Chronic Myeloid Leukemia Management

Evaluation

Determination of Risk Score  

Sokal Prognostic Score  

In the Sokal prognostic score, spleen size, percent blasts, age and platelet count >700,000/µL are used as variables.

• Low risk: <0.8
• Intermediate risk: 0.8-1.2
• High risk: >1.2

Hasford (EURO) Score  

The Hasford (EURO) score has been developed for patients receiving Interferon therapy. It adds eosinophilia and basophilia to other variables.

• Low risk: ≤780
• Intermediate risk: >780 - ≤1480
• High risk: >1480

European Treatment and Outcome Study (EUTOS)  

EUTOS has been developed in 2011. This identifies two risk groups with different probabilities of complete cytogenetic response (CCyR) within 18 months post-therapy. The scoring is based on the percentage of basophils and the size of the spleen. However, additional studies may be needed to confirm the importance of EUTOS in predicting clinical outcomes of patients receiving TKI therapy.

• Low risk: ≤87
• High risk: >87

EUTOS Long-term Survival (ELTS) Score  

The ELTS Score was developed in 2016 by the European LeukemiaNet to distinguish three risk groups with significantly different probabilities of dying of CML. The scoring is based on the percentage of basophils, the size of the spleen, and the Sokal age. 

• Low risk: ≤1.5680
• Intermediate risk: >1.5680 but ≤2.2185
• High risk: >2.2185

Principles of Therapy

In general, the choice of first-line therapy may depend on the risk score, the physician's experience, age of the patient, ability to tolerate therapy, and any existing comorbid conditions. TKIs are the recommended as first-line therapy for patients with CP-CML and AP-CML disease. All TKIs are suitable as primary treatment options for newly diagnosed CP-CML patients across all risk scores. Second-generation TKIs such as Dasatinib, Nilotinib, and Bosutinib are recommended for newly diagnosed CP-CML patients with intermediate- to high-risk. Second-generation TKIs and the allosteric TKI Asciminib 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 second-generation TKIs Bosutinib, Dasatinib, and Nilotinib, and allosteric TKI Asciminib possess higher major molecular response (MMR) rates and faster cytogenetic responses, along with less progression to AP-CML, when compared to Imatinib. For patients with T315I mutation-positive disease, third-generation TKIs such as Asciminib and Ponatinib are viable treatment options. Dasatinib or Bosutinib are the preferred TKIs for CP-CML patients with a history of arrhythmia, cardiac disorders, pancreatitis, or elevated blood glucose. For CP-CML patients with pulmonary disorders or those at increased risk for pleural effusion, Asciminib, Nilotinib, or Bosutinib are preferred. For patients with AP-CML, second- and third-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 a TKI, an alternate TKI that has not been given may be considered. Notably, the BCR::ABL1 kinase domain mutation status should be taken into account.  

Adherence to TKI Therapy  

Adherence to tyrosine kinase inhibitor (TKI) therapy is a key predictor of achieving a deep molecular response (DMR) when using standard-dose Imatinib. The marker that identifies a non-adherent CP-CML patient is the BCR::ABL1 doubling time. Patients are educated on the importance of their adherence to TKI therapy and are monitored closely throughout their treatment. Non-adherence may result to poorer treatment response that can result in the loss of MMR, hematologic failure, cytogenetic relapse, and treatment failure. Appropriate management of side effects is essential, as it significantly contributes to improved patient adherence.  

Discontinuation of TKI Therapy  

Discontinuation 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 the time of diagnosis
• ≥2 years of stable molecular response (molecular response 4 [MR4]; BCR::ABL1 ≤0.01% IS) for ≥2 years in at least four 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 every 1-2 months for the first 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 effects related to TKI therapy discontinuation
  • Disease phase progresses to AP or BP
  • MMR has not been achieved 3 months after resumption of treatment

The discontinuation of TKI therapy should only be considered in patients who are eligible for a clinical trial. However, temporary cessation of TKI treatment may be considered in patients who have a history of treatment change solely due to intolerance, possess typical e13a2 or e14a2 BCR::ABL1 transcripts,  on >5 years on TKI therapy (>4 years if second generation TKI is used), DMR of >2 years, and a history of treatment failure. In patients with responsive disease, the continuation of TKI therapy is recommended.

Clinical Trials  

Considerations for enrollment in clinical trials include:

• 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 second-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 second-line TKIs at 6-month evaluation
• For patients with cytogenetic relapse, or less than PCyR or BCR::ABL1 transcripts >10% (IS) at 12-month evaluation

Pharmacological therapy

Targeted Cancer Therapy  

First Generation TKI  

Imatinib  

Imatinib belongs to a class of signal transduction inhibitors (STIs) that interfere with intracellular signaling pathways associated with malignancies. It inhibits the BCR::ABL1 tyrosine protein kinase in all phases CML. It is recommended as first-line treatment for low-risk patients with CP-CML and for those with advanced phase CML, and second-line treatment for intermediate- to high-risk patients with CP-CML and advanced phase CML. Several studies showed cytogenetic and hematologic response, decreased relapse and disease progression, and high OS rates in patients given Imatinib therapy. It is also preferred for older patients with comorbidities (eg cardiovascular disease).  

Second Generation TKI  

Bosutinib  

Bosutinib is an oral multi-TKI that is used to treat adult patients with CP, AP or BP Ph-positive (Ph+) CML with resistance to multiple therapy (eg Imatinib, Dasatinib and Nilotinib). Bosutinib inhibits the BCR::ABL1 kinase that promotes CML and members of the Src-family of kinases (eg Src, Lyn, and Hck). It is more potent for the BCR::ABL1 kinase than Imatinib. It is not an efficient substrate for multidrug resistant transporters. It is used in 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. It is recommended as a first-line treatment for newly diagnosed patients with CP-CML with any risk score. It is also a treatment option for CP-CML patients who were previously treated with Dasatinib or Nilotinib. However, Bosutinib should not be given in patients with T315I, V299L, G250E, or F317L mutations.  

Dasatanib  

Dasatinib is an multi-TKI that is more potent in inhibiting ABL than Imatinib. It inhibits Src tyrosine kinase, BCR::ABL, and Imatinib-resistant mutations of BCR::ABL, and binds to both the active and inactive conformations of the ABL kinase domain. Dasatinib is recommended for all phases of CML in patients 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 CP. It is a preferred first-line treatment for patients with CP-CML with any risk score. It is also preferred in patients with a history of arrhythmia, heart disease, pancreatitis, and hyperglycemia. It is also used in managing cytogenetic or hematologic resistance to TKIs and in patients with Y253H, E255K/V, or F359V/C/I mutations. However, it should not be used in patients with T315I/A, F317L/V/I/C, or V299L mutations.  

Nilotinib  

Nilotinib is used for adult patients who are newly diagnosed with Ph+ CP-CML. It is also used to treat chronic and accelerated Ph+ CML in patients who are intolerant of or resistant to prior therapy, including Imatinib. It is a preferred first-line treatment option for patients with CP-CML regardless of risk score. It selectively inhibits the BCR::ABL1 tyrosine kinase and enhances binding site affinity which makes Nilotinib 30 times more potent than Imatinib in Imatinib-sensitive CML cell lines and 3 to 7 times more potent in Imatinib-resistant cell lines. It is also used for the management of cytogenetic or hematologic resistance to TKIs and in patients with F317L/V/I/C, T315A, or V299L mutations. However, Nilotinib should not be used in patients with T315I, Y253H, E255K/V, or F359V/C/I mutations.  

Radotinib  

Radotinib is an oral TKI that inhibits the BCR::ABL1 fusion protein. It is approved only in South Korea and is currently being studied in other countries for its potential antineoplastic activity in the treatment of CML.

Third Generation TKI  

Asciminib  

Asciminib is an ABL/BCR::ABL1 TKI that inhibits ABL1 kinase activity through binding to the myristoyl pocket of the protein which results in the formation of an inactive kinase configuration. It is a treatment option for CP-CML and AP-CML T315I mutation-positive patients and/or previously treated CP-CML and AP-CML. However, Asciminib should not be used in patients with A337T, P465S, M244V, or F359V/I/C mutations.  

Ponatinib  

Ponatinib is an oral multi-kinase inhibitor that targets the ABL and the T315I mutant ABL gene. It is used for the treatment of T315I-positive CP-, AP-, or BP-CML, or T315I-positive Ph+ ALL and in patients with CP-, AP-, or BP-CML or Ph+ ALL when no other TKI is suitable. It is also a treatment option for CP-CML patients who are unresponsive to at least 2 prior TKI therapies.  

Cytotoxic Chemotherapy  

Hydroxyurea  

Hydroxyurea is an antimetabolite that rapidly reduces high WBC counts. It works by inhibiting ribonucleotide reductase and DNA synthesis without interfering with protein or RNA synthesis. It is a treatment option for patients with symptomatic leukocytosis or thrombocytosis while awaiting confirmation of BCR::ABL1.

Chronic Myeloid Leukemia_Management 1

• Elevated serum amylase and/or lipase (>2.0 x upper limit of normal [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

Treatment is withheld, the dose reduced, or therapy permanently discontinued with a switch to an alternate TKI if hypertension is not medically controlled, if with persistent moderate to severe nephrotoxicity, immune-mediated adverse events, or if recurrent pancreatitis is present despite dose reduction. Patients currently undergoing treatment with a strong CYP3A4 inhibitor or substrate, or a P-glycoprotein substrate, should be closely monitored for any adverse effects. Additionally, the concomitant use of Asciminib with CYP2C9 substrates should be avoided.

Bosutinib  

If the ANC  <1.0 × 10⁹/L or the platelet count <50 × 10⁹/L, treatment is withheld until the ANC reaches ≥1.0 × 10⁹/L and the platelet count reaches ≥50 × 10⁹/L. Bosutinib may be resumed once blood counts return to normal within two weeks. If blood count remains low after two weeks, the dose is reduced to 100 mg; further dose reduction to 100 mg is considered in the event of cytopenia recurrence. Combination therapy with growth factors may be considered for resistant neutropenia and thrombocytopenia. Transfusion support may be considered in patients with symptomatic grade 3–4 anemia. Therapy is also be withheld if the patient’s liver transaminases >5 times the institutional upper limit of normal (IULN). Treatment may be resumed at 400 mg daily when liver transaminases are reduced to ≤2.5 × IULN. If recovery takes longer than four weeks, or if there are transaminase elevations >3 × IULN, bilirubin >2 × IULN, and alkaline phosphatase <2 × ULN, Bosutinib is discontinued. Therapy is also withheld in cases of grade 3–4 diarrhea, rashes, or other clinically significant moderate, or severe non-hematologic toxicities until symptoms resolve. Treatment may be resumed at 400 mg once daily when the toxicity has been resolved (ie diarrhea resolves to grade ≤1). Bosutinib is permanently discontinued and switched to an alternate TKI if recurrent pleural or pericardial effusions occur despite dose reduction, or if persistent moderate to severe nephrotoxicity, liver function test (LFT) abnormalities, or immune-mediated adverse events are present.  

Dasatanib  

For CP-CML patients with an ANC <0.5 × 10⁹/L or a platelet <50 × 10⁹/L, Dasatinib therapy is withheld until the ANC ≥1.0 × 10⁹/L and the platelet count ≥50 × 10⁹/L. Treatment is also withheld if the platelet count is <25 × 10⁹/L or if there is a recurrence of ANC <0.5 × 10⁹/L for >7 days. Therapy may be resumed if blood count return to normal after ≤7 days or at a reduced dose of 80 mg once daily if cytopenia recurs. A further reduction to 50 mg once daily or discontinuation of treatment is considered upon a third recurrence. In AP-CML and BP-CML patients with ANC <0.5 × 10⁹/L and/or platelet count <10 × 10⁹/L, treatment is withheld if the cytopenia is unrelated to CML. Treatment is resumed at the initial dose if with ANC ≥1.0 x 10⁹/L and platelet count ≥20 x 10⁹/L, or at reduced dose of 100 mg/day if there is recurrence, or at 80 mg once daily for third 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 permanently discontinued and switched to an alternate TKI in cases of confirmed pulmonary arterial hypertension, persistent moderate to severe nephrotoxicity, gastrointestinal (GI) bleeding, immune-mediated adverse events, or if recurrent pleural or pericardial effusions occur despite dose reduction. Therapy is withheld if rashes and severe non-hematologic toxicities develop until symptoms resolve. Treatment may be resumed at a reduced dose depending on the severity of the adverse effects.  

Imatinib  

For CP-CML patients who have an ANC <1.0 × 10⁹/L and/or a platelet count <50 × 10⁹/L, Imatinib therapy is withheld until the ANC reaches ≥1.5 × 10⁹/L and/or the platelet count reaches ≥75 × 10⁹/L. Then, treatment is resumed at an initial dose of 400 mg, or 300 mg for recurrence. In patients with AP-CML or BP-CML with ANC <0.5 × 10⁹/L and/or platelet count <10 × 10⁹/L, the dose is reduced to 400 mg if the cytopenia is unrelated to CML. If there is persistent neutropenia after 2 weeks, the dose is further reduced to 300 mg. If cytopenia persists after four weeks, Imatinib is withheld, and therapy may be resumed at a 300 mg dose if the ANC is ≥1.0 × 10⁹/L and platelet count is ≥20 × 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. Therapy is also withheld if the patient has a bilirubin level >3 times the IULN or liver transaminase levels >5 times the IULN. Imatinib may be resumed when bilirubin levels are reduced to <1.5 times the ULN and liver transaminases to <2.5 times the ULN. Imatinib administration is interrupted if there is any of the following: Severe hepatotoxicity, severe fluid retention, or rashes. Imatinib is discontinued and switched to an alternate TKI if persistent moderate to severe nephrotoxicity, LFT abnormalities, or immune-mediated adverse events occur.  

Nilotinib  

For patients receiving Nilotinib, it is important to monitor serum potassium and magnesium levels, ECG, and 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 <45 msec and within 20 msec of baseline
  • May resume at reduced dose if QTcF between 450-480 msec after 2 weeks
  • Discontinue Nilotnib if QTcF returns to >480 msec after dose reduction
• CP or AP, ANC <1.0 × 10⁹/L and/or platelet count <50 × 10⁹/L
  • May resume treatment within 2 weeks at prior dose if ANC >1.0 × 10⁹/L and/or platelet count >50 × 10⁹/L
  • May reduce dose to 400 mg if blood counts remain low for >2 weeks
• Elevated serum lipase, amylase, bilirubin, or hepatic transaminase grade ≥3
  • May resume at reduced dose of 400 mg if serum levels return to grade ≤1

Nilotinib is discontinued and replaced with an alternate TKI if with confirmed peripheral arterial occlusive disease, QT interval prolongation, any arterial or vascular adverse events, hyperglycemia, persistent moderate to severe nephrotoxicity, immune-mediated adverse events, or recurrent pancreatitis despite dose reduction. Combination therapy 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 × 10⁹/L and/or platelet count <50 × 10⁹/L
  • May resume therapy at initial dose (45 mg), at 30 mg if at second occurrence, and at 15 mg if at third occurrence when results are ANC ≥1.5 × 10⁹/L and platelet count ≥75 × 10⁹/L
• Elevated serum lipase (symptomatic grade ½), amylase, bilirubin, or hepatic transaminase grade >3 the IULN (grade ≥2)
  • May result treatment at reduced dose in patients with liver transaminase <3 x the IULN, serum lipase <1.5 × 10⁹/L 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

Ponatinib is discontinued if patients receiving 15 mg doses present with liver transaminase levels > 3 × IULN, grade 4 symptomatic pancreatitis, in patients with AST/ALT ≥3 × ULN plus bilirubin >2 × ULN and alkaline phosphatase <2 × ULN., and in patients with severe hypertension unresponsive to antihypertensive medications. In addition, Ponatinib is discontinued and replaced with an alternate TKI if with arterial and vascular adverse events, persistent moderate to severe nephrotoxicity, immune-mediated adverse events, or recurrent pancreatitis despite dose reduction. Monitoring for thromboembolism, cardiac function, and hepatic function is important during Ponatinib therapy. 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.

Supportive Care  

Leukocytosis  

The treatment options for patients with symptomatic leukocytosis include Hydroxyurea, apheresis, Imatinib, Dasatinib, or Nilotinib.  

Thrombocytosis  

The available treatment options for symptomatic thrombocytosis are anti-aggregants, Anagrelide, apharesis, and Hydroxyurea.  

Cytopenia  

For patients with persistent cytopenia, growth factor support may be considered.  

Management of Resistance  

Factors that may affect development of 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 to 15% of patients who used Imatinib as first-line treatment and <10% in second generation TKIs.  

In patients showing resistance to current treatment, the following should be considered:

• Evaluation of the patient’s compliance with current treatment regimen, recommended dose and schedule
• Monitoring of Imatinib plasma levels may be useful
• Possible drug interactions
• BCR::ABL1 kinase domain mutational analysis
• Bone marrow cytogenetic analysis

Recommended treatment strategies for patients with confirmed TKI resistance include switching to an alternative TKI, commencing evaluation for allo-HCT, and referring to a specialized CML center and/or enrolling patient into a clinical trial.  

Recommended treatment strategies for patients suspected of TKI resistance:

• Switching to alternative TKI
• If treating with TKI, may consider continuing treatment with the same TKI
• At 12 months after treatment initiation, may consider switching to an alternative TKI or to continue with the same TKI if CCyR is achieved
• Referral to a specialized CML center and/or enrollment into a clinical trial

Recommended treatment strategies of optimal treatment response has not been achieved include referring to a specialized CML center and/or enrolling into a clinical trial, and switching from Imatinib to a second-generation TKI or allosteric TKI.  

Treatment Options  

Asciminib  

Asciminib is an allosteric TKI that is active against Imatinib-resistant BCR::ABL1 kinase domain mutations, including the T315I mutation. It is approved T315I mutation-positive CP-CML patients and/or CP-CML patients with resistance or intolerance to at least 2 prior TKIs.  

Bosutinib  

Bosutinib is active against Imatinib-resistant BCR::ABL1 kinase domain mutations, except for T315I. It is effective in patients with CP-CML resistant to standard-dose Imatinib. Additionally, it has potent activity in patients with resistance to BCR::ABL1 mutations to Nilotinib (Y253H, E255K/V, and F359C/I/V) and Dasatinib (F317L).  

Dasatinib  

Dasatinib is active against Imatinib-resistant BCR::ABL1 kinase domain mutations, except for T3I5I. It is effective in patients with CP-CML resistant to standard- and high-dose Imatinib.  

Imatinib  

Dose escalation of Imatinib is effective in patients who experience a cytogenetic relapse or have suboptimal cytogenetic response. However, patients who exhibit hematologic failure and who never had cytogenetic response are unlikely to benefit from dose escalation.  

Nilotinib  

Nilotinib is active against Imatinib-resistant BCR::ABL1 kinase domain mutations, except for T315I. In vitro studies showed its activity against the F317L mutation. It is also effective in patients with CP-CML who exhibit resistance to standard Imatinib therapy. 

Ponatinib  

Ponatinib is approved for CML patients with resistance or intolerance to ≥2 TKIs, including those with the T315I mutation, and/or CP-CML, or for patients with AP-CML or BP-CML whom no other TKI is indicated. It is also used in patients with BCR::ABL1 mutations such as E255K/V, F317L, F359V, G250E, M351T, and Y253H.  

For discussion of clinical trials and allo-HCT, please refer to the Principles of Therapy and Surgery sections.

Surgery

Hematopoietic Cell Transplant (HCT)  

Patients are first treated with a preoperative or conditioning regimen (eg chemotherapy or radiation therapy or both) followed by infusion of hematopoietic progenitor/stem cells. The parameters for HCT application depends on the patient’s disease and stage of the disease, cell donor, and the source of the progenitor cells.  

Allogeneic Hematopoietic Cell Transplantation (Allo-HCT)  

The indications and outcomes of allo-HCT depend on the age and comorbidities of the patient, donor type, and transplant center. In allo-HCT, progenitor cells are collected from healthy persons and are used to treat hematologic neoplasm, non-malignant marrow disorders (eg acquired and inherited), and inborn errors of metabolism. Allo-HCT is the first-line treatment option for patients diagnosed with BP-CML at initial evaluation. It may be considered for CP-CML patients deemed cytogenetically and molecularly unresponsive or resistant to all available TKI therapy or those with a T315I mutation unresponsive to Ponatinib therapy. Additionally, it may be considered for patients with AP-CML who are unresponsive to TKI therapy, have relapsed disease, are resistant to multiple TKIs, or are intolerant to TKI treatment.

Chronic Myeloid Leukemia_Management 2

• Improve the methods that detect BCR::ABL1 transcripts
• Develop reduced-intensity conditioning regimens
• Modify the delivery of lymphocytes with the depletion of CD8+ cells
• Escalate cell dosage regimen
• Very low-dose DLI and IFN-alpha combination may help reduce GVHD

Imatinib induces durable remissions in patients with relapse in all phases of CML following allo-HCT.