Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor

INTRODUCTION — 

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm associated with the Philadelphia chromosome t(9;22)(q34;q11) and BCR::ABL1 fusion gene. The rearrangement generates a constitutively active tyrosine kinase that is susceptible to BCR::ABL1 tyrosine kinase inhibitors (TKIs).

Treatment of chronic phase (CP) CML generally begins with a BCR::ABL1 TKI, such as imatinib, dasatinib, bosutinib, nilotinib, or asciminib. While their toxicity is generally mild, some patients cannot continue the initial TKI because of intolerable adverse effects.

Patients with suboptimal hematologic, cytogenetic, and/or molecular responses at defined milestones or who lose the treatment response are considered to have TKI resistance.

This topic discusses the management of patients with CP CML who are intolerant or resistant to the initial TKI.

Related topics include:

●(See "Overview of the treatment of chronic myeloid leukemia".)

●(See "Chronic myeloid leukemia in chronic phase: Initial treatment".)

●(See "Accelerated phase chronic myeloid leukemia: Diagnosis and treatment".)

●(See "Chronic myeloid leukemia-blast phase: Diagnosis and treatment".)

INTOLERANCE TO THE INITIAL TKI

Definition — There is no consensus definition of TKI intolerance.

Patients who have persistent or recurrent grade ≥3 nonhematologic adverse effects (AEs) despite symptom management and/or dose adjustment are considered intolerant to ongoing therapy with that TKI [1]. Because TKIs must be taken for years, even grade 1 or 2 AEs may be considered intolerable by some patients.

The extent of interference with daily activities is important for defining treatment intolerance and the appropriateness of dose reduction or treatment interruption versus switching TKI therapies.

●Early AEs – Mild AEs are common soon after beginning any TKI. For example, nausea, muscle cramps, rash, and/or edema are often experienced in the first months of therapy.

Most early TKI-associated AEs are mild and resolve spontaneously or can be controlled with symptom management or a brief dose adjustment; the TKI can often be restarted at the same dose without a recurrence of the AE. The management of early AEs is discussed separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Common early toxicities'.)

●TKI-specific toxicity – In addition to the early AEs, each TKI is also associated with unique patterns of AEs that can range from mild to severe and potentially life-threatening. The toxicity profile of individual TKIs is discussed separately. (See 'Individual TKIs' below.)

In some cases, symptom management and/or a brief dose adjustment or "drug holiday" can ameliorate these symptoms. The following section describes the management of AEs that do not resolve with these measures.

Management of TKI intolerance — For severe AEs that do not improve with optimal symptom management, dose adjustment, or a brief drug holiday, we choose a second-line TKI (algorithm 1) according to the toxicity profile (table 1) and comorbidities.

As examples:

●Dasatinib might be favored for patients with pancreatitis, elevated bilirubin, or hyperglycemia.

●Nilotinib might be favored for patients with pleural or pericardial disease, gastrointestinal bleeding, or diarrhea.

●Bosutinib might be favored for patients with cardiovascular AEs or QTc prolongation, despite correction of electrolyte imbalances and discontinuation of other medications that might affect the QTc interval.

●Imatinib might be favored in patients with pleural effusions, pancreatitis, or cardiovascular toxicity.

●Asciminib might be favored in patients with pleural effusions or gastrointestinal toxicity.

TKI RESISTANCE

Evaluation — Resistance to the initial TKI is a failure to achieve and/or maintain hematologic, cytogenetic, and/or molecular responses at defined milestones (algorithm 2). Details of response monitoring for the initial TKI are presented separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Response monitoring'.)

Loss of a treatment response should be confirmed by repeating the studies that indicate TKI resistance, including quantitative reverse transcription polymerase chain reaction (qRT-PCR) [2]. Patients with suspected TKI resistance should be questioned carefully to ensure adherence to the prescribed dose and to assess medications or herbal supplements that may impair TKI efficacy.

All patients with confirmed TKI resistance should have a bone marrow examination to assess possible disease progression. The examination should include microscopy, cytogenetic analysis, and testing for BCR::ABL1 kinase domain (KD) mutations. Although KD mutation analysis can be performed with peripheral blood, a bone marrow examination is needed to accurately assess the number of marrow blasts and additional cytogenetic abnormalities. (See "Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis and classification'.)

Management of patients with accelerated phase (AP) or blast phase (BP) CML is discussed separately. (See "Accelerated phase chronic myeloid leukemia: Diagnosis and treatment" and "Chronic myeloid leukemia-blast phase: Diagnosis and treatment".)

Resistance to the initial TKI is uncommon in chronic phase (CP) CML. Imatinib resistance is reported in approximately 10 to 15 percent of patients, while resistance to a second-generation (2G) TKI occurs in <10 percent of patients [3].

Our approach to managing TKI resistance is consistent with guidelines from the European LeukemiaNet (ELN) 2020 [3] and the United States National Cancer Center Network (NCCN) [4].

Management of TKI resistance — For CP CML with documented TKI resistance, we suggest changing the TKI regimen rather than allogeneic hematopoietic cell transplantation (HCT).

Treatment with a second-line TKI based on BCR::ABL1 KD mutation status can be effective and well tolerated. Allogeneic HCT is potentially curative, but it is associated with substantial short-term and long-term toxicity and is only suitable for medically fit patients.

Choice of a second-line TKI — Selection of a second-line TKI regimen (algorithm 1) is guided by the BCR::ABL1 KD mutation analysis, toxicity profile, and patient comorbidities. (See 'TKI resistance' above.)

No TKI has been shown to be superior for treating resistance to initial treatment with imatinib.

For patients with resistance to a 2G TKI or asciminib, imatinib is not a consideration because many TK mutations are resistant to imatinib.

T315I mutation — For CP CML with the BCR::ABL1 T315I mutation, we suggest either ponatinib or asciminib (algorithm 1) rather than other TKIs or allogeneic HCT. Ponatinib and asciminib are less toxic than allogeneic HCT, and the T315I mutation is resistant to imatinib, dasatinib, nilotinib, and bosutinib (table 2).

We simultaneously evaluate eligibility for allogeneic HCT and initiate a donor search in case the response to ponatinib or asciminib is inadequate.

The choice of ponatinib or asciminib is individualized according to the TKI toxicity profile and comorbidities. Ponatinib is associated with potentially life-threatening cardiovascular adverse effects (AEs) and hepatotoxicity; it is not suitable for many patients with pre-existent liver disease or risk factors for myocardial infarction, cerebrovascular accidents, and other arterial thrombotic events. Asciminib is associated with hypertension and pancreatitis but is generally better tolerated; however, there are limited long-term outcomes data with asciminib for treating the T315I mutation.

●Ponatinib – We generally start with ponatinib 45 mg and reduce the dose to 15 mg when BCR::ABL1 is <1 percent to reduce the risk for AEs. (See 'Ponatinib' below.)

●Asciminib – We treat with asciminib 200 mg twice daily. Note that this dose is higher than the asciminib dose for other BCR::ABL1 mutations. (See 'Asciminib' below.)

If response milestones (table 3) are not achieved using either ponatinib or asciminib, we proceed promptly to allogeneic HCT for transplant-eligible patients. (See 'Treatment response' below.)

No prospective studies have directly compared outcomes with ponatinib or asciminib versus allogeneic HCT in patients with the T315I mutation. In a retrospective analysis comparing ponatinib and allogeneic HCT in this population, ponatinib was associated with better overall survival (OS) at 48 months (73 versus 56 percent; hazard ratio [HR] 0.37 [95% CI 0.16-0.84]) [5].

Omacetaxine mepesuccinate (previously known as homoharringtonine), a protein synthesis inhibitor with activity against T315I, is no longer manufactured and is no longer available in most settings.

Outcomes with ponatinib and asciminib are presented below. (See 'Individual TKIs' below.)

Other kinase domain mutations — For patients with BCR::ABL1 KD mutations other than T315I, we select a second-line TKI (algorithm 1) based on the mutation's sensitivity to various TKIs.

The table (table 2) presents resistance patterns of specific BCR::ABL1 KD mutations according to in vitro studies; many TK mutations are also resistant to imatinib [4,6]. The choice of TKI is informed by the toxicity profile (table 1), comorbidities, and patient preference.

The selection of a TKI according to toxicity and comorbidities is discussed above. (See 'Management of TKI intolerance' above.)

If the mutation is sensitive to multiple TKIs, we suggest a 2G TKI (ie, dasatinib, nilotinib, bosutinib) or asciminib because they are more likely to be effective and achieve faster responses than imatinib, and they are less toxic than ponatinib. However, imatinib is an acceptable alternative if the mutation is sensitive to it.

For patients with comorbidities that preclude treatment with a 2G TKI or asciminib, imatinib may be acceptable if the mutation is known to be sensitive to imatinib. (See 'Imatinib' below.)

No kinase domain mutation — For patients with no BCR::ABL1 KD mutation, we select a 2G TKI or asciminib according to the toxicity profile (table 1) and comorbidities (algorithm 1).

The selection of a TKI according to toxicity and comorbidities is discussed above. (See 'Management of TKI intolerance' above.)

TREATMENT RESPONSE — 

The response to a second-line TKI is guided by hematologic, cytogenetic, and molecular responses, as detailed in the accompanying table (table 3) [3].

FAILURE TO RESPOND AFTER ≥2 TKIS — 

For patients who fail to respond adequately after ≥2 TKIs, we consider either a third-line TKI or allogeneic hematopoietic cell transplantation (HCT) acceptable.

The decision should be made jointly with a well-informed patient and is individualized according to medical fitness for transplantation, comorbidities, and patient preference. No studies have directly compared a third-line TKI with allogeneic HCT in this setting.

Eligibility for allogeneic HCT is discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

Management of chronic phase (CP) CML with the T315I mutation that does not respond adequately to ponatinib or asciminib is discussed above. (See 'T315I mutation' above.)

●Third-line TKI – The choice of a third-line TKI is guided by kinase domain (KD) mutation analysis, toxicity profile, and patient comorbidities. No TKI has been proven to provide superior survival, but few studies have directly compared TKIs in this setting.

The resistance pattern of TK mutations to specific TKIs (table 2) is discussed above. (See 'Other kinase domain mutations' above.)

In the ASCEMBL trial, patients who were resistant or intolerant to ≥2 TKIs were randomly assigned (2:1) to asciminib 40 mg twice daily versus bosutinib 500 mg once daily [7]. At 96 weeks, asciminib achieved a superior rate of major molecular response (BCR::ABL1 <0.1 percent; 37.6 versus 15.8 percent). There were fewer grade ≥3 adverse effects (AEs) with asciminib (56.4 versus 68.4 percent) and fewer patients with AEs leading to treatment discontinuation (7.7 versus 26.3 percent).

Administration, toxicity, and outcomes with various TKIs are presented below. (See 'Individual TKIs' below.)

●Allogeneic HCT – Allogeneic HCT is the only proven curative therapy for CML, but it is only appropriate for medically fit patients with a suitable donor and is associated with substantial morbidity and mortality.

Transplantation is associated with up to 80 percent five-year survival, but early mortality is in the 10 to 20 percent range.

INDIVIDUAL TKIS — 

Various TKIs are effective for treating chronic phase (CP) CML in patients with TKI intolerance or resistance.

The following TKIs are approved for use in CML by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), although their approved indications may differ for some TKIs.

Dasatinib — Dasatinib is a second-generation (2G) TKI that is associated with pleural effusions, QT prolongation, and bleeding (table 1).

The starting dose of dasatinib is 100 mg once daily, and it can be taken with or without food. Details of administration and adverse effects (AEs) are presented separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Dasatinib'.)

Studies of dasatinib for second-line therapy in CP CML include:

●Dasatinib 70 mg twice daily for CP CML with imatinib resistance (73 percent) or intolerance reported 90 percent complete hematologic response (CHR), 52 percent major cytogenetic response (MCyR), and 40 percent complete cytogenetic response (CCyR) with 15 months median follow-up [8,9]. Grade ≥3 AEs included pleural effusions (6 percent), leukopenia (25 percent), neutropenia (49 percent), thrombocytopenia (47 percent), and anemia (22 percent). Only 9 percent of patients discontinued dasatinib due to AEs.

●A phase 3 trial in 670 patients with CP CML and imatinib resistance (74 percent) or intolerance compared four dosing regimens for dasatinib (ie, 50 mg twice daily, 100 mg once daily, 70 mg twice daily, or 140 mg once daily) [10,11]. After six years, overall survival (OS) was 71 percent and progression-free survival (PFS) was 49 percent. For patients with BCR::ABL1 <10 percent at six months, seven-year OS and PFS were 74 and 57 percent, respectively; for those with BCR::ABL1 >10 percent at six months, the corresponding rates were 50 and 4 percent. Compared with 70 mg twice daily, 100 mg daily dosing was associated with less grade ≥3 thrombocytopenia, fewer pleural effusions, fewer dose reductions or interruptions, and fewer discontinuations due to toxicity.

●A randomized phase 2 study showed superior response rates with dasatinib compared with increased-dose imatinib in patients who had failed imatinib therapy [12]. (See 'Imatinib' below.)

Nilotinib — Nilotinib is a 2G TKI that is taken twice daily. There are two formulations of nilotinib (capsule and tablet) that have different dosing and food restrictions; they cannot be substituted on a milligram-for-milligram basis. Nilotinib is associated with prolongation of the QTc interval, increased arterial cardiovascular AEs, and rare cases of sudden death.

Dosing of nilotinib for CP CML in patients with TKI resistance or intolerance is:

●Tablet – Nilotinib tablets taken 142 mg twice daily (approximately 12 hours apart) with no restriction related to food.

●Capsule – Nilotinib capsules 400 mg twice daily (approximately 12 hours apart) with water; patients should avoid food ≥2 hours before and ≥1 hour after each dose.

Note that these doses differ from dosing for patients receiving front-line therapy of CP CML. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Nilotinib'.)

Studies of nilotinib in this setting include:

●A phase 2 study examined nilotinib in 321 patients with CP CML and imatinib resistance (70 percent) or intolerance [13-15]. Patients received nilotinib 400 mg twice daily, with escalation to 600 mg twice daily for an inadequate response. Four-year OS and PFS were 78 and 57 percent, respectively. Responses were durable, with 89 percent of patients maintaining a CCyR after four years. Grade ≥3 AEs included thrombocytopenia (28 percent), neutropenia (28 percent), elevated lipase (15 percent), hyperglycemia (11 percent), hypophosphatemia (10 percent), and QTc prolongation (3 percent).

●In the ENESTcmr trial, 207 patients in CCyR with detectable BCR::ABL1 after ≥2 years of imatinib were randomly assigned to continue imatinib or switch to nilotinib [16,17]. With ≥5 years follow-up, molecular response (MR)4.5 was higher with nilotinib 400 mg twice daily (52 percent) than with imatinib (31 percent) [17]. Patients taking nilotinib had more cardiovascular AEs (13.4 versus 2.1 percent).

Bosutinib — Bosutinib is a 2G TKI that targets both the ABL and SRC pathways. Bosutinib is associated with diarrhea, nausea/vomiting, and elevated serum transaminases.

Bosutinib is taken 500 mg once daily with food. This dose differs from the 400 mg daily dose used for front-line therapy of CP CML. Details of bosutinib administration and AEs are presented separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Bosutinib'.)

Treatment with bosutinib in patients with CP CML and imatinib resistance (69 percent) or intolerance reported 91 percent two-year OS and 81 percent two-year PFS [18-20]. Rates of CHR, MCyR, and CCyR were 86, 53, and 41 percent, respectively; among patients with CCyR, 64 percent attained a major molecular response (MMR). The most common grade ≥3 AEs were diarrhea (8 percent) and cytopenias.

Ponatinib — Ponatinib is a third-generation TKI that is active against multiple BCR::ABL1 kinase domain (KD) mutations, including the T315I mutation. Ponatinib is associated with substantial cardiovascular AEs and hepatotoxicity, and it is not suitable for many patients.

The starting dose is ponatinib 45 mg once daily with or without food, but the dose is often titrated down to the lowest effective dose to prevent and reduce AEs [21]. The ponatinib label carries a boxed warning about the significant risk of arterial thrombosis and liver toxicity. Some clinicians add aspirin for patients receiving ponatinib, although no studies have evaluated this.

Details of ponatinib administration and toxicity are presented separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Ponatinib'.)

Studies of ponatinib for TKI resistance include:

●In the OPTIC trial, patients who were refractory to ≥2 TKIs were randomly assigned to ponatinib 45 mg, 30 mg, or 15 mg [22]. Ponatinib was reduced to 15 mg in patients who achieved BCR::ABL1 <1 percent. Interim analysis reported that patients taking 45 mg, 30 mg, and 15 mg had BCR::ABL <1 percent at 12 months in 44, 29, and 23 percent, respectively, and arterial occlusive events in 10, 5, and 3 percent, respectively [21].

●The PACE study of ponatinib reported MCyR in 56 percent of 203 patients with CP CML who were resistant or intolerant to dasatinib or nilotinib and in 72 percent of the 64 patients in CP CML with BCR::ABL1 T315I mutations [23,24]. Five-year OS was 73 percent, and responses included 60 percent MCyR, 40 percent MMR, and 24 percent MR4.5. The median time to MCyR was 2.8 months, and 82 percent of these responses were sustained at five years. The initial dose of ponatinib was 45 mg daily, but it was reduced to 30 or 15 mg daily in response to AEs; later in the study, it was reduced prospectively for all patients. Cardiovascular, cerebrovascular, and peripheral vascular events were reported in 31 percent of patients with CML, with the cumulative incidence increasing over time and three deaths.

Asciminib — Asciminib is an allosteric inhibitor of BCR::ABL1 that binds to a myristoyl site and locks the protein in an inactive conformation; this is a different mechanism of action than other TKIs. Asciminib is active against various BCR::ABL1 KD mutations, including T315I.

Asciminib 80 mg is taken once daily (or 40 mg twice daily at approximately 12-hour intervals) without food. Administration and toxicity are discussed separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Asciminib'.)

Studies of asciminib for TKI-resistant CP CML include:

●The phase 3 ASCEMBL trial reported that asciminib had superior efficacy compared with bosutinib for patients previously treated with ≥2 TKIs [25]. Patients were randomly assigned (2:1) to receive asciminib (40 mg twice daily by mouth) versus bosutinib (500 mg once daily by mouth). MMR at 96 weeks was 37.6 percent with asciminib and 15.5 percent with bosutinib [7]. Asciminib was associated with fewer grade ≥3 AEs (51 versus 61 percent, respectively) and fewer AEs leading to treatment discontinuation (6 versus 21 percent).

●Asciminib was active and well tolerated in 141 heavily pretreated patients with CP CML who were resistant or intolerant of ≥2 prior TKIs [26]. Among patients with a hematologic relapse, asciminib achieved CHR in 92 percent; CCyR was achieved in 54 percent of patients without a prior CCyR; and 48 percent of evaluable patients had MMR at 12 months. Among patients with the T315I mutation, 28 percent had MMR at 12 months, including patients for whom ponatinib had failed. Dose-limiting AEs included elevated serum lipase and clinical pancreatitis.

●An abstract reported preliminary results from 43 patients with CP CML treated with asciminib 80 mg once daily for resistance or intolerance to one prior TKI; patients with T315I were excluded [27]. MMR was reported in 86 percent at 24 weeks (including 29 percent MR4.0 and 7 percent MR4.5). Asciminib was escalated to 200 mg daily for patients with BCR::ABL1 >0.1 percent at 48 weeks.

Imatinib — Imatinib is a first-generation TKI with a generally favorable toxicity profile, but it is ineffective against many BCR::ABL1 KD mutations.

For patients with resistance to imatinib 400 mg once daily, the dose can be increased to 600 mg or 800 mg, if tolerated. However, we generally favor a 2G TKI or asciminib in this setting unless they are contraindicated by patient comorbidities.

Imatinib can be effective for patients with a cytogenetic relapse following a cytogenetic response with imatinib 400 mg daily, but the duration of response is usually short [28,29]. Imatinib is unlikely to benefit patients who did not experience a hematologic or cytogenetic response with imatinib 400 mg daily.

A study that randomly assigned dasatinib versus high-dose imatinib for patients with imatinib resistance reported better hematologic, cytogenetic, and molecular responses with dasatinib [12,30].

Details of imatinib administration and toxicity are presented separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Imatinib'.)

CLINICAL TRIALS — 

Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

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 info" and the keyword(s) of interest.)

●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 AND RECOMMENDATIONS

●Description – BCR::ABL1 tyrosine kinase inhibitors (TKIs) are effective for treating chronic phase (CP) chronic myeloid leukemia (CML). Some patients must change the initial TKI because of drug intolerance, a suboptimal response to initial therapy, or a relapse after an initial response.

●Intolerance

•Definition – TKI intolerance is persistent or recurrent grade ≥3 nonhematologic adverse effects (AEs) despite symptom management and/or dose adjustment, or persistent lower-grade AEs that are not tolerable for the patient. Most early AEs are mild and resolve spontaneously or are controlled with symptom management and/or brief dose adjustment. (See 'Definition' above.)

•Management of TKI intolerance – For persistent TKI intolerance, we select a second-line TKI according to toxicity profile (table 1) and comorbidities (algorithm 1). Suitable TKIs with various comorbidities are discussed above. (See 'Management of TKI intolerance' above.)

●TKI resistance – TKI resistance is failure to achieve or maintain hematologic, cytogenetic, and/or molecular responses at defined milestones (algorithm 2). (See 'TKI resistance' above.)

Testing should be repeated to confirm resistance, and patients questioned about treatment adherence and medications/supplements that may impair TKI efficacy.

Bone marrow examination to assess disease progression, including cytogenetic/molecular analysis and BCR::ABL1 kinase domain (KD) mutation testing.

●Management of TKI resistance – For CP CML with documented TKI resistance, we suggest changing the TKI rather than allogeneic hematopoietic cell transplantation (HCT) (Grade 2C). (See 'TKI resistance' above.)

The choice of a second-line TKI is guided by KD mutation(s), toxicity, and comorbidities. (See 'Choice of a second-line TKI' above.)

•T315I mutation – For the T315I mutation, we suggest either ponatinib or asciminib (algorithm 1) rather than other TKIs or allogeneic HCT (Grade 2C). The choice is guided by toxicity and comorbidities. (See 'T315I mutation' above.)

We simultaneously evaluate eligibility for allogeneic HCT and initiate a donor search in case the response to ponatinib or asciminib is inadequate.

For transplant-eligible patients with an inadequate response (table 3) to ponatinib or asciminib, we proceed to allogeneic HCT. (See 'Treatment response' above.)

•Other KD mutations – For KD mutations other than T315I, we select a second-line TKI based on mutation(s), toxicity, and comorbidities (algorithm 1). The table (table 2) lists resistance patterns of various TK mutations. (See 'Other kinase domain mutations' above.)

If the mutation is sensitive to multiple TKIs, we suggest a second-generation (2G) TKI (ie, dasatinib, nilotinib, bosutinib) or asciminib (Grade 2C), which are more likely effective and achieve faster responses than imatinib and are less toxic than ponatinib. However, imatinib is acceptable if the mutation is sensitive to it.

•No KD mutation – For patients without a KD mutation, we suggest a 2G TKI or asciminib (algorithm 1) rather than imatinib or ponatinib (Grade 2C). The choice is based on toxicity and comorbidities. (See 'No kinase domain mutation' above.)

The management of patients with accelerated phase or blast phase CML is discussed separately. (See "Accelerated phase chronic myeloid leukemia: Diagnosis and treatment" and "Chronic myeloid leukemia-blast phase: Diagnosis and treatment".)

●Treatment response – Response milestones for second-line TKI therapy are detailed in the table (table 3). (See 'Treatment response' above.)

●Failure to respond to ≥2 TKIs – For inadequate response or relapse after ≥2 TKIs, either a third-line TKI or allogeneic HCT is acceptable. The choice is individualized and made jointly with the patient. (See 'Failure to respond after ≥2 TKIs' above.)

●Individual TKIs – Administration, AEs, and outcomes with individual TKIs are presented above:

•(See 'Dasatinib' above.)

•(See 'Nilotinib' above.)

•(See 'Bosutinib' above.)

•(See 'Ponatinib' above.)

•(See 'Asciminib' above.)

•(See 'Imatinib' above.)