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.

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
  • >35% Ph-positive metaphases - Minor cytogenetic response

Molecular response

  • Early molecular response rate (EMR) is defined as BCR-ABL1 transcripts ≤10% by QPCR (IS) at 3 & 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) & 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 therapy

Bone marrow & cytogenetics

  • Establish the phase of the disease
  • May be used after the initiation of a tyrosine kinase inhibitors at 3 & 6 months, & 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)

  • Recommended every 3 months after the initiation of therapy
    • May be repeated every 3 months for 2 years & 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 & 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 & Imatinib treatment
  • Age
  • Dose of Imatinib
  • Living alone
  • Male

3 months follow-up therapy

  • For patients with BCR-ABL1 transcripts ≤10% by QPCR (IS) or PCyR on bone marrow cytogenetics, if QPCR (IS) is not available
    • Advise the patient to continue with the same dose of Imatinib, Nilotinib or Dasatinib
      • Monitor with/ QPCR every 3 months
  • For patients with BCR-ABL1 transcripts >10% by QPCR (IS) or lack of PCyR on bone marrow cytogenetics, if QPCR (IS) is not available
    • Evaluate the compliance of the patient & report for drug interactions
    • Advise the patient to have mutational analysis
    • For patients whose primary treatment is Imatinib
      • Advise the patient to enroll in a clinical trial
      • Change the therapy to other tyrosine kinase inhibitors
      • May increase the dose of Imatinib to 800 mg
      • Evaluate the patient for hematopoietic stem cell transplantation
    • For patients whose primary treatment is Nilotinib or Dasatinib
      • Advise the patient to enroll in a clinical trial
      • May continue with the same dose of Nilotinib or Dasatinib
      • Change the therapy to other tyrosine kinase inhibitors
      • Evaluate the patient for hematopoietic stem cell transplantation

6 months follow-up therapy

  • For patients with BCR-ABL1 transcripts <10% by QPCR (IS) or >PCyR on bone marrow cytogenetics, if QPCR is not available
    • Advise the patient to continue with the same dose of tyrosine kinase inhibitor
      • QPCR (IS) should be monitored every 3 months
  • For patients with BCR-ABL1 transcripts >10% (IS) or lack of PCyR on bone marrow cytogenetics, if QPCR is not available
    • Evaluate the compliance of the patient & report for drug interactions
      • Advise the patient to have mutational analysis
      • Advise the patient to enroll in a clinical trial
      • Change therapy to other tyrosine kinase inhibitors
      • Evaluate the patient for hematopoietic stem cell transplantation

12 months follow-up therapy & beyond

  • For patients with CCyR or BCR-ABL1 transcripts ≤1% but is >0.1% by QPCR (IS)
    • Advise to continue taking same dose of tyrosine kinase inhibitor
    • Tests that can be used in monitoring the response of the patient to tyrosine kinase inhibitor & analysis of mutations are bone marrow cytogenetics, QPCR (IS) & BCR-ABL kinase domain mutation analysis
  • For patients with PCyR or BCR-ABL1 transcripts ≤10% but is >1% by QPCR (IS)
    • Evaluate the compliance of the patient & report for drug interactions
    • Consider the patient for mutational analysis
      • Change therapy to other tyrosine kinase inhibitors
      • May continue with the same dose of tyrosine kinase inhibitor or increase the dose of Imatinib to 800 mg
      • Other treatment options that can be considered for those patients who are unable to tolerate the tyrosine kinase inhibitors therapy (eg Interferon/Peginterferon, Omacetaxine, hematopoietic stem cell transplantation)
  • For patients with <PCyR or BCR-ABL1 transcripts >10% by QPCR (IS)
    • Evaluate the compliance of the patient & report for drug interactions
    • Consider the patient for mutational analysis
      • May change to an alternative tyrosine kinase inhibitor other than Imatinib & evaluate the patient for hematopoietic stem cell transplantation or enroll in a clinical trial
  • For patients with cytogenetic relapse
    • Evaluate the compliance of the patient & report for drug interactions
      • May change to an alternative tyrosine kinase inhibitor other than Imatinib or increase the dose of Imatinib to 800 mg & evaluate the patient for hematopoietic stem cell transplantation or enroll to a clinical trial
  • For patients with PCyR or BCR-ABL1 transcripts ≤10% but is >1% by QPCR (IS), <PCyR or BCR-ABL1 transcripts >10% by QPCR (IS) & cytogenetic relapse, bone marrow evaluation is repeated at 3 months
    • To document CCyR & if the CCyR is less, then treat as <PCyR

Management of Resistance

Primary resistance
  • Failure in achieving the desired response to a tyrosine kinase inhibitor (TKI) & usually occurs in patients treated with Imatinib

Secondary resistance

  • Seen or observed in patients with initial response to a TKI relapse

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 & F359C/I/V) & 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- & high-dose Imatinib

Imatinib

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

Nilotinib

  • Active against Imatinib-resistant BCR-ABL1 kinase domain mutations, except for T3151

Omacetaxine

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

Ponatinib

  • Used for patients with E255K/V, F317L, F359V, G250E, M351T, T315I & Y253H mutations

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

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