• In general, the choice of first-line therapy may depend on risk score, physician's experience, age, ability to tolerate therapy & comorbid conditions

Targeted Cancer Therapy

Adherence to tyrosine kinase inhibitors (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 & monitor them closely
• Non-adherence may result to poorer treatment response that can result to loss of major molecular response, hematologic failure, cytogenic relapse & treatment failure
• Appropriate management of the side effects will improve patient adherence

Discontinuation of tyrosine kinase inhibitors (TKI) therapy

• Should only be considered in patients who are eligible for clinical trial
• In patients with responsive disease, continuation of tyrosine kinase inhibitors therapy is recommended

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-ABL tyrosine protein kinase in all phases of chronic myeloid leukemia
• Recommended as 1st-line treatment for patients with chronic phase & advanced phase chronic myeloid leukemia
• Several studies showed cytogenic response, hematologic response, decreased relapse & disease progression, & high overall survival in patients given Imatinib therapy

Second-generation tyrosine kinase inhibitors (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 with resistance or intolerance to previous therapy (eg Imatinib, Dasatinib & Nilotinib)
• Inhibits BCR-ABL1 kinase that promotes chronic myeloid leukemia & Src-family of kinases (eg Src, Lyn & 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 tyrosine kinase inhibitors & in patients with E255K/V, F317L/V/I/C, F359V/C/I, T315A, or Y253H mutations
• At present, Bosutinib is not recommended as 1st-line therapy for patients newly diagnosed with chronic phase chronic myeloid leukemia

Dasatinib

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

Nilotinib

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

Ponatinib

• An oral multi-kinase inhibitor that inhibits the ABL & T315l mutant ABL genes
• Used for the treatment of T3151l-positive CP-, AP-, or BP-CML or T315l-positive Ph+ALL & in patients with CP-, AP-, or BP-CML or Ph+ALL for patients when no other tyrosine kinase inhibitor is indicated

Management of Tyrosine kinase inhibitors Therapy Toxicities

Imatinib

• Chronic phase chronic myeloid leukemia with ANC <1.0 x 10⁹/L &/or platelet count <50 x 10⁹/L
  
  • Withhold therapy until ANC ≥1.5 x 10⁹/L &/or platelet count ≥75 x 10⁹/L, then resume at 400 mg initial dose, or 300 mg initial dose for recurrence
• Accelerated & blast phase chronic myeloid leukemia with ANC <0.5 x 10⁹/L &/or platelet count <10 x 10⁹/L
  
  • Reduce dose to 400 mg if patient develops cytopenia unrelated to chronic myeloid leukemia
  • Reduce dose further to 300 mg if with persistent neutropenia after 2 weeks
  • Withhold Imatinib is still with cytopenia after 4 weeks, then resume at 300 mg dose if ANC ≥1.0 x 10⁹/L & 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 & 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 & 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 & 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, & alkaline phosphatase <2 x ULN
• Withhold therapy if with grade 3-4 diarrhea, rashes, & 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

• Chronic phase chronic myeloid leukemia with ANC <0.5 x 10⁹/L or platelet count <50 x 10⁹/L
  
  • Withhold therapy until ANC ≥1.0 x 10⁹/L & 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
• Accelerated & blast phase chronic myeloid leukemia with ANC <0.5 x 10⁹/L &/or platelet count <10 x 10⁹/L
  
  • Withhold treatment if patient develops cytopenia unrelated to chronic myeloid leukemia, then resume at initial dose if with ANC ≥1.0 x 10⁹/L & 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 & 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 & severe non-hematologic toxicities until symptoms resolve
  
  • May resume treatment at reduced dose depending on severity of adverse effect

Nilotinib

• Monitor serum potassium & 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 & 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 &/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 & 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 &/or platelet count <50 x 10⁹/L
    
    • May resume therapy at initial dose (45 mg), at 30 mg if at 2nd occurrence, & at 15 mg if at 3rd occurrence when results are ANC ≥1.5 x 10⁹/L & 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, & in patients with AST/ALT ≥3 x ULN plus bilirubin >2 x ULN & alkaline phosphatase <2 x ULN
• Monitor for thromboembolism, cardiac function, & hepatic function
• Combination with growth factors may be considered for resistant neutropenia & thrombocytopenia
• Transfusion support may be considered in patients with symptomatic grade 3-4 anemia

Antineoplastic agent

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 & reduces the protein levels of BCR-ABL & myeloid leukemia cell 1 (MCL-1) that is independent of the direct BCR-ABL binding
• Used to treat patients who have chronic phase chronic myeloid leukemia or accelerated phase chronic myeloid leukemia with disease progression that is resistant or intolerant to 2 or more tyrosine kinase inhibitors
• Reported adverse effects with Omacetaxine therapy include grade 3 or 4 hyperglycemia & 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 & platelet count ≥50 x 10⁹/L

Cytotoxic chemotherapy

Hydroxyurea

• An antimetabolite that rapidly reduces high white blood cell counts
• Inhibits the ribonucleotide reductase & DNA synthesis & does not interfere with protein or RNA synthesis
• Treatment option for symptomatic leukocytosis or thrombocytosis

Clinical trials

• Considerations for enrollment in clinical trials
  
  • In patients with accelerated phase chronic myeloid leukemia or blast phase chronic myeloid leukemia
  • In patients with treatment failure after Imatinib therapy
  • For patients with BCR-ABL1 transcripts >10% (IS) after initial treatment with 2nd-line tyrosine kinase inhibitors at 3-months evaluation
  • For patients with BCR-ABL1 transcripts >10% (IS) or lack of PCyR on bone marrow cytogenetics after initial treatment with 2nd-line tyrosine kinase inhibitors at 6-months evaluation
  • For patients with cytogenic relapse, or less than PCyR or BCR-ABL1 transcripts >10% (IS) at 12-months evaluation