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 Treatment

Principles of Therapy

  • In general, the choice of 1st-line therapy may depend on risk score, physician's experience, age, ability to tolerate therapy and comorbid conditions
  • TKIs are recommended 1st-line therapy for patients with CP-CML and AP-CML
    • Both 1st and 2nd generation TKIs are recommended as primary treatment for newly diagnosed low-risk CP-CML patients
    • Second generation TKIs Dasatinib, Nilotinib and Bosutinib are recommended for newly diagnosed CP-CML patients with intermediate- to high-risk
      • First-generation TKI Imatinib was previously recommended as 1st-line treatment for CML patients with intermediate- to high-risk but with the emergence of 2nd generation TKIs, these are now preferred over Imatinib therapy
      • Studies showed that Bosutinib, Dasatinib and Nilotinib possess higher major molecular response (MMR) rate and deeper molecular responses compared to Imatinib
    • Dasatinib or Bosutinib are preferred TKIs for CP-CML patients with history of arrhythmia, cardiac disorders, pancreatitis, or increased blood glucose
    • For CP-CML patients with pulmonary disorders and those at increased risk for pleural effusion, Nilotinib or Bosutinib are preferred
  • For patients with disease progression despite previous monotherapy with TKI, an alternate TKI not previously given may be considered
  • Omacetaxine therapy or Allo-HCT may be considered for AP-CML patients unresponsive to multi-TKI therapy
  • Allo-HCT is the recommended 1st-line treatment option for newly-diagnosed BP-CML patients

Adherence to Tyrosine Kinase Inhibitor (TKI) Therapy

  • Predicts the achievement of complete molecular response (CMR) on standard-dose Imatinib
  • The marker that identifies a non-adherent CP-CML patient is the BCR-ABL1 doubling time
  • Educate the patient on their adherence to tyrosine kinase inhibitor therapy and monitor them closely
  • Non-adherence may result to poorer treatment response that can result to loss of major molecular response, hematologic failure, cytogenic relapse and treatment failure
  • Appropriate management of the side effects will improve patient adherence

Discontinuation of TKI Therapy

  • May be considered if all of the criteria are present
  • Criteria for discontinuation of TKI therapy include:
    • Patient aged ≥18 years old
    • Disease in chronic phase without any history of accelerated or blast phase
    • At least 3 years of TKI therapy
    • Presence of BCR-ABL1 transcripts at time of diagnosis-
    • ≥2 years of stable molecular response (BCR-ABL1 ≤0.01% IS) for ≥2 years in at least 4 tests obtained ≥3 months apart
    • Reliable qPCR test (MR4.5 and BCR-ABL1 ≤0.0032% IS) easily accessible with results processed within 2 weeks
    • Able to comply with strict follow-up in patients with MMR (MR3; BCR-ABL1≤0.1% IS) after TKI discontinuation: Molecular monitoring conducted monthly for the 1st 6 months, every 2 months for the next 6 months, then quarterly thereafter
    • Can promptly resume TKI therapy (within 4 weeks) after loss of MMR with molecular monitoring 4-weekly until MMR is achieved, then 12-weekly monitoring thereafter
      • Perform BCR-ABL1 testing for patients who does not achieve MMR 3 months after resuming TKI therapy, and molecular monitoring should be conducted monthly for 6 months
    • Patient agrees to report any of the following:
      • Significant adverse events related to TKI therapy discontinuation
      • Disease phase progresses to accelerated or blast phase
      • MMR has not been achieved after resumption of treatment
  • Should only be considered in patients who are eligible for clinical trial
  • May consider temporarily stopping TKI treatment in patients with history of treatment change only due to intolerance, typical e13a2 or e14a2 BCR–ABL1 transcripts, >5 years on TKI therapy (>4 years if 2nd generation TKI used), deep molecular response of >2 years, and history of treatment failure
  • In patients with responsive disease, continuation of TKI therapy is recommended

Clinical Trials

  • Considerations for enrollment in clinical trials
    • In patients with AP-CML or BP-CML
    • In patients with treatment failure after Imatinib therapy
    • For patients with BCR-ABL1 transcripts >10% (IS) after initial treatment with 2nd-line TKIs at 3-month evaluation
    • For patients with BCR-ABL1 transcripts >10% (IS) or lack of partial cytogenetic response (PCyR) on bone marrow cytogenetics after initial treatment with 2nd-line TKIs at 6-month evaluation
    • For patients with cytogenic relapse, or less than PCyR or BCR-ABL1 transcripts >10% (IS) at 12-month evaluation

Pharmacotherapy

Targeted Cancer Therapy
First-generation Tyrosine Kinase Inhibitors (TKI)

Imatinib

  • Belongs to a class of signal transduction inhibitors (STIs) that interferes with the intracellular signaling pathways associated with malignancies
  • Inhibits the BCR-ABL1 tyrosine protein kinase in all phases of chronic myeloid leukemia
  • Recommended as 1st-line treatment for patients with chronic phase chronic myeloid leukemia (CP-CML) and advanced phase chronic myeloid leukemia (AP-CML)
    • Several studies showed cytogenic response, hematologic response, decreased relapse and disease progression, and high overall survival in patients given Imatinib therapy

Second-generation TKI

Bosutinib

  • An oral multi-TKI that is used to treat adult patients with chronic phase, accelerated phase or blast phase Ph-positive (Ph+) chronic myeloid leukemia (CML) with resistance or intolerance to previous therapy (eg Imatinib, Dasatinib and Nilotinib)
  • Inhibits BCR-ABL1 kinase that promotes CMLand Src-family of kinases (eg Src, Lyn and Hck)
  • More potent for the BCR-ABL1 kinase than Imatinib
  • Not an efficient substrate for multidrug resistant transporters
  • Used for the management of cytogenetic or hematologic resistance to TKIs and in patients with E255K/V, F317L/V/I/C, F359V/C/I, T315A, or Y253H mutations
  • Recommended 1st-line treatment for newly diagnosed patients with CP-CML with any risk score
  • Treatment option for CP-CML patients previously treated with Dasatinib or Nilotinib

Dasatinib

  • An oral multi-TKI and is more potent in the inhibition of ABL than Imatinib
  • Inhibits Src tyrosine kinase, BCR-ABL and Imatinib-resistant mutations of BCR-ABL and binds to both active and inactive conformation of the ABL kinase domain
  • Recommended for all phases of CML with resistance or intolerance to prior therapy of Imatinib, Ph+ ALL with resistance or intolerance to prior therapy and in newly diagnosed Ph+ CML in the chronic phase
  • Preferred 1st-line treatment for patients with CP-CML with intermediate- to high-risk score
    • Also preferred in patients with history of arrhythmia, heart disease, pancreatitis and hyperglycemia
  • Used for the management of cytogenetic or hematologic resistance to TKIs and in patients with Y253H, E255K/V or F359V/C/I mutations

Nilotinib

  • Used for adult patients who are newly diagnosed with Ph+ CP-CML
  • Also used to treat chronic and accelerated Ph+ CML patients who are intolerant or resistant to a prior therapy that includes Imatinib
  • Preferred 1st-line treatment for patients with CP-CML with intermediate- to high-risk score
  • Selectively inhibits the BCR-ABL1 tyrosine kinase and enhances the binding site affinity which makes Nilotinib 30 times more potent than Imatinib in Imatinib-sensitive CML cell lines and 3-7 times more potent in Imatinib-resistant CML cell lines
  • Used for the management of cytogenetic or hematologic resistance to TKIs and in patients with F317L/V/I/C, T315A or V299L mutations

Ponatinib

  • An oral multi-kinase inhibitor that inhibits the ABL and T315l mutant ABL genes
  • Used for the treatment of T3151-positive CP-, AP-, or BP-CML or T315l-positive Ph+ALL and in patients with CP-, AP-, or BP-CML or Ph+ALL for patients when no other TKI is indicated
  • Treatment option for CP-CML patients unresponsive to multiple TKI therapy

Radotinib

  • An oral TKI that inhibits the BCR-ABL1 fusion protein, approved only in South Korea, is currently being studied in other countries for its potential for antineoplastic activity in CML

Management of TKI Therapy Toxicities

Imatinib

  • CP-CML with ANC <1.0 x 109/L and/or platelet count <50 x 109/L
    • Withhold therapy until ANC ≥1.5 x 109/L and/or platelet count ≥75 x 109/L, then resume at 400 mg initial dose, or 300 mg initial dose for recurrence
  • AP-CML and blast phase chronic myeloid leukemia (BP-CML) with ANC <0.5 x 109/L and/or platelet count <10 x 109/L
    • Reduce dose to 400 mg if patient develops cytopenia unrelated to CML
    • Reduce dose further to 300 mg if with persistent neutropenia after 2 weeks
    • Withhold Imatinib if still with cytopenia after 4 weeks, then resume at 300 mg dose if ANC ≥1.0 x 109/L and platelet count ≥20 x 109/L
  • Combination with growth factors may be considered for resistant neutropenia
  • Transfusion support may be considered in patients with symptomatic grade 3-4 anemia
  • Withhold therapy if patient has bilirubin >3 x institutional ULN (IULN) or liver transaminases >5 x IULN
    • Resume therapy when bilirubin level is reduced to <1.5 x ULN and liver transaminases to <2.5 x IULN
  • Interrupt administration if any the following are present: Severe hepatotoxicity, severe fluid retention, rashes

Bosutinib

  • ANC <1.0 x 109/L or platelet count <50 x 109/L
    • Withhold treatment until ANC reaches ≥1.0 x 109/L and platelet count ≥50 x 109/L
    • May resume Bosutinib treatment when blood count returns to normal within 2 weeks
    • Reduce dose to 100 mg if blood counts remain low after 2 weeks; further dose reduction to 100 mg more may be considered for recurrence of cytopenia
  • Combination with growth factors may be considered for resistant neutropenia and thrombocytopenia
  • Transfusion support may be considered in patients with symptomatic grade 3-4 anemia
  • Withhold therapy if patient's liver transaminases >5 x IULN
    • Resume therapy at 400 mg daily when liver transaminases are reduced to ≤2.5 x IULN
    • Discontinue Bosutinib if recovery takes longer than 4 weeks, or if with transaminase elevations >3 x IULN, bilirubin >2 x IULN, and alkaline phosphatase <2 x ULN
  • Withhold therapy if with grade 3-4 diarrhea, rashes, and other clinically significant, moderate, or severe non-hematologic toxicities until symptoms resolve
    • May resume treatment at 400 mg once daily when toxicity has resolved (ie diarrhea resolves to grade ≤1)

Dasatinib

  • CP-CML with ANC <0.5 x 109/L or platelet count <50 x 109/L
    • Withhold therapy until ANC ≥1.0 x 109/L and platelet count ≥50 x 109/L, if platelet count is <25 x 109/L, or for recurrence of ANC <0.5 x 109/L for 7 days
    • May resume treatment if blood count returns to normal after ≤7 days or at a reduced dose of 80 mg once daily for recurrence; reduce dose further to 50 mg once daily or discontinue treatment if at 3rd recurrence
  • AP-CML and BP-CML with ANC <0.5 x 109/L and/or platelet count <10 x 109/L
    • Withhold treatment if patient develops cytopenia unrelated to CML, then resume at initial dose if with ANC ≥1.0 x 109/L and platelet count ≥20 x 109/L, or at a reduced dose of 100 mg/day if for recurrence, or at 80 mg once daily for 3rd recurrence 
  • Combination with growth factors may be considered for resistant neutropenia and thrombocytopenia
  • Transfusion support may be considered in patients with symptomatic grade 3-4 anemia
  • Dasatinib should be discontinued permanently for confirmed presence of pulmonary arterial hypertension
  • Withhold therapy if with rashes and severe non-hematologic toxicities until symptoms resolve
    • May resume treatment at reduced dose depending on severity of adverse effect

Nilotinib

  • Monitor serum potassium and magnesium levels, ECG, glucose levels
  • Withhold treatment for any of the following:
    • ECG with QTc >480 msec
      • May resume treatment within 2 weeks at prior dose if with QTcF <450 msec and within 20 msec of baseline
      • May resume at reduced dose if QTcF between 450-480 msec after 2 weeks
      • Discontinue Nilotinib if QTcF returns to >480 msec after dose reduction
    • Chronic or accelerated phase, ANC <1.0 x 109/L and/or platelet count <50 x 109/L
    • Elevated serum lipase, amylase, bilirubin, or hepatic transaminases grade ≥3
  • Discontinue Nilotinib if with confirmed peripheral arterial occlusive disease
  • Combination with growth factors may be considered for resistant neutropenia and thrombocytopenia
  • Transfusion support may be considered in patients with symptomatic grade 3-4 anemia

Ponatinib

  • Withhold treatment for any of the following:
    • ANC <1.0 x 109/L and/or platelet count <50 x 109/L
      • May resume therapy at initial dose (45 mg), at 30 mg if at 2nd occurrence, and at 15 mg if at 3rd occurrence when results are ANC ≥1.5 x 109/L and platelet count ≥75 x 109/L
    • Elevated serum lipase (symptomatic grade 1/2), amylase, bilirubin, or hepatic transaminases grade >3 x IULN (grade ≥2)
      • May resume treatment at reduced dose in patients with liver transaminase <3 x IULN, serum lipase <1.5 x ULN or ≤grade 1
    • Symptomatic grade 3 pancreatitis
      • Consider treatment resumption when serum lipase levels return to ≤grade 1 at a lower dose
    • Cerebral or GI hemorrhage, rashes, or fluid retention
  • Discontinue Ponatinib if patients receiving 15 mg doses present with liver transaminase of >3 x IULN, grade 4 symptomatic pancreatitis, and in patients with AST/ALT ≥3 x ULN plus bilirubin >2 x ULN and alkaline phosphatase <2 x ULN
  • Monitor for thromboembolism, cardiac function, and hepatic function
  • Combination with growth factors may be considered for resistant neutropenia and thrombocytopenia
  • Transfusion support may be considered in patients with symptomatic grade 3-4 anemia

Cytotoxic Chemotherapy

Hydroxyurea

  • An antimetabolite that rapidly reduces high white blood cell counts
  • Inhibits the ribonucleotide reductase and DNA synthesis and does not interfere with protein or RNA synthesis
  • Treatment option for symptomatic leukocytosis or thrombocytosis awaiting confirmation of BCR-ABL1

Omacetaxine mepesuccinate

  • A cephalotaxine ester that inhibits protein synthesis by binding to the A-site located at the peptidyl-transferase center of the large ribosomal subunit and reduces the protein levels of BCR-ABL and myeloid leukemia cell 1 (MCL-1) that is independent of the direct BCR-ABL binding
  • Used to treat patients who have CP-CML or AP-CML with disease progression that is resistant or intolerant to 2 or more TKIs and for patients with T315I mutation
  • Reported adverse effects with Omacetaxine therapy include grade 3 or 4 hyperglycemia and CBC abnormalities
    • Delay treatment if patient presents with ANC <0.5 x 109/L or platelet count <50 x 109/L
    • May resume at reduced dose every 2 days for the next cycle if with ANC ≥1.0 x 109/L and platelet count ≥50 x 109/L

Cancer Immunotherapy

  • Clinical trials on the therapeutic potential of Pegylated interferon α in combination with a TKIs in CP-CML showed promising results
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