second Line TKI (depends on prior TKI/toxicity/co-morbidities) -> INTOLERANCE -> Switch (Start donor search if transplant eligible)
➔
Third Line TKI -> INTOLERANCE -> Switch
➔
Fourth Line TKI -> INTOLERANCE (Persistent >Grade 2 toxicity leading to discontinuation) -> AlloSCT (if eligible and low risk) OR Fifth Line TKI / Clinical Trial (if alloSCT ineligible/high risk)

Balance risk of contraindicated TKI vs. allograft based on individual factors.

Key AlloSCT Recommendations:

  • CP CML: Consider alloSCT for resistance to at least one 2GTKI; trial of 3GTKI reasonable first (Grade 2B).
  • AP CML: Recommended for most eligible progressing to AP or with suboptimal TKI response if presenting in AP (Grade 2A).
  • BC CML: Aim for CP2 pre-alloSCT (Grade 2A).
  • Post-transplant monitoring and intervention for MRD/relapse (Grade 2A).

Treatment-Free Remission (TFR)

Discontinuation of TKI is feasible and safe for selected patients in sustained Deep Molecular Response (DMR).

Eligibility Criteria for Attempting TFR:

Monitoring Post-Discontinuation (Grade 2B):

Key TFR Recommendations:

  • Re-initiate TKI (full dose) within 1 month of confirmed loss of MR3 (MMR) (Grade 1B).
  • Monitor 4-weekly until MR3 re-established (Grade 1B).
  • If MR3 not achieved by 6 months post-restart, perform KD mutation analysis (Grade 1B).

~1/3 develop transient 'withdrawal syndrome' (musculoskeletal symptoms).

CML and Parenting

Male Patients:

Risks of adverse pregnancy consequences for partners of men on imatinib or dasatinib appear similar to unaffected population. Less data for other TKIs.

Female Patients:

  • Presenting in pregnancy: Individualised approach (no treatment, leucapheresis, IFN-alpha, TKI in later pregnancy - though BSH advises avoiding TKIs throughout pregnancy if possible). Termination not advised unless patient's request.
  • Unplanned pregnancy on TKI: Discontinue TKI immediately, fetal scans.
  • Considering pregnancy (Fig 4, Smith et al. simplified):
    • Ideally: Aim for TFR criteria (sustained MR4 for >12 months). If successful, conceive off TKI.
    • If
    • If becomes pregnant & loses MMR: Stay off TKI until delivery if possible; consider other strategies.
    • Options if not meeting TFR: Substitute TKI with IFN, IVF (stop TKI, reimplant fresh embryos; or freeze embryos, restart TKI, reimplant when TKI stopped for sustained MR4).
  • Breastfeeding: Avoid while on TKI (Grade 1B).

Key Parenting Recommendations:

  • Female patients presenting in pregnancy: Individualised approach (Grade 1B).
  • Women wishing to conceive: Ideally meet TFR criteria (no prior resistance, MR4 for >12m) before stopping TKI (Grade 1B).

Key Takeaways & Conclusion

The BSH 2020 guidelines provide a comprehensive framework for CML management, emphasizing individualized care, robust monitoring, and consideration of patient life goals.

Continuous research and adherence to guidelines are key to optimizing outcomes for CML patients.