Approach

Patients with chronic myeloid leukaemia (CML) should be referred to a haematology/oncology consultant for management of their disease.

Treatment with tyrosine kinase inhibitors (TKIs) is highly effective in chronic-phase CML. Life expectancy is approaching that of the general population, and progression of disease to accelerated phase or blast crisis is uncommon.[45][46] For patients with accelerated or blast-phase CML, BCR::ABL1 mutation profile may help guide choice of TKI.

For management of blast-phase CML, see Blast crisis.

Therapeutic goals

The goals of treatment are to achieve complete haematological 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][47] There is no clear consensus on whether patients who achieve a CCyR should have their therapy changed. MMR response does, however, afford patients lower risk of disease progression and higher likelihood of DMR.[5][48] DMR of sufficient duration, under the appropriate conditions and if the patient desires, can facilitate TFR and functional cure.[49]

Goals should be individualised; 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.

Chronic phase

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.

First-line treatment

Imatinib, bosutinib, dasatinib, nilotinib, and asciminib are all first-line options for chronic-phase disease.[5] Choice of treatment should be based on the patient’s risk score, age, comorbidities, and preferences, and should take into account toxicity, possible drug interactions, and the patient's ability to tolerate therapy.[5]

First-generation TKI (imatinib)

  • Imatinib is well tolerated and remains a standard initial treatment.[50][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]

Second-generation TKIs (bosutinib, dasatinib, nilotinib) and newer-generation BCR::ABL TKI (asciminib)

  • Bosutinib, dasatinib, nilotinib, and asciminib 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 consultants 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][31]

Resistance to initial therapy

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 individualised approach, taking into account the clinical context, is recommended when milestones are not reached.[31][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 haematopoietic stem cell transplant [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][38][70]

Patients with chronic-phase CML with resistance and/or intolerance to all TKIs should be evaluated for allogeneic HSCT.[5]

For patients with resistance to imatinib:

  • Switching to an alternative TKI is recommended, with choice of treatment taking 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]

Third-generation TKI (ponatinib)

  • 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 re-start should be guided by a benefit-risk assessment. Patients should be assessed for cardiovascular risk factors and appropriately counselled 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]

Discontinuation of TKI treatment

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 re-starting TKI therapy.[6]

Allogeneic haematopoietic stem cell transplant (HSCT)

The advent of TKI therapy has significantly reduced the indications for allogeneic 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:[5][6][82]

  • Resistance and/or intolerance to all available TKIs

  • Advanced-phase CML at diagnosis

  • Disease progression to blast phase

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 pre-transplant TKI therapy.[87] Retrospective review of 147 HSCT patients with advanced-phase CML (median age 39 years; 81.5% received pre-transplant TKI) reported overall survival of 34% at 15 years.[88]

Accelerated phase

Patients with progression to accelerated-phase CML are treated with a TKI followed by consideration of allogeneic 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][38] 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]

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][38][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

Treatment is 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][31]

For management of patients who progress to blast-phase CML, see Blast crisis.

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