Chronic Myeloid Leukemia Management

Evaluation

Determination of Risk Score  

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. This is the preferred prognostic tool. The scoring is based on the patient’s age, spleen size by palpation (cm below the costal margin), platelet count and percentage of blasts in the peripheral blood. 

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

Sokal Prognostic Score  

In the Sokal Prognostic Score, the patient’s age, spleen size, percent blasts, and platelet count 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) Score

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: ≤0.8754
• High risk: >0.8754

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.

Factors that may influence choice of TKI are as follows:

• CP-CML patients: BCR::AML1 transcript type, age, comorbidities, toxicity profile of TKI, dosing schedule, possible drug interactions, treatment goal, medication cost, patient preferences
• AP-CML patients: BCR::ABL1 transcript type, prior therapy and/or BCR::ABL1 mutation profile, toxicity profile, possible drug interactions, medication cost

TKIs are 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 disease. 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. Asciminib is contraindicated in patients with CML lacking ABL1 exon 2. 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. Lumbar puncture and CNS prophylaxis are recommended for patients with lymphoid BP-CML. Limited available evidence from small cohort studies suggests that initiation of first-line TKIs (Bosutinib, Dasatinib, or Nilotinib) at lower doses and dose reduction in optimal responders are appropriate strategies to limit long-term toxicities; however, the minimum effective dose and optimal TKI de-escalation remain undefined.

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:

• Disease in CP-CML without any history of AP or BP
• At least 3 years of TKI therapy
• Presence of quantifiable BCR::ABL1 transcripts at the time of diagnosis
• 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 kinase domain mutation testing for patients who do not achieve MMR 3 months after resuming TKI therapy, and molecular monitoring should be continued monthly for another 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

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, >5 years on TKI therapy (>4 years if second generation TKI is used) and DMR of >2 years. In patients with responsive disease, continuation of TKI therapy is recommended.
 
Switching of TKI Therapy  

Switching to an alternative TKI therapy should be considered in the presence of the following adverse effects:

• Asciminib: Recurrent pancreatitis despite dose reduction, severe hypertension not responsive to antihypertensive medications
• Bosutinib: Liver function test (LFT) abnormalities, recurrent pleural or pericardial effusions despite dose reduction (less common)
• Dasatinib: Pulmonary arterial hypertension, GI bleeding, recurrent pleural or pericardial effusions despite dose reduction, neurotoxicity (rare) (eg dementia-like condition, parkinsonism, intracranial hypertension)
• Imatinib: LFT abnormalities, neurotoxicity (rare) (eg dementia-like condition, parkinsonism, intracranial hypertension)
• Nilotinib: Hyperglycemia, recurrent pancreatitis despite dose reduction, arterial/vascular adverse events
• Ponatinib: Recurrent pancreatitis despite dose reduction, severe hypertension not responsive to antihypertensive medications, arterial/vascular adverse events
• All TKIs: Persistent moderate to severe nephrotoxicity, immune-mediated adverse events (eg colitis, pneumonitis, hepatitis, myocarditis, pericarditis, nephritis)

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 the preferred first-line treatment for low-risk patients with CP-CML and first-line treatment option for patients at intermediate- to high-risk patients with CP-CML and advanced phase CML. It may only be considered as first-line treatment option in AP-CML and as an alternative agent for BP-CML when second- or third-generation TKI is contraindicated. Several studies showed cytogenetic and hematologic response, decreased relapse and disease progression, and high OS rates in patients given Imatinib therapy. It may also be 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, F359V/C/I, T315A, or Y253H mutations. It is the preferred first-line treatment for newly diagnosed patients with CP-CML with any risk score and advanced CML. Monotherapy is an option in patients with myeloid BP-CML and combination with corticosteroids may be considered in patients with lymphoid BP-CML if the patient is not a candidate for induction chemotherapy. However, Bosutinib should not be given in patients with T315I, V299L, G250E, or F317L mutations.

 
Dasatinib

Dasatinib is an oral 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 and advanced phase CML. It is also preferred in patients with a history of arrhythmia, heart disease, pancreatitis, and hyperglycemia. Monotherapy is an option in patients with myeloid BP-CML and combination with corticosteroids may be considered in patients with lymphoid BP-CML if the patient is not a candidate for induction chemotherapy. It is also used in managing cytogenetic or hematologic resistance to TKIs and in patients with Y25253H, E5K/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 with any risk score and advanced CML. Monotherapy is an option in patients with myeloid BP-CML and combination with corticosteroids may be considered in patients with lymphoid BP-CML if the patient is not a candidate for induction chemotherapy. 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  

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 for patients when no other TKI is indicated. It is also the preferred first-line treatment for patients with AP-CML. Monotherapy is an option with myeloid BP-CML and combination with corticosteroids may be considered in patients with lymphoid BP-CML if the patient is not a candidate for induction chemotherapy. 

Allosteric 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 preferred first-line treatment option for patients with CP-CML regardless of risk score; it is also a treatment option for previously treated CP-CML and selected AP-CML. It is contraindicated in patients with CML lacking ABL1 exon 2. However, Asciminib should not be used in patients with A337T, P465S, M244V, or F359V/I/C mutations.

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

• 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 (other than Imatinib), 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 the first-line treatment option for CP-CML based on the ASC4FIRST trial. It is approved T315I mutation-positive CP-CML and AP-CML, and/or CP-CML patients and AP-CML patients with resistance or intolerance to at least two 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 depend 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 who achieved morphologic remission after ALL- or AML-type induction plus TKI. 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.