Overview of the treatment of chronic myeloid leukemia

INTRODUCTION — Chronic myeloid leukemia (CML; previously called chronic myelogenous leukemia) is a myeloproliferative neoplasm (MPN), in which cells of the granulocytic lineage are the predominant proliferative component. CML is associated with the Philadelphia chromosome, t(9;22)(q34;q11), which creates a BCR::ABL1 fusion gene (figure 1). This genetic abnormality encodes the constitutively active tyrosine kinase BCR::ABL1, which is essential to the development of CML and is the primary target for treatment of CML.

CML shares the following biologic features with the other MPNs, namely, polycythemia vera, essential thrombocythemia, and primary myelofibrosis (table 1) (see "Overview of the myeloproliferative neoplasms"):

●Stem cell origin – Clonal disorders that arise in a hematopoietic stem or early progenitor cell

●Dysregulated proliferation – Dysregulated production of a particular lineage of mature myeloid cells with fairly normal differentiation

●Progression to acute leukemia – Variable rates of progression to acute leukemia

An overview of treatment of CML is presented in this topic.

Clinical presentation, diagnosis, and initial treatment of CML are discussed separately. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia" and "Initial treatment of chronic myeloid leukemia in chronic phase".)

DISEASE PHASES — Diagnostic criteria for CML and its disease phases are evolving [1-3]. The natural history of CML has been traditionally described as triphasic; however, some experts now view CML as biphasic process:

●Chronic phase (CP) – The most common clinical presentation of CML is CP, which is manifest as leukocytosis (with neutrophils in various stages of maturation), hypercellular bone marrow with marked granulocytic proliferation and few blasts (eg, <5 percent), with or without splenomegaly. CP CML is a relatively indolent disorder that is easily controlled with oral agents.

●Advanced disease (accelerated phase [AP] and/or blast phase [BP]) – Together, AP and BP may be considered as a continuum of more aggressive CML. Advanced CML most often arises during treatment of CP CML. AP and BP are uncommon initial presentations of CML, but this is more likely in settings of limited access to medical care where diagnosis may be delayed.

Advanced disease is characterized by increasing blood/marrow blasts (AP: 10 to 19 percent; BP: ≥20 percent) and/or extramedullary collections of blasts. This is often accompanied by increasing splenomegaly, constitutional symptoms, worsening cytopenias, and/or genetic instability (eg, additional chromosomal abnormalities). Advanced disease may manifest as an acute leukemia, which can resemble acute myeloid leukemia (AML) or, less often, acute lymphoblastic leukemia. Compared with CP CML, advanced CML is considerably more difficult to control.

Evolving diagnostic criteria should be kept in mind when reviewing treatment outcomes. Diagnostic criteria for CML and its phases are discussed in greater detail separately. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

PRETREATMENT EVALUATION — CML disease phase, prognostic score, and comorbid conditions should be determined before initiating treatment.

Clinical/laboratory — Clinical evaluation should assess comorbidities (eg, cardiovascular, pulmonary, kidney, pancreatic, or liver disease and diabetes) that may influence the choice of initial therapy and medications that may interact with tyrosine kinase inhibitors (TKIs) (table 2 and table 3).

In addition to history and physical examination, the following studies should be obtained:

●Hematology – Complete blood count (CBC) with differential count.

●Serum chemistries – Electrolytes, glucose, liver function tests, kidney function tests, uric acid.

●Cytogenetic and molecular testing – Cytogenetic and molecular testing of marrow or blood:

•Cytogenetics – Chromosome banding to confirm detection of the t(9;22) (Philadelphia chromosome [Ph]) rearrangement and to identify additional chromosomal abnormalities (ACA).

•Polymerase chain reaction (PCR) – Quantitative PCR to establish a baseline value for BCR::ABL1 rearrangement.

●Viral testing – Hepatitis B panel; there are rare cases of hepatitis B reactivation with treatment.  

●Electrocardiogram (EKG) – Assess arrhythmias and QT interval.

●Chest radiography – Pleural effusions or parenchymal disease.

Diagnostic criteria for CML and discussion of pretreatment evaluation are discussed in greater detail separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase".)

Prognostic score — CML prognosis is estimated using one of the validated CML clinical scoring systems.

We favor the ELTS (EUTOS Long Term Survival) score, which is based on data from tyrosine kinase inhibitor (TKI)-treated patients (rather than non-TKI-based management) and uses simple hematologic data, spleen size, and age [4,5].

Validated CML clinical scoring systems (table 4) are:

●ELTS (EUTOS Long Term Survival) score (calculator 1) [4]

●Sokal (calculator 2) [6]

●Euro (Hasford) [7]

●EUTOS (online calculator [8]) [9]

Details of CML prognostic models are presented separately. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Prognosis'.)

TREATMENT OVERVIEW — CML is associated with the Philadelphia chromosome (Ph), which refers to the t(9;22)(q34;q11) chromosomal translocation. This rearrangement creates a BCR::ABL1 gene fusion, which encodes the constitutively active tyrosine kinase, BCR::ABL1. Because of the essential role of this genetic rearrangement in the generation and maintenance of CML, BCR::ABL1 tyrosine kinase inhibitors (TKIs) play an important role in management of all phases of CML.

●Goals of care – The goals of care for patients with CML are to achieve clinical, cytogenetic, and molecular remission; maintain long-term disease control; and avoid progression to advanced disease (ie, accelerated phase [AP] or blast phase [BP]), while optimizing quality of life by limiting treatment-related toxicity.

Many patients and clinicians also consider achieving a treatment-free remission (TFR) an important goal. (See 'TKI discontinuation' below.)

Palliation of symptoms may be the goal for severely debilitated or frail patients.

●Treatments – Patients are treated with a BCR::ABL1 TKI, unless there is a specific contraindication. Selection of a TKI is influenced by disease phase and comorbid conditions.

•Tyrosine kinase inhibitors – TKIs are oral agents that are the preferred treatment for almost all newly-diagnosed patients with CML.

Selection of a TKI is guided by disease phase, CML risk score, adverse effects (AEs), and comorbid conditions. For patients with advanced disease, selection of a TKI is also influenced by BCR::ABL1 mutations. (See 'Initial treatment' below.)

Individual TKIs are discussed below. (See 'Tyrosine kinase inhibitors (TKI)' below.)

•Other agents – Other medications can provide symptomatic relief for patients who cannot take a TKI (eg, pregnancy), who have intolerance/severe AEs with multiple TKIs, or who require additional symptomatic relief. Examples of other agents include interferon alfa, hydroxyurea, and/or cytotoxic agents (eg, cytarabine, busulfan). (See 'Other agents' below.)

•Allogeneic hematopoietic cell transplantation (HCT) – Allogeneic HCT refers to treatment with intensive chemotherapy and/or radiation therapy to reduce the burden of CML cells, followed by restoration of blood cell formation by infusion of hematopoietic stem/progenitor cells from another individual (donor). Allogeneic HCT can cure some patients with CML (with outcomes related to the phase of disease at transplantation), but it is associated with substantial short-term and long-term toxicity (including graft-versus-host disease [GVHD] and second cancers) and treatment-related mortality. HCT is reserved for patients with advanced disease. (See 'Hematopoietic cell transplantation' below.)

INITIAL TREATMENT — BCR::ABL1 tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for all phases of CML and are used for initial treatment, unless there is a specific contraindication (eg, pregnancy).

The development of TKIs has been one of the most exhilarating stories in modern medicine. With the elucidation of BCR::ABL1 as the key molecular defect in CML came a more complete understanding of the underlying pathophysiology, culminating in development of these highly effective agents.

Initial treatment of CML is stratified according to disease phase (ie, chronic phase versus advanced disease) and prognostic score (ie, low/intermediate-risk versus high-risk), as described in the sections that follow.

Initial treatment of CML generally uses either imatinib or a second-generation (2G) TKI (ie, dasatinib, nilotinib, bosutinib). Other TKIs (ie, ponatinib, asciminib) are reserved for patients who have demonstrated resistance to other TKIs or with specific BCR::ABL1 mutations (eg, T315I). (See 'Tyrosine kinase inhibitors (TKI)' below.)

Monitoring the response to TKI treatment is discussed below. (See 'Monitoring response' below.)

Chronic phase (CP) — For patients with CP CML, we stratify selection of a BCR::ABL1 TKI according to:

●Prognostic score – CML risk score (ie, low/intermediate-risk versus high-risk) (table 4). (See 'Pretreatment evaluation' above.)

●Other considerations – Toxicity profile, comorbid illnesses, medications that may interact with TKIs (table 2 and table 3), availability, cost, patient preference, and the weight the patient places on achieving a treatment-free remission (TFR).

All BCR::ABL1 TKIs are effective for initial treatment of CP CML. There is no significant difference in overall survival (OS) between patients who begin treatment with imatinib versus a 2G TKI (eg, dasatinib, nilotinib, bosutinib). However, compared with imatinib, 2G TKIs generally achieve faster and deeper remissions and have lower rates of progression to advanced phase CML.

Administration, adverse effects (AEs), and outcomes of individual TKIs are presented separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase".)

Hydroxyurea can provide urgent relief for some patients with extreme leukocytosis (eg, >100,000/microL) or who are severely symptomatic with splenomegaly or systemic symptoms [10]. Occasional patients are not candidates for treatment with a TKI (eg, initial diagnosis during pregnancy, due to potential teratogenicity). (See 'Other agents' below.)

Detailed discussion of management of CP CML is presented separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase".)

Low/intermediate-risk CP CML — For patients with low-risk or intermediate-risk CP CML (table 4), the choice of a TKI is influenced by the importance assigned to achievement of a TFR:

●TFR is an important goal – For patients who consider TFR an important goal, we generally treat with a 2G TKI, rather than imatinib, based on faster, deeper remissions and lower rates of progression to advanced phase CML. Nevertheless, no studies have directly demonstrated greater success in achieving TFR using a 2G TKI.

Selection of a 2G TKI should consider the toxicity profile (table 5), comorbid conditions, availability, cost, and patient preference. (See 'Tyrosine kinase inhibitors (TKI)' below.)

●Less importance assigned to TFR – For patients who do not consider TFR a high priority, treatment with either imatinib or a 2G TKI is acceptable. The choice of TKI for initial treatment is based on toxicity profile (table 5), comorbid conditions, availability, cost, and patient preference. (See 'Tyrosine kinase inhibitors (TKI)' below.)

High-risk score CP CML — For patients with high-risk score CP CML (table 4), we favor initial treatment with a 2G TKI (ie, dasatinib, nilotinib, bosutinib) rather than imatinib because 2G TKIs are associated with a lower risk of progression to advanced disease (ie, accelerated phase [AP] or blast phase [BP]) CML.

None of the individual 2G TKIs has proven to be superior in this setting. Selection of a 2G TKI should consider the toxicity profile (table 5), comorbid conditions, availability, cost, and patient preference. (See 'Tyrosine kinase inhibitors (TKI)' below.)

Advanced disease (accelerated phase/blast phase — We treat patients with advanced disease using a 2G TKI, ponatinib, or asciminib, rather than imatinib; selection of a specific TKI is guided by mutation analysis of BCR::ABL1, toxicity profile (table 5), and comorbidities. (See 'Tyrosine kinase inhibitors (TKI)' below.)

Patients with myeloid blast phase CML may also need cytotoxic chemotherapy, using regimens similar to those for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), together with a TKI.

We initiate a search for a human leukocyte antigen (HLA)-matched donor at the time of diagnosis of advanced CML. A decision to proceed to allogeneic hematopoietic cell transplantation (HCT) is guided by the response to TKI therapy, medical fitness, and availability of a suitable donor. (See 'Hematopoietic cell transplantation' below.)

MONITORING RESPONSE — Response to tyrosine kinase inhibitor (TKI) therapy must be monitored on a regular schedule.

Schedule — Response to initial therapy is assessed according to hematologic, cytogenetic, and molecular criteria.

●Hematology – Monitor complete blood count (CBC) with differential every one to two weeks until a complete hematologic response (CHR) (table 6) is achieved, then repeat at times of cytogenetic or molecular testing, or as needed.

CHR is described below. (See 'Response milestones' below.)

●Cytogenetics – Monitoring the karyotype is used primarily for patients with atypical translocations (ie, rare or atypical BCR::ABL1 transcripts that cannot be measured by quantitative polymerase chain reaction [PCR]), treatment failure or resistance (ie, to exclude additional chromosomal abnormalities), and with progression to advanced disease (ie, accelerated phase [AP] or blast phase [BP]). Fluorescence in situ hybridization (FISH) may be helpful for monitoring response in patients with atypical transcripts, but chromosome banding is needed for detection of additional chromosomal translocations. Note that monitoring the karyotype alone (ie, without molecular analysis) is not sufficiently sensitive to monitor response for most patients with CML.

Descriptions of cytogenetic response are provided below (table 6). (See 'Response milestones' below.)

●Reverse transcriptase polymerase chain reaction (RT-PCR) – Monitor quantitative RT-PCR of blood every three months until achievement of major molecular response (MMR; ie, 3 log reduction of BCR::ABL1). Subsequent testing is performed every three to six months.

Descriptions of molecular response are provided below. (See 'Response milestones' below.)

Continued testing after MMR is important to assess eligibility for treatment discontinuation. (See 'TKI discontinuation' below.)

Response criteria — Response to TKI therapy (table 6) is defined according to European LeukemiaNet guidelines [11,12].

Hematologic response — Complete hematologic response (CHR) is defined as [11,12]:

●White blood cell count (WBC) <10,000/microL

●No circulating immature myeloid cells and <5 percent basophils

●Platelet count <450,000/microL

●Spleen not palpable

Cytogenetic response — Cytogenetic response is assessed by chromosome banding of marrow metaphases with ≥20 metaphases analyzed. Chromosome banding generally requires a bone marrow aspirate sample.

Cytogenetic response is classified according to the percentage of Philadelphia chromosome positive (Ph+) cells (table 6) [11,12]:

●No cytogenetic response – >95 percent Ph+ cells

●Minimal cytogenetic response – 66 to 95 percent Ph+ cells

●Minor cytogenetic response – 36 to 65 percent Ph+ cells

●Major cytogenetic response – 1 to 35 percent Ph+ cells

●Complete cytogenetic response (CCyR) – No Ph+ cells

For patients with an inadequate number of metaphases, CCyR can also be documented by FISH of blood interphase cell nuclei that demonstrate <1 percent BCR::ABL1-positive nuclei among ≥200 nuclei [13].

Molecular response — Molecular response is determined according to the International Scale (IS) as the ratio of BCR::ABL1 transcripts to ABL1 transcripts (or other housekeeping genes) and is expressed as BCR::ABL1 percentage, on a log scale [11]. Results are presented as log reduction of BCR::ABL1/ABL1 compared to a standardized baseline, which is defined as 100 percent (note that molecular response is not compared with the patient's own baseline value):

Key molecular response milestones are:

●MR 3 (Major molecular response [MMR]) – 0.1 percent of baseline BCR::ABL1/ABL1 (ie, ≥3 log reduction)

●MR 4 – 0.01 percent

●MR 4.5 – 0.0032 percent

●MR 5 – 0.001 percent

Response milestones — Milestones for molecular response to therapy are used to determine if the current treatment should be continued (ie, Optimal response), changed (ie, Failure/resistance), or considered for continuation (ie, Warning) [11].

Molecular milestones of BCR::ABL1 transcript levels are assessed at 3, 6, and 12 months. Additional testing may be needed if the response kinetics are uncertain or if toxicity/intolerance causes treatment interruptions or dose reductions.

In most circumstances, changes in a single PCR result alone should not be used to define treatment failure. However, a pattern of increasing PCR signal, with or without hematologic or cytogenetic evidence of failure, should trigger BCR::ABL1 mutational analysis [11,14-16]. (See 'Evaluation at loss of response' below.)

The following definitions apply:

●3 months – Optimal (≤10 percent); Warning (>10 percent); Failure (>10 percent, if confirmed within 1 to 3 months)

●6 months – Optimal (≤1 percent); Warning (>1 to 10 percent); Failure >10 percent

●12 months – Optimal (≤0.1 percent); Warning (>0.1 to 1 percent); Failure >1 percent

●Any time – Optimal (≤0.1 percent); Warning (>0.1 to 1 percent, with loss of MMR [ie, ≤0.1 percent]); Failure >1 percent, resistance mutations, or acquisition of additional chromosomal abnormalities

Achieving MMR (ie, BCR::ABL1 ≤0.1 percent) within one year predicts a CML-specific survival close to 100 percent [11]. Prospective and retrospective studies that support use of milestone criteria for managing CML are presented separately [17-27]. (See "Initial treatment of chronic myeloid leukemia in chronic phase".)

TREATMENTS

Tyrosine kinase inhibitors (TKI) — TKIs are effective oral agents that target the BCR::ABL1 tyrosine kinase.

Selection of a TKI is guided by disease phase (ie, chronic phase [CP] versus advanced disease) and CML risk score (ie, low/intermediate-risk versus high-risk) (table 4). Other considerations include side effect profile, comorbid illnesses, medications that may interact with TKIs (table 2 and table 3), availability, cost, patient preference/convenience, and importance assigned by a patient to achieving a treatment-free remission (TFR). (See 'Initial treatment' above.)

All TKIs are associated with common, generally mild toxicities (eg, rash, nausea, edema, fatigue, myalgias/arthralgias) in the first months of treatment; most resolve spontaneously or can be controlled by dose adjustments. Management of these early adverse effects (AEs) is discussed separately. Interruption of TKI therapy has been associated with poor long-term outcomes. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Managing toxicity'.)

In addition, each TKI is associated with particular AEs (table 5):

●Imatinib – Muscle cramps, fatigue, edema, nausea, diarrhea.

●Nilotinib – Coronary, cerebral, and peripheral vascular disease; prolonged QTc interval; hyperglycemia; pancreatitis.

●Dasatinib – Pleural or pericardial effusion, pulmonary hypertension, prolonged QTc interval, platelet dysfunction.

●Bosutinib – Diarrhea, abnormal liver function, rash, pancreatitis.

●Ponatinib – Arterial and venous thrombosis, embolic events, liver toxicity.

●Asciminib – Pancreatitis, upper respiratory tract infection, musculoskeletal pain.

As examples of how we consider comorbidities and AEs in selecting a TKI for initial treatment of CML:

●Heart disease or hyperglycemia – For patients with arrhythmias, coronary artery disease, or hyperglycemia, we favor imatinib, bosutinib, or dasatinib.

●Pancreatitis – For patients with a history of pancreatitis we favor imatinib, or dasatinib.

●Lung disease – For patients with a history of lung disease or at risk for pleural effusion, we favor imatinib, nilotinib, or bosutinib.

Detailed discussion of selecting a TKI for initial treatment of CML is presented separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Choosing a TKI'.)

Dasatinib, nilotinib, bosutinib, and radotinib have been tested against imatinib in randomized, company-sponsored trials, but they have not been tested against each other. Comparisons among these and other clinical studies are difficult because of differences in protocols and methods of evaluation [28].

Imatinib, dasatinib, nilotinib, and bosutinib are approved for initial treatment of CML by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA); radotinib has been approved in South Korea only. Asciminib is approved for patients with CP CML previously treated with ≥2 TKIs or with T315I mutation. Ponatinib is approved for patients with CP CML with resistance or intolerance to ≥2 prior TKIs, advanced phase CML for which no other TKIs are indicated, and for patients with T315I-positive CML (CP or advanced disease).

Other agents — Other drugs can be used for treatment of CML in certain settings. None of these agents approaches the efficacy of TKIs, but they may be used when TKIs cannot be given safely (eg, pregnancy), to relieve symptoms or prevent complications while awaiting results of mutation analysis, or for managing TKI resistance.

Examples of settings in which non-TKI agents might be used include:

●Hydroxyurea – A short course of hydroxyurea (eg, 20 to 40 mg/kg/day, adjusted up or down to the nearest pill) [10] may be given to patients with significant leukocytosis (eg, >100,000/microL), systemic symptoms, or symptomatic splenomegaly while awaiting results from cytogenetic or molecular confirmation of the diagnosis of CML or for management of advanced phase CML while awaiting BCR::ABL1 mutation analysis. The dose should be tapered as the white blood cell count decreases.

●Interferon – Interferon (IFN) alfa can be given to patients who are diagnosed with CML during pregnancy. TKIs are contraindicated in women who seek to become pregnant and in the first trimester of pregnancy because of increased rates of miscarriage and fetal abnormalities. IFN alfa is considered safe during pregnancy. (See "Initial treatment of chronic myeloid leukemia in chronic phase".)

●Omacetaxine mepesuccinate – This agent, previously known as homoharringtonine, can be used for treatment of resistance and/or intolerance to ≥2 TKIs.

These and other agents (eg, cytarabine, busulfan) are mostly of historic interest, although they can benefit patients who are not candidates for transplantation and are intolerant of or refractory to treatment with TKIs.

Hematopoietic cell transplantation — Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment option for medically-fit patients with advanced disease (ie, accelerated phase [AP]/blast phase [BP]). HCT is occasionally offered for younger patients with chronic phase (CP) CML who have a suitable donor and are not responding adequately to TKI therapy. However, HCT is associated with significant early and late toxicity and an increased rate of early mortality.

A decision to proceed to allogeneic HCT must consider:

●Medically eligible – Eligibility for transplantation, based on age (eg, <70 years in many institutions) and medical fitness. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

●Suitable donor – Donors may include a human leukocyte antigen (HLA)-matched related or unrelated donor, haploidentical related donor, or umbilical cord blood.

Selection of a donor, method for graft collection, and choice of a conditioning (preparative) regimen are discussed separately. (See "Hematopoietic cell transplantation in chronic myeloid leukemia".)

TKI DISCONTINUATION — Treatment with a tyrosine kinase inhibitor (TKI) is generally continued indefinitely, as long as the drug is tolerated and treatment milestones are met. However, patients with a sustained, deep molecular response may seek TKI discontinuation because of toxicity, convenience, cost, a desire to become pregnant, or other reasons.

TKI discontinuation should take place only after meeting all criteria for treatment discontinuation including:

●Reliable use of the TKI for ≥3 years

●No prior resistance to a second-generation (2G) TKI that required switching to another agent

●Stable molecular response on repeated testing (ie, MR4; BCR-ABL1 ≤0.01 percent)

●Access to a reliable quantitative polymerase chain reaction (PCR) test that can detect at least MR 4.5 and can provide results within two weeks

Details of criteria for treatment discontinuation, adverse effects of discontinuation, and outcomes are presented separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'TKI discontinuation for TFR'.)

DISEASE RESISTANCE — Patients who appear to have resistant disease should be questioned carefully to assure that they are taking the tyrosine kinase inhibitor (TKI) at the recommended dose and schedule and avoiding medications or herbal supplements that may impair efficacy (table 2 and table 3).

Management of adverse effects of TKIs is discussed separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Managing toxicity'.)

Evaluation at loss of response — For patients who are reliably taking the TKI, yet do not achieve molecular milestones (ie, "Failure" or "Warning"), disease status must be re-evaluated. Response milestones are discussed above. (See 'Response milestones' above.)

For patients with suspected TKI resistance, testing includes:

●Hematology – Complete blood count with differential count

●Bone marrow examination – Including microscopy and cytogenetic testing to evaluate progression to advanced disease (ie, accelerated phase [AP] or blast phase [BP])

●Mutation status – ABL1 kinase domain (KD) mutation analysis

Treatment of disease resistance or drug intolerance — Resistance to a TKI is usually detected when a patient with an initial response to a TKI loses that response. Approximately 40 to 50 percent of patients change from their initial TKI due to resistance or intolerance [29].

Management of TKI resistance is guided by ABL1 KD mutation analysis.

The more common acquired ABL1 KD mutations include:

●T315I – Resistant to all TKIs, except ponatinib and asciminib

●Y253F and F359V – Sensitive to dasatinib, bosutinib, ponatinib and asciminib, but resistant to imatinib and nilotinib

●E255V – Sensitive to dasatinib and asciminib, but resistant to bosutinib and nilotinib

●F317L – Sensitive to bosutinib, nilotinib, ponatinib and asciminib, but resistant to dasatinib

●V299L – Sensitive to imatinib, nilotinib, ponatinib and asciminib, but resistant to bosutinib and dasatinib

Omacetaxine mepesuccinate (previously known as homoharringtonine) may also be considered for treatment of TKI resistance.

Drug selection for treatment of TKI resistance is discussed separately. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy".)

Allogeneic hematopoietic cell transplantation (HCT) is an option for patients who progress to advanced disease (ie, accelerated phase or blast phase) who are resistant to multiple TKIs or are unable to tolerate a TKI . (See "Hematopoietic cell transplantation in chronic myeloid leukemia".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic myeloid leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Chronic myeloid leukemia (CML) (The Basics)")

●Beyond the Basics topics (see "Patient education: Chronic myeloid leukemia (CML) in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY

●Description – Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm associated with the Philadelphia chromosome, t(9;22)(q34;q11), which creates a BCR::ABL1 fusion gene (figure 1) and the constitutively active tyrosine kinase, BCR::ABL1.

●Disease phases – Diagnostic criteria for disease phases of CML are evolving. Briefly, CML disease phases can be described as follows:

•Chronic phase (CP) – A relatively indolent condition with leukocytosis (that includes various stages of neutrophil maturation), hypercellular marrow, few blasts, with or without splenomegaly. CP CML is readily controlled with oral agents.

•Advanced disease – Accelerated phase (AP) and blast phase (BP) can be considered a continuum of more aggressive CML that is unusual at initial presentation but arises more often during treatment of CP CML. Advanced disease is generally manifest with increasing blasts, splenomegaly, constitutional symptoms, worsening cytopenias, and/or genetic instability.

●Pretreatment evaluation – Includes comorbid conditions (eg, heart, lung, kidney diseases), CML phase, and prognostic score.

●Initial treatment – BCR::ABL1 tyrosine kinase inhibitors (TKI) are the initial treatment of CML, unless contraindicated (eg, pregnancy). TKI choice is stratified by disease phase (ie, chronic phase versus advanced disease).

●Treatment of CP – Choice of TKI is based on CML risk score (table 4), toxicity, comorbidities, availability, cost, and patient preference.

•Low/intermediate risk – Stratified by importance of achieving treatment-free remission (TFR) (see 'Low/intermediate-risk CP CML' above):

-TFR is an important goal – For patients who consider TFR an important goal, we generally treat with a second generation (2G) TKI (eg, dasatinib, nilotinib, bosutinib), rather than imatinib.

-TFR is less important – If a TFR is not a high priority, treatment with imatinib or a 2G TKI is acceptable.

•High risk – We favor initial treatment with a 2G TKI, rather than imatinib. Ponatinib or asciminib should be given if BCR::ABL1 T315I mutation is present. (See 'High-risk score CP CML' above.)

●Treatment of advanced disease – We favor treatment with a 2G TKI, ponatinib, or asciminib, rather than imatinib; selection of a TKI is based on mutation analysis, toxicities, and comorbidities. (See 'Advanced disease (accelerated phase/blast phase' above.)

●Response – The schedule for monitoring hematologic, cytogenetic, and molecular responses and various treatment milestones are discussed above. (See 'Monitoring response' above.)

●TKIs – TKI selection is guided by disease phase, CML risk score (table 4), side effect profile, comorbid illnesses, availability, cost, and patient preferences. (See 'Tyrosine kinase inhibitors (TKI)' above.)

●Other treatments – Hydroxyurea, interferons, and other agents are used occasionally. (See 'Other agents' above.)

●Transplantation – Allogeneic hematopoietic cell transplantation is a consideration for medically-fit patients with a suitable donor who have advanced disease or intolerance/resistance to all TKIs. (See 'Hematopoietic cell transplantation' above.)

●TKI discontinuation – Selected patients who achieve a sustained, deep remission may be candidates for TKI discontinuation, as discussed above. (See 'TKI discontinuation' above.)

●Disease resistance – For patients who are taking the TKI properly, evaluation for disease progression or emergence of BCR::ABL1 mutation resistance and selection of an alternative TKI or other treatment is discussed above. (See 'Disease resistance' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert S Negrin, MD, who contributed to an earlier version of this topic review.