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
- Second-generation TKIs are preferred over Imatinib therapy for younger patients particularly females desiring fertility
- First-generation TKI Imatinib may be preferred for older patients with comorbidities, especially cardiovascular comorbidities
- 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 AP-CML, 2nd- and 3rd-generation TKIs are recommended as primary treatment for accelerated phase disease, ALL-type induction chemotherapy with TKI or TKI with steroids for lymphoid BP-CML, and AML-type induction chemotherapy with TKI or TKI monotherapy for myeloid BP-CML
- 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
Adherence to Tyrosine Kinase Inhibitor (TKI) Therapy
- Predicts the achievement of deep molecular response (DMR) 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 MMR, 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 following criteria are present:
- Patient aged ≥18 years old
- Disease in CP without any history of AP or BP
- At least 3 years of TKI therapy
- Presence of BCR::ABL1 transcripts at time of diagnosis
- ≥2 years of stable molecular response (molecular response 4 [MR4]; 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 every 4 weeks until MMR is achieved, then every 12 weeks monitoring thereafter
- Perform BCR::ABL1 testing for patients who do 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 AP or BP
- MMR has not been achieved 3 months 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), DMR 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 low-risk patients with chronic phase chronic myeloid leukemia (CP-CML) and advanced phase chronic myeloid leukemia (AP-CML) and 2nd-line treatment for patients at intermediate- to high-risk with CP-CML and advanced phase CML
- Several studies showed cytogenic response, hematologic response, decreased relapse and disease progression, and high overall survival (OS) 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
- Should not be given in patients with T315I, V299L, G250E, or F317L mutations
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
- Should not be given in patients with T315I/A, F317L/V/I/C, or V299L 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
- Should not be given in patients with T315I, Y253H, E255K/V, or F359V/C/I mutations
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
Third Generation TKI
Asciminib
- An ABL/BCR::ABL1 TKI that inhibits ABL1 kinase activity by binding to the myristoyl pocket of the protein which results in the formation of an inactive kinase configuration
- Treatment option for CP-CML T315I mutation-positive patients and/or CP-CML patients with resistance or intolerance to at least 2 prior TKIs
- Should not be given in patients with A337T or P465S 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
Management of TKI Therapy Toxicities
Asciminib
- ANC <1.0 x 109/L, and/or platelets <50 x 109/L
- Withhold treatment until ANC reaches ≥1.0 x 109/L and platelet count ≥50 x 109/L
- Resume Asciminib at reduced dose for presence of recurrent severe thrombocytopenia and/or neutropenia
- May resume Asciminib treatment or may reduce dose when blood count returns to normal within 2 weeks
- Withhold treatment until ANC reaches ≥1.0 x 109/L and platelet count ≥50 x 109/L
- Withhold therapy for any of the following:
- Elevated serum amylase and/or lipase (>2.0 x ULN)
- May resume treatment at reduced dose once serum levels return to <1.5 x ULN
- Permanently discontinue if recurrence occurs even at reduced dose or if serum levels remain at <1.5 x ULN
- Grade ≥3 hypersensitivity or cardiovascular toxicity
- May resume treatment at reduced dose when symptoms resolve to grade ≤1
- Permanently discontinue if signs/symptoms persist
- Elevated serum amylase and/or lipase (>2.0 x ULN)
- Withhold treatment, reduce dose, or permanently discontinue therapy if hypertension is not medically controlled
- Patients currently undergoing treatment with a strong CYP3A4 inhibitor/substrate or P‑glycoprotein substrate should be closely monitored for any adverse effects; concomitant use of Asciminib with CYP2C9 substrates should be avoided
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
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 upper limit of normal (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
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
- CP or AP, ANC <1.0 x 109/L and/or platelet count <50 x 109/L
- May resume treatment within 2 weeks at prior dose if ANC >1.0 x 109/L and/or platelet count >50 x 109/L
- May reduce dose to 400 mg if blood counts remain low for >2 weeks
- Elevated serum lipase, amylase, bilirubin, or hepatic transaminases grade ≥3
- May resume at reduced dose of 400 mg if serum levels return to grade ≤1
- ECG with QTc >480 msec
- 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
- ANC <1.0 x 109/L and/or platelet count <50 x 109/L
- 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
- Avoid in patients with poorly controlled diabetes until good glycemic control has been established
Cancer Immunotherapy
- Clinical trials on the therapeutic potential of Pegylated interferon α in combination with TKIs in CP-CML showed promising results