Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

chronic phase

1st line – tyrosine kinase inhibitor (TKI)

Back
ACUTE
|
chronic phase
|
first presentation
1st line – 

tyrosine kinase inhibitor (TKI)

Patients with chronic myeloid leukemia (CML) should be referred to a hematology/oncology specialist for management of their disease.

The goals of treatment are to achieve complete hematologic response, early molecular response (EMR), complete cytogenetic response (CCyR), major molecular response (MMR), and deep molecular response (DMR). When feasible and desired, treatment-free remission (TFR) may be attempted for select patients with stable DMR.

Treatment may not achieve all of these goals. The most important goals are to prevent progression to accelerated or blast phase, and achieve either CCyR or MMR. Although MMR is superior to CCyR (i.e., indicates a better treatment response), improved overall survival has not been demonstrated in patients with MMR compared with those in stable CCyR.[5][48] Goals should be individualized; for example, an optimal response of CCyR at 12 months may be appropriate if the goal is long-term survival; a response of MMR at 12 months may be chosen if the goal is TFR.

Risk assessment is recommended before starting TKI therapy in patients with chronic-phase CML. The European treatment and outcome study long-term survival (ELTS), Sokal, and Hasford (Euro) scoring systems use prognostic factors to stratify patients into low, intermediate, and high risk.[4][5][9][10]​​​ European LeukemiaNet: chronic myeloid leukemia (CML) Opens in new window [ EUTOS long-term survival (ELTS) score Opens in new window ] [ Sokal score for chronic myeloid leukemia Opens in new window ]

Note that the Sokal and Hasford scores were developed before TKI treatment was available.

Imatinib, a first-generation TKI, is well tolerated and remains a standard initial treatment.[45][51][52] Imatinib is the preferred option for patients with a low risk score, and has a superior toxicity profile to second-generation TKIs, making it a suitable option for older patients with comorbidities (e.g., cardiovascular disease).[5]

Overall survival rate (≥10 years follow-up) is in excess of 80%.[52][53][54] Progression typically happens in the first 2-4 years following start of therapy.[2][3][52][54] There is a 7% risk of disease progression to accelerated or blast phase in the first 5 years.[3][52]

Bosutinib, dasatinib, nilotinib (second-generation TKIs), and asciminib (a newer-generation BCR::ABL TKI) can be used for initial treatment across all risk scores or as second-line therapy (e.g., if the patient is intolerant or unresponsive to initial treatment with imatinib or if the response to imatinib is suboptimal).[5][55][56][57][58][59][60] While bosutinib is approved for initial treatment, many specialists reserve bosutinib treatment for patients who are intolerant or unresponsive to other TKIs.

Use of second-generation TKIs and asciminib as first-line therapy for chronic-phase CML can induce more rapid and more frequent early and major molecular responses than imatinib, and they may be associated with fewer transformations to accelerated phase or blast crisis.[55][59][61][62][63][64][65][66] Benefits of second-generation TKIs are balanced by more intense, and potentially more serious, adverse effects.

Asciminib has a novel mechanism of action, specifically targeting the ABL myristoyl pocket, and is active against most of the resistant BCR::ABL1 kinase domain mutants, including T315l. Asciminib as first-line therapy for chronic-phase CML may result in a higher rate of major molecular response than imatinib or second-generation TKIs.[59] Adverse events with asciminib appear to be reduced compared with other TKIs.[67][68] In one phase 3 trial, adverse events leading to discontinuation of treatment were less frequent with asciminib (4.5%) compared with imatinib (11.1%) and second-generation TKIs (9.8%).[59]

Second-generation TKIs and asciminib are preferred for patients with intermediate- or high-risk scores, who will benefit most from rapid results and reduced progression.[5] They may be a good option for younger patients if TFR is a goal, and for women of childbearing age who will need to discontinue TKI treatment if trying to become pregnant.

The choice between a second-generation TKI and asciminib should be based on differences in toxicity profile and the presence of comorbidities.[5] Asciminib, bosutinib, or nilotinib may be preferred for patients with lung disease or at risk of pleural effusions; for patients with cardiovascular disease or hypertension, bosutinib or dasatinib should be considered.[5]

Limited evidence suggests that low-dose and dose-reduction strategies may reduce toxicity of second-generation TKIs while maintaining efficacy; however, optimal strategies have not been established.[5][30]

Low-dose dasatinib has been suggested as a first-line treatment option for older patients with CML, and for patients who develop clinically significant intolerance to standard doses of dasatinib.[5][30][90][91][92]

For most patients with CML, TKI therapy should be continued indefinitely if there is a response and treatment is well tolerated. However, for highly selected patients who have maintained a stable DMR for at least 2 years, discontinuation of TKI treatment may be considered under close expert medical supervision and following detailed discussion with the patient.[5][6]

Between 40% and 60% of patients who discontinue TKI after >2 years of durable DMR maintain a successful treatment-free remission, rising to more than 80% after >5 years of durable DMR.[78][79][80] Guidelines include criteria for TKI discontinuation and recommendations for frequent monitoring.[5][6] TKI therapy should be resumed promptly in patients who relapse; over 90% regain their DMR after restarting TKI therapy.[6]

See local specialist protocol for dosing guidelines.

Primary options

imatinib

OR

dasatinib

OR

nilotinib

OR

bosutinib

OR

asciminib

1st line – alternative tyrosine kinase inhibitor (TKI)

Back
ACUTE
|
chronic phase
|
resistant to initial therapy
1st line – 

alternative tyrosine kinase inhibitor (TKI)

Resistance to TKI therapy can develop due to point mutations in the BCR::ABL1 kinase domain, BCR::ABL1 compound mutations, or for other reasons.[5] Patients with resistant disease may fail to respond to primary therapy, have a suboptimal response, or lose their initial response.

Monitoring BCR::ABL1 transcript levels (using an international scale [IS]) for treatment response milestones at 3 months, 6 months, and 12 months helps to guide decisions about continuing or changing treatment. An individualized approach, taking into account the clinical context, is recommended when milestones are not reached.[30][69] Consider patient adherence to therapy and the potential role of drug interactions in patients with suboptimal response.[5]

TKI resistance, defined as BCR::ABL1 >10% at 6 months or later, indicates the need to change to an alternative TKI (and evaluation of the patient for allogeneic hematopoietic stem cell transplantation [HSCT]). Consideration should be given to BCR::ABL1 kinase domain mutational analysis to help guide changes to treatment (e.g., switching to a different TKI).[5][37][70]

For patients with resistance to imatinib, switching to an alternative TKI is recommended. Choice of treatment takes into account BCR::ABL1 kinase mutation status. Dasatinib, nilotinib, and bosutinib are active against many imatinib-resistant BCR::ABL1 kinase domain mutants (except T315l). Asciminib is active against T315l (which confers resistance to imatinib, bosutinib, dasatinib, and nilotinib) and most other resistant BCR::ABL1 kinase domain mutants.[5] Asciminib dosing differs for T315I mutated versus non-T315I mutated cases.

For patients with resistance to a second-generation TKI or asciminib: an alternative TKI (not imatinib) is recommended for patients with treatment-resistant chronic-phase CML who have an identifiable BCR::ABL1 mutation that confers resistance to TKI therapy. Asciminib is recommended for patients with chronic-phase disease and the T315l mutation.[5][67][71] The third-generation TKI, ponatinib, is recommended if the patient has no identifiable BCR::ABL1 mutations.[5] Ponatinib is also an option for patients with the T315l mutation and/or with resistance or intolerance to at least two prior TKIs.[5][72][73]

Ponatinib is active against most of the resistant BCR::ABL1 kinase domain mutants, including T315l.[5]

Ponatinib is associated with a significant risk of serious vascular events, heart failure, pancreatitis, and hepatotoxicity (approaching 30% in a phase 2 study).[74] Post-marketing cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported.[75] Ponatinib should be interrupted immediately if RPLS is confirmed, and a decision to restart should be guided by a benefit-risk assessment. Patients should be assessed for cardiovascular risk factors and appropriately counseled regarding the risks associated with ponatinib therapy.[75] A response-adjusted dosing regimen should be used to reduce the risk of adverse effects (including cardiovascular risks) and improve tolerability.[5][76][77]

For most patients with chronic myeloid leukemia, TKI therapy should be continued indefinitely if there is a response and treatment is well tolerated. However, for highly selected patients who have maintained a stable DMR for at least 2 years, discontinuation of TKI treatment may be considered under close expert medical supervision and following detailed discussion with the patient.[5][6]

Between 40% and 60% of patients who discontinue TKI after >2 years of durable DMR maintain a successful treatment-free remission, rising to more than 80% after >5 years of durable DMR.[78][79][80] Guidelines include criteria for TKI discontinuation and recommendations for frequent monitoring.[5][6] TKI therapy should be resumed promptly in patients who relapse; over 90% regain their DMR after restarting TKI therapy.[6]

See local specialist protocol for dosing guidelines.

Primary options

dasatinib

OR

nilotinib

OR

bosutinib

OR

asciminib

Secondary options

ponatinib

1st line – allogeneic HSCT plus tyrosine kinase inhibitor (TKI) maintenance therapy

Back
ACUTE
|
chronic phase
|
not in remission, relapsed, or disease progression after TKI therapy
1st line – 

allogeneic HSCT plus tyrosine kinase inhibitor (TKI) maintenance therapy

The advent of TKI therapy has significantly reduced the indications for allogeneic hematopoietic stem cell transplantation (HSCT).[81]

Patients who do not achieve a molecular or cytogenetic response after second- and subsequent-line drug therapy may be considered for allogeneic HSCT, if eligible.

Allogeneic HSCT is only considered in patients who are fit enough for the procedure and who have: resistance and/or intolerance to all available TKIs; advanced-phase CML at diagnosis; or disease progression to blast phase.[5][6][82]

Timing of allogeneic HSCT should be tailored individually in those with resistance to TKI therapy, whether this is due to the development of BCR::ABL1 mutations or clonal evolution.[81]

Following allogeneic HSCT, TKI maintenance therapy should be considered for at least 1 year to reduce the risk of relapse.[5][83][84][85]

Long-term survival and mortality depend on age, disease status at transplant, and donor type.[86][87][88] One registry study reported 5-year overall survival rates of 82.8% (chronic phase at diagnosis; n=124), 71.1% (accelerated phase at diagnosis; n=23), and 73.3% (blast phase at diagnosis; n=53) for HSCT patients (<30 years; n=200) who received pretransplant TKI therapy.[87] Retrospective review of 147 HSCT patients with advanced-phase CML (median age 39 years; 81.5% received pretransplant TKI) reported overall survival of 34% at 15 years.[88]

Patients should be referred to a transplantation center for evaluation.

See local specialist protocol for choice of appropriate TKI maintenance therapy regimen and dosing guidelines.

accelerated phase

1st line – tyrosine kinase inhibitor (TKI)

Back
ACUTE
|
accelerated phase
|
first presentation
1st line – 

tyrosine kinase inhibitor (TKI)

Patients with chronic myeloid leukemia (CML) should be referred to a hematology/oncology specialist for management of their disease.

The goals of treatment are to achieve complete hematologic response, early molecular response, complete cytogenetic response (CCyR), major molecular response (MMR), and deep molecular response (DMR). When feasible and desired, treatment-free remission (TFR) may be attempted for select patients with stable DMR. Treatment may not achieve all of these goals. The most important goal is to achieve either CCyR or MMR. Although MMR is superior to CCyR (i.e., indicates a better treatment response), improved survival has not been demonstrated in patients with MMR compared with those in CCyR.[48]

Patients with progression to accelerated-phase CML are treated with a TKI followed by evaluation for allogeneic hematopoietic stem cell transplantation (HSCT).[5] Patients with de novo accelerated-phase CML, and a suboptimal response to TKI therapy, should also be considered for allogeneic HSCT, if eligible.[5]

BCR::ABL1 kinase domain mutational analysis should be performed to help guide treatment (e.g., selecting a TKI).[5][37] If no BCR::ABL1 mutations are identified, analysis with a myeloid mutation panel may be considered. Prognosis is poorer for patients with progression while on treatment compared with de novo accelerated-phase CML.[5]

For patients with progression to accelerated phase, choice of treatment should be based on prior therapy and/or mutation profile, with a previously untried second-generation TKI (bosutinib, dasatinib, nilotinib) or third-generation TKI (ponatinib).[5][6][37][89] Ponatinib is recommended for patients with the T315I mutation, resistance to two or more prior TKIs, or who are not candidates for other TKIs.[5][72][73] Asciminib may be considered for patients with progression to accelerated phase, but evidence is limited.[5][71]

Patients with de novo accelerated-phase CML are treated with a second- or third-generation TKI, taking into account mutation profile. Imatinib may be considered if second- or third-generation TKIs are contraindicated. Asciminib may be considered for patients with de novo accelerated-phase CML, but evidence is limited.[5][71]

Patients with de novo accelerated-phase CML with an optimal response to TKI therapy within 6 months may continue with TKI treatment.[5]

See local specialist protocol for dosing guidelines.

Primary options

dasatinib

OR

nilotinib

OR

bosutinib

OR

ponatinib

Secondary options

imatinib

OR

asciminib

1st line – allogeneic HSCT plus tyrosine kinase inhibitor (TKI) maintenance therapy

Back
ACUTE
|
accelerated phase
|
not in remission, relapsed, or disease progression after TKI therapy
1st line – 

allogeneic HSCT plus tyrosine kinase inhibitor (TKI) maintenance therapy

Patients with progression to accelerated-phase CML are treated with a TKI followed by consideration of allogeneic hematopoietic stem cell transplantation (HSCT).[5] Patients with de novo accelerated-phase CML, and a suboptimal response to TKI therapy, should also be considered for allogeneic HSCT, if eligible.[5]

Allogeneic HSCT is only considered for patients who are fit enough for the procedure and who have: resistance and/or intolerance to all available TKIs; advanced-phase CML at diagnosis; or disease progression to blast phase.[5][6][82]

Timing of allogeneic HSCT should be tailored individually in those with resistance to TKI therapy, whether this is due to the development of BCR::ABL1 mutations or clonal evolution.[81]

Following allogeneic HSCT, TKI maintenance therapy should be considered for at least 1 year to reduce the risk of relapse.[5][83][84][85]

Long-term survival and mortality depend on age, disease status at transplant, and donor type.[86][87][88] One registry study reported 5-year overall survival rates of 82.8% (chronic phase at diagnosis; n=124), 71.1% (accelerated phase at diagnosis; n=23), and 73.3% (blast phase at diagnosis; n=53) for HSCT patients (<30 years; n=200) who received pretransplant TKI therapy.[87] Retrospective review of 147 HSCT patients with advanced-phase CML (median age 39 years; 81.5% received pretransplant TKI) reported overall survival of 34% at 15 years.[88]

Patients should be referred to a transplantation center for evaluation.

See local specialist protocol for choice of appropriate TKI maintenance therapy regimen and dosing guidelines.

back arrow

Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

Use of this content is subject to our disclaimer