chronic%20myeloid%20leukemia
CHRONIC MYELOID LEUKEMIA

Chronic myelogenous leukemia (CML) is a malignant myeloid disorder characterized by the presence of a distinctive cytogenetic abnormality known as the Philadelphia chromosome.

Exposure to ionizing radiation is the only known risk factor with median presentation at age >50 years old.

Three phases of the disorder are chronic, accelerated and blast.

Choice of therapy is influenced by age, availability of a donor, comorbidities and phase of CML.

Chronic%20myeloid%20leukemia Management

Monitoring

Complete Hematologic Response

  • <10 x 109/L of leukocytes in the peripheral blood
  • <450 x 109/L platelet count
  • <5% basophils
  • Immature granulocytes not present
  • Spleen is non-palpable

Cytogenetic Response

  • No Ph-positive metaphases - CCyR
  • 1-35% Ph-positive metaphases - PCyR
  • 0-35% Ph-positive metaphases - Major cytogenetic response (MCyR)
  • >35% Ph-positive metaphases - Minor cytogenetic response
  • 36-95% Ph-positive metaphases - Minimal cytogenetic response
  • >95% Ph-positive metaphases - Cytogenetic response absent

Molecular Response

  • Early molecular response rate (EMR) is defined as BCR-ABL1 transcripts ≤10% by QPCR (IS) at 3 and 6 months
  • Major molecular response rate (MMR) is defined as BCR-ABL1 transcripts <0.1% by QPCR (IS) or a reduction of >3-log in the BCR-ABL1 mRNA, if QCPR (IS) is unavailable
  • In complete molecular response (CMR), there is no detectable BCR-ABL1 mRNA by QPCR (IS) and is best defined by assay's sensitivity level (at least 4.5 logs below the standard baseline)

Relapse

  • Any signs of loss of response
  • 1-log increase in the BCR-ABL transcript levels with loss of major molecular response rate would prompt bone marrow evaluation for loss of CCyR but is not itself defined as relapse

Monitoring Response to Tyrosine Kinase Inhibitors (TKIs) Therapy

Bone Marrow and Cytogenetics

  • Establish the phase of the disease
  • May be used after the initiation of a TKI at 3 and 6 months, and if the quantitative PCR (QPCR) (IS) is not available
  • If the CCyR or major molecular response rate was not achieved at 12 months, starting from the initiation of therapy
  • Not considered a treatment failure even if the major molecular response rate is absent in the presence of CCyR
  • The BCR-ABL1 transcript levels have increased by 1-log even in the absence of an major molecular response rate

Quantitative RT-PCR (QPCR)

  • Preferred method for monitoring response to TKI therapy 
  • Recommended every 3 months after the initiation of therapy, including patients who met response milestones
  • May be repeated every 3 months for 2 years and every 3-6 months thereafter, if the CCyR has been achieved 
  • Should be repeated in 1-3 months if the BCR-ABL1 transcript levels with major molecular response rate have increased by 1-log

BCR-ABL Kinase Domain Mutation Analysis

  • Recommendations for chronic phase:
    • Failure to reach response milestones
    • There are signs of loss of response (eg hematologic or cytogenetic relapse)
    • There is loss of major molecular response rate and the BCR-ABL1 transcript levels have increased by 1-log 
  • Recommendations for accelerated or blast phase:
    • To monitor if the disease has progressed to accelerated or blast phase

Follow Up

Factors Affecting Patient's Compliance:

  • Length of time from diagnosis to treatment and Imatinib treatment
  • Age
  • Dose of TKI
  • Living alone
  • Male

3 Months Follow-up Therapy

  • For patients with BCR-ABL1 transcripts ≤10% by qPCR (IS) 
    • Advise the patient to continue with the same dose of TKI
      • Monitor response with qPCR and for adverse effects 
      • May continue same TKI
  • For patients with BCR-ABL1 transcripts >10% by qPCR (IS)
    • Evaluate the compliance of the patient and report for drug interactions
    • Advise the patient to have mutational analysis
    • Bone marrow cytogenetic analysis to assess MCyR at 3 months or CCyR at 12 months should be considered
    • Advise the patient to enroll in a clinical trial
    • Change the therapy to other tyrosine kinase inhibitors (TKIs)
    • May increase the dose of Imatinib to 800 mg
    • May continue same TKI other than Imatinib for another 3 months if with >50% reduction from baseline or >10% above the cutoff
    • Evaluate the patient for allogeneic hematopoietic stem cell transplantation (allo-HCT)

6 Months Follow-up Therapy

  • For patients with BCR-ABL1 transcripts <10% by qPCR (IS)
    • Advise the patient to continue with the same TKI
    • Monitor response with qPCR and for adverse effects
  • For patients with BCR-ABL1 transcripts >10% (IS)
    • Evaluate the compliance of the patient and report for drug interactions
    • Advise the patient to have mutational analysis
    • Advise the patient to enroll in a clinical trial
    • Change therapy to other TKIs
    • Evaluate the patient for allo-HCT

12 Months Follow-up Therapy

  • For patients with BCR-ABL1 transcripts ≤1% by qPCR (IS)
    • Advise to continue taking same TKI
    • Monitor response with qPCR and for adverse effects
  • For patients with BCR-ABL1 transcripts ≤10% but is >1% by qPCR (IS)
    • Evaluate the compliance of the patient and report for drug interactions
    • Consider the patient for mutational analysis
    • Bone marrow cytogenetic analysis to assess MCyR at 3 months or CCyR at 12 months should be considered 
    • Change therapy to other TKIs
    • May continue with the same dose of TKI if other than Imatinib or increase the dose of Imatinib to 800 mg
    • Evaluate the patient for allo-HCT
  • For patients with BCR-ABL1 transcripts >10% by qPCR (IS)
    • Evaluate the compliance of the patient and report for drug interactions
    • Consider the patient for mutational analysis
    • May change to an alternative TKI and evaluate the patient for allo-HCT or enroll in a clinical trial

≥15 Months Follow-up Therapy

  • For patients with BCR-ABL1 transcripts ≤1% by qPCR (IS)
    • Advise to continue taking same TKI
    • Monitor response with qPCR and for adverse effects
  • For patients with BCR-ABL1 transcripts >10% by qPCR (IS)
    • Evaluate the compliance of the patient and report for drug interactions
    • Consider the patient for mutational analysis
    • May change to an alternative TKI and evaluate the patient for allo-HCT or enroll in a clinical trial

Management of Resistance

  • Factors that may affect development of primary resistance to TKI therapy:
    • Aberrant expression of drug transporters
    • Plasma protein binding of TKI
    • BCR-ABL1 kinase domain-mutation coding
    • Clonal evolution
    • Activation of BCR-ABL1 independent pathways
  • Resistance has been recorded in 10-15% of patients who used Imatinib as 1st-line treatment and <10% in 2nd generation TKIs
  • In patients showing resistance to current treatment, the following should be considered:
    • Evaluation of patient's compliance with current treatment regimen, recommended dose and schedule
      • Monitoring of Imatinib plasma levels may be useful
    • Possible drug interactions
    • BCR-ABL kinase domain mutational analysis
    • Bone marrow cytogenetic analysis
  • Recommended treatment strategies for patients with confirmed TKI resistance:
    • Switch to alternative TKI
    • Commence evaluation for allogeneic HCT
  • Recommended treatment strategies for patients suspected of TKI resistance:
    • Switching to alternative TKI
    • If treating with TKI other than Imatinib, may consider continuing treatment with the same TKI or increasing the dose to 800 mg if using Imatinib
    • Commence evaluation for allogeneic HCT

Treatment Options

Bosutinib

  • Active against Imatinib-resistant BCR-ABL1 kinase domain mutations, except for T3151
  • Effective in patients with CP-CML resistance to a standard-dose Imatinib
  • Has potent activity in patients with resistance to BCR-ABL1 mutations to Nilotinib (Y253H and F359C/I/V) and Dasatinib (F317L)

Dasatinib

  • Active against Imatinib-resistant BCR-ABL1 kinase domain mutations, except for T3151
  • Effective in patients with CP-CML resistance to a standard- and high-dose Imatinib

Imatinib

  • Dose escalation of Imatinib is effective in patients with cytogenetic relapse and suboptimal cytogenetic response
  • Patients with hematologic failure and who never had cytogenetic response are unlikely to benefit from dose

Nilotinib

  • Active against Imatinib-resistant BCR-ABL1 kinase domain mutations, except for T3151
  • In vitro studies showed activity against F317L mutation
  • Effective in patients with CP-CML resistance to a standard Imatinib

Omacetaxine

  • Used for patients with advanced phase CML lines including the T3151 mutation or who are intolerant to 2 or more TKIs and those with resistant disease that is not responding to prior use of 2 or more TKI

Ponatinib

  • Approved for CML patients with resistance to ≥2 TKIs, including T315I mutation 
  • Also used for patients with E255K/V, F317L, F359V, G250E, M351T, T315I and Y253H mutations

For the discussion of clinical trials and allo-HCT (please refer to the discussion above)

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