Chronic myeloid leukemia in chronic phase: Initial treatment

INTRODUCTION — 

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

Most patients with CML present in the chronic phase (CP), which typically manifests as leukocytosis and immature myeloid cells in peripheral blood, with or without anemia, thrombocytopenia, constitutional symptoms, splenomegaly, and/or bleeding. CP CML can progress from a relatively indolent disorder to a more aggressive disorder, such as accelerated phase or blast phase.

The initial treatment of CP CML will be discussed here.

Clinical presentation and diagnosis of CML, treatment of relapsed/resistant CML, and management of accelerated phase and blast phase are discussed separately.

●(See "Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

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

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

PRETREATMENT EVALUATION — 

Prior to treatment, patients with CP CML are evaluated clinically and with screening laboratory studies, bone marrow examination, measurement of the level of BCR::ABL1, and determination of CML risk score.

Clinical and laboratory

●Clinical – History should determine performance status (table 1) and identify medical comorbidities, current medications, cardiovascular risk factors, and insurance status. Physical examination must include documentation of blood pressure and measurements of liver and spleen size (below the costal margin) by palpation.

●Laboratory studies

•Complete blood count (CBC) with differential count.

•Serum chemistries – Electrolytes, renal and liver function tests, uric acid, and lactate dehydrogenase.

•Hepatitis B panel – HBsAg, HBsAb, anti-HBc immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies; reactivation of hepatitis B in association with tyrosine kinase inhibitor (TKI) therapy has been described in case reports, but the risk is not well-defined.

•Electrocardiogram (ECG) to measure baseline QTc interval; some clinicians obtain an ECG only in patients who will be treated with nilotinib or dasatinib. (See 'Society guideline links' below.)

●BCR::ABL1 – Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for BCR::ABL1 is performed before beginning therapy to establish a baseline for the monitoring of treatment response and to ensure that quantifiable transcripts can be identified using a standard BCR::ABL1 primer pair. (See 'Treatment response' below.)

●Mutation analysis – Mutation testing (eg, for kinase domain and/or myristoyl site mutations) is not routinely performed prior to the initial treatment of CP CML.

Mutation testing for patients who have an inadequate response to initial treatment is discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

●Bone marrow examination – Bone marrow should be examined for morphology and cytogenetics as a baseline measure.

Some experts consider that bone marrow examination is not required if CP CML is diagnosed using cytogenetics and PCR from peripheral blood. However, bone marrow examination enables the determination of blast count and the detection of excessive fibrosis.

Management of patients with cytogenetic abnormalities in addition to t(9;22) are discussed below. (See 'Additional chromosomal abnormalities' below.)

CML risk score — CML risk score, using one of the validated CML scoring systems (table 2), is calculated prior to treatment initiation. The preferred scoring system varies by practitioner, but any one of the following is acceptable:

●Sokal (calculator 1) [1]

●Euro (Hasford) [2]

●EUTOS [3]

●ELTS (EUTOS long-term survival score) (calculator 2) [4]

The Sokal, Hasford, and ELTS scoring systems stratify patients into three risk groups: low, intermediate, and high; EUTOS stratifies patients into low- and high-risk groups.

ELTS was derived from survival data that reflect treatment of CML with TKIs, and it provides the best discrimination for the probability of CML-specific death [4,5]. The other models were derived from data sets that included some patients who were treated before the routine use of TKIs.

The use of clinical scoring systems for defining a prognosis in CML is described separately. (See "Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Prognostic scoring systems'.)

GOALS OF CARE — 

The goals of care for all patients with CP CML are to achieve and maintain clinical remission, avoid disease progression to accelerated phase or blast phase, and limit treatment-related toxicity.

Most patients with CP CML require lifelong treatment with a tyrosine kinase inhibitor (TKI). A trial of TKI discontinuation to achieve treatment-free remission (TFR) is a potential long-term goal for selected patients who achieve a sustained, deep molecular remission. Criteria for considering a trial of TFR are presented below. (See 'Eligibility' below.)

Milestones for hematologic, cytogenetic, and molecular responses (table 3) are described below. (See 'Treatment response' below.)

INITIAL THERAPY — 

For CP CML, we recommend initial treatment with a BCR::ABL1 tyrosine kinase inhibitor (TKI), rather than cytotoxic agents, interferons, and hematopoietic cell transplantation (HCT) based on the superior balance of efficacy and toxicity of TKIs [6].

All BCR::ABL1 TKIs are potentially teratogenic; the initial management of CP CML diagnosed in pregnancy is discussed below. (See 'Pregnancy' below.)

Long-term survival of patients with CP CML who are treated with a TKI is normal or near-normal compared with age- and sex-matched control populations [7-11]. By contrast, cytotoxic agents, interferons, and allogeneic HCT are associated with inferior efficacy and/or greater toxicity. Prior to TKIs, registry studies reported survival rates of 50 to 60 percent among patients with CP CML who received chemotherapy alone or radiotherapy plus chemotherapy followed by HCT [12,13]. Imatinib (a first-generation BCR::ABL1 TKI) achieved superior outcomes and less toxicity than interferon alfa plus cytarabine in the phase 3 IRIS trial, as described below. (See 'Imatinib' below.)

The selection of a TKI for the initial treatment of CP CML is described below. (See 'Selection of a tyrosine kinase inhibitor' below.)

SELECTION OF A TYROSINE KINASE INHIBITOR — 

The initial treatment of CP CML is stratified according to CML risk score.

The determination of CML risk score is discussed above. (See 'CML risk score' above.)

No individual BCR::ABL1 tyrosine kinase inhibitor (TKI) has proven superior for the treatment of CP CML. The selection of a TKI for the initial treatment of CP CML is individualized (algorithm 1). In addition to stratifying according to high-risk versus low- or intermediate-risk CML risk score, other important considerations include toxicity profile (table 4), comorbidities, availability, cost, and whether the patient seeks to achieve a treatment-free remission (TFR). Administration, adverse effects (AEs), and outcomes with individual TKIs are presented below. (See 'Individual tyrosine kinase inhibitors' below.)

●There is no difference in overall survival (OS) with imatinib versus second-generation (2G) TKIs (ie, nilotinib, dasatinib, bosutinib) for the initial treatment of CP CML [14-17]. However, 2G TKIs generally achieve faster, deeper remissions and are associated with less progression to accelerated phase (AP) and/or blast phase (BP), which is a concern in patients with high-risk CP CML.

A meta-analysis of eight randomized trials of TKIs in CP CML reported that imatinib and 2G TKIs were associated with comparable OS and progression-free survival (PFS) [18]. However, compared with imatinib, 2G TKIs achieved more complete cytogenetic responses (relative risk [RR] 0.72 [95% CI 0.60-0.85]), higher rates of major molecular response (ie, BCR::ABL1 <0.1 percent; RR 0.76 [95% CI 0.63-0.91]), and lower rates of disease progression (0.8 versus 3.0 percent, respectively; RR 0.35 [95% CI 0.18-0.72]). Note that the finding of less disease progression with 2G TKIs was strongly influenced by one trial (ENESTnd) among the six that reported this outcome; methodologic aspects that may have affected the rate of progression in ENESTnd are discussed below [15]. (See 'Nilotinib' below.)

●Asciminib is at least as effective as the 2G TKIs for achieving deep molecular remissions in patients with CP CML [19], but long-term survival data for asciminib as an initial therapy of CP CML are not currently available. (See 'High-risk CML' below and 'Low- or intermediate-risk CML' below.)

Imatinib, nilotinib, dasatinib, bosutinib, and asciminib are approved by the US Food and Drug Administration (FDA) for the initial treatment of CP CML, while ponatinib is approved for the initial treatment of CP CML with the BCR::ABL1 T315I mutation.

Imatinib, nilotinib, dasatinib, and bosutinib are approved by the European Medicines Agency (EMA) for the initial treatment of CP CML, while ponatinib is approved for the initial treatment of CP CML with the BCR::ABL1 T315I mutation.

TKI selection for patients who seek a TFR is discussed below. (See 'If treatment-free remission is an important goal' below.)

High-risk CML — For high-risk CP CML, we suggest initial treatment with a 2G TKI (ie, nilotinib, dasatinib, bosutinib), rather than imatinib, asciminib, or ponatinib (algorithm 1). This suggestion is based on the lower risk of progression to advanced CML with 2G TKIs compared with imatinib, the lack of long-term survival data with asciminib, and the toxicity of ponatinib.

No individual 2G TKI has proven superior in this setting. Selection of a TKI should consider the toxicity profile (table 4), comorbidities, availability, cost, and patient preference. For patients with comorbidities that preclude treatment with a 2G TKI, initial treatment with imatinib or asciminib is acceptable. Selection of a 2G TKI is discussed below. (See 'Second-generation tyrosine kinase inhibitors' below.)

●Imatinib and 2G TKIs are associated with comparable OS, PFS, and AEs, but 2G TKIs are associated with less progression to advanced-stage CML [18], as discussed above. (See 'Selection of a tyrosine kinase inhibitor' above.)

●Asciminib achieved deeper molecular responses than other TKIs for the initial therapy of CP CML, but long-term outcomes with asciminib are not presently available. In a trial that included 201 patients with newly diagnosed high-risk CP CML, there was no difference in OS (after 16 months) or achievement of major molecular response (MMR; ie, BCR::ABL1 ≤0.1 percent at 48 weeks) among patients randomly assigned to asciminib versus the investigator's preselected choice of a 2G TKI [19]. Asciminib caused fewer AEs leading to treatment discontinuation.

Low- or intermediate-risk CML — For patients with low-risk or intermediate-risk CP CML, initial therapy is influenced by the importance assigned by the patient to achieving a TFR.

Patients may seek a TFR because of TKI toxicity, convenience, cost, a desire to become pregnant, or other reasons. However, only selected patients with CP CML are candidates for a trial of TFR; selection criteria are presented below. (See 'Eligibility' below.)

If treatment-free remission is an important goal — For patients with low- or intermediate-risk CP CML who consider TFR an important goal, we suggest a 2G TKI rather than imatinib, asciminib, or ponatinib (algorithm 1).

If no 2G TKI is available or suitable for the patient, asciminib (if available) or imatinib is acceptable.

All 2G TKIs are associated with comparable rates of TFR, but they have not been directly compared in prospective studies. Nilotinib was superior to imatinib for achieving sustained TFR in a phase 3 trial [20], but the other 2G TKIs have not been directly compared with imatinib for achieving TFR. Asciminib achieved deeper and more rapid molecular remissions than 2G TKIs or imatinib for the initial therapy of CP CML [19], but there are no reports of TFR using asciminib as initial therapy, and the long-term outcomes with asciminib are not presently available. The toxicity of ponatinib is excessive in this setting.

Selection of a 2G TKI is individualized and should consider toxicity profile (table 4), comorbidities, availability, cost, and patient preference, as discussed below. (See 'Second-generation tyrosine kinase inhibitors' below.)

Overall, long-term TFR can be achieved in 10 to 15 percent of patients with newly diagnosed CML: approximately one-third of patients achieve a sustained, deep molecular remission with a 2G TKI, and one-half of those patients remain in long-term TFR after discontinuing therapy. Outcomes of studies of TFR in CP CML are presented below. (See 'Outcomes' below.)

Eligibility — The following should be met to attempt a TFR:

●Criteria

•Age ≥18 years.

•Reliably taking a TKI for ≥3 years.

•No prior resistance to a 2G TKI that required switching to another agent.

•Quantitative polymerase chain reaction (qPCR) assay that can detect molecular response (MR) 4.5 (≥4.5 log reduction; BCR::ABL1 ≤0.0032 percent) and provide results within two weeks.

•Stable molecular response (ie, MR 4; BCR::ABL1 ≤0.01 percent by the International Scale [IS]) (table 3) for ≥2 years, as documented by ≥4 separate tests performed ≥3 months apart.

●AEs – Aggravation of or new development of musculoskeletal pain has been reported in 25 to 42 percent of patients who discontinued a TKI [21,22].

Treatment-free remission monitoring — We monitor BCR::ABL1 by qPCR after TKI discontinuation.

For loss of MR 3 (BCR::ABL1 ≤0.1 percent), we repeat testing within two weeks; if repeat testing confirms loss of MR 3, the TKI should be resumed within four weeks.

For patients with sustained MR 3, we monitor as follows:

●First six months – Monthly for the first six months.

●Next 18 months – Every two months.

●Subsequent monitoring – For sustained MR 3, we measure qPCR every three months and lengthen the monitoring interval to four to six months after several years of sustained MR 3. We continue testing indefinitely because late relapses (eg, >2 years) have been reported [23].

Outcomes — Prospective studies report that approximately one-half of patients remain in a TFR after discontinuing a TKI.

Long-term TFR is most likely in patients with prolonged TKI treatment and/or years of undetectable BCR::ABL1 [24,25]. However, even in individuals with sustained MR 4.5, one-half experience a molecular recurrence within a year of discontinuing the TKI, since viable CML stem cells can remain in a quiescent state in the marrow [26-33]. Nevertheless, nearly all patients who show evidence of progression can again achieve a deep molecular response upon resumption of therapy.

Following are examples of studies that evaluated TKI discontinuation:

●In the ENESTnd trial, there was no difference in 10-year OS in patients randomly assigned to nilotinib versus imatinib, but more patients taking nilotinib were eligible for TFR, compared with imatinib (47 versus 30 percent, respectively) [20].

●In the EURO-SKI (European Stop Kinase Inhibitor) study, 50 percent of patients remained in TFR after 24 months [34]. The prospective study included 758 patients who took a TKI for ≥3 years and had sustained MR 3 for ≥1 year (94 percent taking imatinib).

●The prospective LAST (Life After Stopping TKIs) study of 173 patients who achieved MR 4 for ≥2 years while taking either imatinib (60 percent), dasatinib, nilotinib, or bosutinib reported 61 percent sustained TFR with median follow-up of 42 months [35]. Clinically meaningful improvement of fatigue, depression, diarrhea, and sleep disturbance was reported in 80, 35, 88, and 21 percent, respectively. AEs increased in patients who restarted a TKI.

●Similar results have been reported by discontinuation trials in patients receiving nilotinib or dasatinib [21,36-48].

At present, there are no reports of TFR studies in patients taking asciminib or ponatinib.

When treatment-free remission is not an important goal — For patients who do not consider TFR a high priority, treatment with imatinib, a 2G TKI, or asciminib is acceptable (algorithm 1). The choice of a TKI is guided by the side effect profile (table 4), comorbidities, availability, cost, and patient preference. (See 'Toxicities' below.)

Imatinib and 2G TKIs (eg, nilotinib, dasatinib, bosutinib) achieve comparable rates of OS, PFS, and AEs [18]. Some clinicians favor imatinib because it has the longest record of safety and efficacy, is widely available, and is generally the least expensive. Others favor 2G TKIs because they achieve faster and deeper molecular responses than imatinib. Asciminib achieved deeper molecular responses than other TKIs for patients with CP CML, but long-term outcomes with asciminib as an initial treatment are not yet available.

Asciminib is approved by the FDA for the initial treatment of CP CML. (See 'Individual tyrosine kinase inhibitors' below.)

Toxicities — All TKIs are associated with certain common AEs (eg, cytopenias, rash, nausea, muscle cramps, edema, diarrhea, fatigue) early in the course of treatment. Most of these early AEs are modest and self-limited or can be managed as discussed below. (See 'Common early toxicities' below.)

Each TKI is also associated with particular AEs, some of which may not be manifest for months or years (table 4). We consider the following to be such defining toxicities:

●Imatinib – Muscle cramps, fatigue, edema, nausea, diarrhea. (See 'Imatinib' below.)

●Nilotinib – Coronary, cerebral, and peripheral vascular disease; prolonged QTc interval; hyperglycemia; pancreatitis. (See 'Nilotinib' below.)

●Dasatinib – Pleural effusion, pulmonary hypertension, prolonged QTc interval, platelet dysfunction. (See 'Dasatinib' below.)

●Bosutinib – Diarrhea, abnormal liver function, rash, pancreatitis, hypersensitivity. (See 'Bosutinib' below.)

●Asciminib – Pancreatitis, hypertension, heart failure, prolonged QTc interval. (See 'Asciminib' below.)

●Ponatinib – Excessive arterial and venous thromboembolic complications and other AEs generally preclude the use of ponatinib for frontline therapy of CP CML. (See 'Ponatinib' below.)

As examples of how we consider comorbidities and AEs in selecting a TKI (algorithm 1):

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

●For patients with a history of pancreatitis, we try to avoid nilotinib, bosutinib, and asciminib.

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

●For patients who require long-term treatment with a proton pump inhibitor, we try to avoid dasatinib and nilotinib.

Approximately one-third of patients switched to an alternative TKI in randomized trials of CP CML; most switched because of toxicity or suboptimal response. Treatment, toxicities, and outcomes with individual TKIs are presented below. (See 'Individual tyrosine kinase inhibitors' below.)

INDIVIDUAL TYROSINE KINASE INHIBITORS — 

Individual tyrosine kinase inhibitors (TKIs) are associated with different administration schedules and adverse effects (AEs). Regulatory approval by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) differ for some TKIs.

Imatinib — Imatinib has the longest record of safety and efficacy, is available as a generic medication, and is generally less expensive than other TKIs.

Long-term outcomes with imatinib are comparable to those with second-generation (2G) TKIs, but imatinib may be slower to achieve cytogenetic and molecular responses [18]. Imatinib is associated with cytopenias and edema, and it causes substantial fluid retention in some patients. We generally avoid imatinib in patients with a history of significant fluid retention or nausea, and we favor 2G TKIs for patients with high-risk CML and for those who assign high priority to achieving a treatment-free remission (TFR), as discussed above. (See 'High-risk CML' above and 'If treatment-free remission is an important goal' above.)

●Initial treatment – Imatinib 400 mg once daily with a meal and a large glass of water; tablets can also be dispersed in water or apple juice.

The initial dose of imatinib should be adjusted for liver or renal impairment, and concurrent use of strong CYP3A4 inducers should be avoided.

Imatinib is approved by the FDA and the EMA for the treatment of adults and children with CP CML.

●Toxicity – The most common AEs, such as cytopenias, edema, nausea, diarrhea, rash, and muscle cramps (table 4), are generally mild; grade ≥3 AEs occur in ≤5 percent of patients. Imatinib may be associated with hypophosphatemia and decreased bone mineral density [49,50].

The dose should be adjusted for changes in liver and kidney function, and the patient should be monitored for fluid retention, particularly in older patients and in those with cardiovascular (CV) comorbidities.

Monitoring/managing toxicity is discussed below. (See 'Tyrosine kinase inhibitor toxicity' below.)

●Outcomes – In patients with CP CML, imatinib achieves complete hematologic response (CHR), complete cytogenetic response (CCyR), and major molecular response (MMR); ie, >3-log reduction in BCR::ABL1 transcripts by the International Scale (IS) (table 3) in >95 percent, >75 percent, and nearly 60 percent, respectively [12]. Long-term outcomes with imatinib are comparable to those with 2G TKIs [18]. Definitions of hematologic, cytogenetic, and molecular responses are described below. (See 'Definitions of response' below.)

Phase 3 trials that included imatinib as the initial treatment of CP CML include:

•The IRIS (International Randomized Study of Interferon [IFN] and STI571 [imatinib]) trial reported that imatinib is superior to IFN alfa plus cytarabine [12]. In the IRIS trial, 1106 patients with newly diagnosed CP CML were randomly assigned to imatinib (400 mg once daily) versus IFN alfa (5 million units/m² daily) plus cytarabine (20 mg/m² daily for 10 days/month). After 18 months, compared with IFN alfa plus cytarabine, imatinib achieved superior CHR (97 versus 69 percent), CCyR (76 versus 15 percent), MMR (39 versus 2 percent), and progression-free survival (PFS; 97 versus 92 percent). Imatinib was also associated with better quality of life and was better tolerated than IFN alfa plus cytarabine [12,51-53]. After a 10-year follow-up of 204 patients, 93 percent had MMR and 63 percent had molecular response (MR) 4.5 (>4.5-log reduction in BCR::ABL1) [14]. Although 10-year overall survival (OS) in this trial was 84 percent, imatinib did not achieve a survival advantage because approximately 90 percent of patients assigned to receive IFN alfa plus cytarabine ultimately crossed over to imatinib [14,54-56].

•The CML-IV trial evaluated various imatinib doses and combinations with other agents [8]. In CML-IV, 1551 patients were randomly assigned to imatinib 400 mg per day, imatinib 800 mg per day, or imatinib 400 mg daily plus either IFN alfa or cytarabine. After 10 years, PFS and OS were 80 and 82 percent, respectively, and there were no survival differences among treatment arms. Other studies of imatinib in CP CML reported similar clinical outcomes and toxicities [57-68].

Prospective trials that compared imatinib to 2G TKIs in CP CML are described below. (See 'Nilotinib' below and 'Dasatinib' below and 'Bosutinib' below.)

Second-generation tyrosine kinase inhibitors

Nilotinib — Nilotinib is the only 2G TKI that must be 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 CV AEs, and rare cases of sudden death (table 4).

●Initial treatment – Dosing of nilotinib for initial treatment of CP CML follows:

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

•Capsule – Nilotinib capsules 300 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 nilotinib for accelerated phase (AP) CML and for CP CML after resistance or intolerance to the initial TKI.

Lipase and amylase should be tested prior to treatment. Patients should be screened by ECG for QTc interval at baseline, potassium and magnesium levels should be corrected, and other medications that may prolong QTc interval (table 5) should be avoided. Caution is advised for patients with poorly controlled diabetes, liver disease, pancreatitis, or substantial CV risk factors.

Nilotinib is approved by the FDA and the EMA for adults and children ≥1 year with CP CML.

●Toxicity – Most AEs (table 4) are mild and self-limited, but pancreatitis and a low incidence of sudden deaths (which may be related to ventricular repolarization abnormalities) have been reported. Late AEs include occlusive cardiac, cerebral, and peripheral artery disease; liver disease; and hyperglycemia.

The dose should be adjusted for prolongation of QTc interval, elevation of lipase/amylase, or changes in liver and kidney function.

Monitoring/managing toxicity is discussed below. (See 'Tyrosine kinase inhibitor toxicity' below.)

●Outcomes – Compared with imatinib, nilotinib was associated with comparable survival, more molecular responses, more CV events, and less progression to AP/blast phase (BP).

The following trials directly compared nilotinib with imatinib:

•In ENESTnd, 846 previously untreated patients with CP CML were randomly assigned to nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg daily [15,69-72]. Compared with imatinib, nilotinib 300 mg twice daily (the approved dose) was associated with comparable five-year OS, PFS, and event-free survival (EFS). Compared with imatinib (33 patients progressed to AP/BP), progression was reported in 12 patients taking nilotinib 300 mg twice daily (hazard ratio [HR] 0.46; 95% CI 0.22-0.99) and 9 patients taking nilotinib 400 mg twice daily (HR 0.28; 95% CI 0.11-0.68) [15]. Most progression events occurred in patients with intermediate- or high-risk disease. Nilotinib 400 mg twice daily was superior to imatinib with regard to OS, PFS, EFS, and progression, but this dose was associated with unacceptable levels of CV toxicity [15,69-72]. More than one-half of all patients treated with nilotinib (at either dose level) achieved MR 4.5, compared with less than one-third with imatinib.

In ENESTnd, the incidence of grade ≥3 AEs and toxicity that led to treatment discontinuation were comparable between nilotinib 300 mg twice daily and imatinib [15]. Nilotinib was associated with less fluid retention, pleural effusion, pericardial effusion, pulmonary edema, and grade ≥3 neutropenia than imatinib. However, all-grade CV events (eg, ischemic heart disease, ischemic CV events, peripheral artery disease) were reported in 7.5, 13.4, and 2.1 percent of patients in the nilotinib 300 mg, nilotinib 400 mg, and imatinib arms, respectively. With five years of follow-up, new or worsening grade ≥3 elevations of lipase, glucose, and liver enzymes were more common with the nilotinib arm than with imatinib. Grade ≥3 symptomatic prolongation of QTc was reported in 0.7 and 1.4 percent of patients treated with nilotinib 300 mg or 400 mg.

•In ENESTchina, 267 patients with newly diagnosed CP CML were randomly assigned to nilotinib (300 mg twice daily) versus imatinib (400 mg daily) [73]. Nilotinib achieved higher MMR at 12 months (52 versus 28 percent) and similar rates of both CCyR (84 versus 87 percent) and freedom from progression (95 percent each) at 24 months [73]. AEs were like those in ENESTnd.

Dasatinib — Dasatinib is a 2G TKI that is associated with cytopenias, pleural effusions, other fluid retention, QT prolongation, and bleeding (table 4). It should not be given to patients with hypokalemia, hypomagnesemia, or who have or may develop prolongation of the QTc interval. We generally avoid dasatinib in patients with a bleeding history, pleural effusion, and heart failure. Caution is advised when it is given with certain medications (described below).

●Initial treatment – Dasatinib 100 mg once daily, with or without a meal; tablets should not be crushed or cut.

Patients should be screened by ECG for QTc interval at baseline, and hypokalemia or hypomagnesemia should be corrected before administration of dasatinib. No initial dose adjustment is required for patients with liver or kidney impairment, but caution is advised in patients who require anticoagulants, medications that inhibit platelet function, antiarrhythmic medicines or other products that may lead to QTc prolongation (table 5), strong CYP3A4 inducers or inhibitors (table 6), St. John's wort, antacids, H2 antihistamines, and proton pump inhibitors (PPIs).

Dasatinib is approved by the FDA and the EMA for treatment of adults and children ≥1 year with CP CML.

●Toxicity – Most AEs (table 4) are mild and self-limited. However, patients may experience QTc prolongation, fluid retention (grade ≥3 in approximately 4 percent), exacerbation of congestive heart failure, or significant bleeding [74]. Severe and potentially fatal central nervous system (CNS) and gastrointestinal hemorrhages have been reported in approximately 1 and 4 percent of patients, respectively; most bleeding events were associated with severe thrombocytopenia, anticoagulants, and/or inhibitors of platelet function.

The dose of dasatinib should be adjusted for prolongation of QTc interval. Patients who develop dyspnea, dry cough, or other findings suggestive of pleural effusion should be evaluated with a chest radiograph; some patients develop a patchy interstitial pneumonitis with fever that can mimic an infection and rare cases of pulmonary hypertension have been reported. Lymphocytosis (likely representing T/natural killer [NK] cells) that persisted for >12 months occurred in one-third of patients treated with dasatinib, and these patients were more likely to have pleural effusions and favorable cytogenetic and molecular responses [75].

Monitoring/managing toxicity is discussed below. (See 'Tyrosine kinase inhibitor toxicity' below.)

●Outcomes – Dasatinib achieved 97 percent OS and 93 percent PFS at three years and MMR in more than three-quarters of patients with CP CML [76]. The following trials directly compared dasatinib with imatinib:

•The DASISION trial randomly assigned 519 patients with previously untreated CML to dasatinib 100 mg daily versus imatinib 400 mg daily [16,77-79]. At five-year follow-up, compared with imatinib, dasatinib did not achieve superior PFS or OS, but 26 percent of patients initially treated with imatinib were subsequently treated with a 2G TKI. Dasatinib produced faster and deeper molecular responses, with a molecular response (MR) at three months (84 versus 64 percent) and MMR 4.5 (42 versus 33 percent). After five years, progression to AP/BP occurred in 4.6 and 7.3 percent of patients treated with dasatinib and imatinib, respectively [16]. AEs led to discontinuation of therapy in 16 and 7 percent of patients treated with dasatinib and imatinib, respectively [16]. Except for pleural effusion (28 versus 1 percent), nonhematologic AEs (eg, nausea, vomiting, rash, myalgia) and hematologic AEs were less common with dasatinib than with imatinib.

•Similar results were noted in a randomized phase 2 study of dasatinib (100 mg daily) versus imatinib (400 mg daily) in 246 patients with newly diagnosed CP CML [76]. After three years, dasatinib and imatinib achieved comparable OS (97 percent each), PFS (93 versus 90 percent, respectively), and relapse-free survival (91 versus 88 percent), but dasatinib resulted in higher rates of CCyR (84 versus 69 percent) and MMR at 12 months (59 versus 44 percent). Pleural effusions, headache, and diarrhea were more common with dasatinib, while edema, nausea, and muscle pain were more common with imatinib.

A lower starting dose of dasatinib may be effective, but we await long-term outcomes before suggesting its routine use outside of a clinical trial. In a phase 2 study, 81 patients with newly diagnosed CP CML were treated with dasatinib 50 mg daily; with >12-month follow-up, CCyR was achieved by 77 and 95 percent of patients by 6 and 12 months, respectively [80]. At 12 months, the cumulative MMR rate was 81 percent, and MR 4 and MR 4.5 rates were 55 and 49 percent, respectively. The 50 mg daily dose was well-tolerated, with pleural effusion in 6 percent.

Bosutinib — Bosutinib is a 2G TKI that is associated with cytopenias, diarrhea, abnormal liver function, and fluid retention. We generally avoid using bosutinib in patients with liver or kidney dysfunction, diarrhea, and heart failure, and caution is advised when it is given with certain medications.

●Initial treatment – Bosutinib 400 mg once daily. Some clinicians begin with bosutinib 100 mg once daily and escalate the dose by 100 mg every week until reaching 400 mg daily to reduce diarrhea or liver toxicity [81].

The dose should be reduced for liver or kidney disease or patients taking CYP3A4 inducers or inhibitors (table 6) and PPIs.

Bosutinib is approved by the FDA and the EMA for treatment of adults and children ≥1 year with CP CML.

●Toxicity – Most AEs (table 4) are mild and self-limited. However, diarrhea, nausea, and abdominal pain occur commonly, and grade ≥3 diarrhea or abnormal liver function tests are each reported in approximately 8 percent, with most occurring during the first one to two months of treatment and later resolving; bosutinib should be temporarily held or the dose adjusted for significant gastrointestinal toxicity.

Monitoring/managing toxicity is discussed below. (See 'Tyrosine kinase inhibitor toxicity' below.)

●Outcomes – Bosutinib achieves cytogenetic and molecular responses that are comparable to other 2G TKIs and imatinib [18]. The following randomized trials directly compared bosutinib versus imatinib in newly diagnosed CP CML:

•The BELA trial randomly assigned 502 patients to bosutinib (500 mg daily) versus imatinib (400 mg daily) [82,83]. Bosutinib achieved faster cytogenetic responses, but compared with imatinib, had similar rates of CCyR and MMR after ≥24-month follow-up. Bosutinib was associated with a lower rate of a composite outcome of disease progression/lack of efficacy (3 versus 10 percent, respectively), and responses to bosutinib did not differ based on Sokal score. Bosutinib was associated with more diarrhea, elevations of liver function tests, and a higher rate of drug discontinuation due to AEs (19 versus 6 percent) [82].

•The BFORE trial randomly assigned 536 adults to bosutinib (400 mg once daily) versus imatinib (400 mg once daily) [17]. Bosutinib achieved higher rates of MMR (47 versus 37 percent, respectively) and CCyR (77 versus 66 percent) at 12 months and reached these milestones more quickly. Any type of grade ≥3 toxicity occurred in 56 percent of patients receiving bosutinib and 43 percent of patients receiving imatinib; treatment was discontinued by 22 percent of patients receiving bosutinib and 27 percent of patients receiving imatinib. Bosutinib was associated with more grade ≥3 diarrhea (8 versus 1 percent, respectively) and elevated serum transaminases, but cardiac and vascular toxicities were uncommon with both treatments.

Asciminib — Asciminib is an allosteric inhibitor of BCR::ABL1 that targets the ABL1 myristoyl pocket.

Asciminib differs from other TKIs because it binds to the myristoyl pocket, rather than the ATP binding site (which is bound by other TKIs); binding to the myristoyl pocket locks the BCR::ABL1 protein in an inactive conformation.

●Initial treatment – Asciminib 80 mg by mouth once daily or 40 mg twice daily at approximately 12-hour intervals. Food consumption should be avoided for ≥2 hours before and one hour after taking asciminib.

Initial treatment of BCR::ABL1 T315I should be with asciminib 200 mg twice daily.

Asciminib is approved by the FDA for the initial treatment of CP CML. Asciminib is approved by the EMA for CP CML previously treated with ≥2 TKIs.

●Toxicity – AEs include myelosuppression, pancreatic toxicity, hypertension, cardiovascular toxicity, and hypersensitivity.

●Outcomes – A phase 3 trial that randomly assigned patients with CP CML to asciminib versus imatinib or a 2G TKI (according to CML risk score) is discussed above. (See 'Initial therapy' above.)

Ponatinib — Ponatinib is a third-generation TKI that is associated with substantial arterial and venous thromboembolic events, heart failure, and hepatotoxicity.

For initial therapy of CP CML, ponatinib is generally reserved for patients with a known BCR::ABL1 T315I mutation, but asciminib has less toxicity and is also acceptable for BCR::ABL1 T315I. (See 'Asciminib' above.)

●Initial treatment – For initial treatment of CP CML with BCR::ABL1 T315I, ponatinib is generally started at 45 mg by mouth daily, and the dose is reduced to 15 mg orally once BCR::ABL1 is ≤1 percent. For loss of response, the dose can be re-escalated to a previously tolerated dose of 30 mg or 45 mg orally once daily.

Ponatinib is approved for the initial treatment of CML with BCR::ABL1 T315I; it is also approved by the FDA and the EMA for CP CML after ≥2 TKIs or for patients who are intolerant of prior TKIs.

●Toxicity – Hematologic, cardiovascular, and other serious AEs with ponatinib are discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor", section on 'Ponatinib'.)

●Outcomes – Treatment of CP CML in patients with BCR::ABL1 T315I or intolerance to other TKIs is discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

Other tyrosine kinase inhibitors — Other TKIs have been approved for treatment of CML in specific clinical settings or countries:

●Radotinib – Radotinib is a 2G TKI approved by the Korea Food and Drug Administration (KFDA) for initial treatment of CML or CML that is refractory to other TKIs. Compared with imatinib, radotinib achieved faster cytogenetic and molecular responses in the RERISE study, which randomly assigned 241 patients with previously untreated CML to radotinib (either 300 or 400 mg twice daily) versus imatinib (400 mg once daily) [84]. Compared with imatinib, radotinib achieved superior MMR and CCyR at 12 months and early molecular response at three months. Responses were similar with both doses of radotinib.

●Flumatinib – Flumatinib is a 2G TKI available in China. In one trial, 394 patients with CP CML were randomly assigned to flumatinib (600 mg once daily) versus imatinib (400 mg once daily) [85]. At 12 months, compared with patients receiving imatinib, more patients receiving flumatinib achieved MR 4 (23 versus 12 percent) and no patients progressed to AP/BC (versus four patients taking imatinib). This trial differed from other large phase 3 studies of 2G TKIs because only 7 percent of patients had high-risk CML.

TREATMENT RESPONSE

Response monitoring — Response to treatment with a tyrosine kinase inhibitor (TKI) is evaluated by the timely achievement of hematologic, cytogenetic, and molecular milestones (table 7). (See 'Definitions of response' below.)

●Achievement of milestones – For patients who achieve treatment milestones on schedule, sustain the response, and have acceptable levels of toxicity, treatment should continue indefinitely.

For certain patients, a trial of TKI discontinuation or de-escalation may be considered. (See 'If treatment-free remission is an important goal' above.)

●Failure to achieve milestones – All patients who fail to achieve treatment response milestones (table 7) should be evaluated for adherence to treatment and possible drug interactions. Evidence of loss of response should be confirmed with repeat studies before treatment changes are initiated.

Management of CML that is resistant to TKI therapy is discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

Serial measurement in peripheral blood of BCR::ABL1 by quantitative polymerase chain reaction (qPCR) is the preferred method for monitoring treatment response; the qPCR assay should be standardized and have a sensitivity of ≥4.5-log reduction from the baseline, as described below. (See 'Definitions of response' below.)

Optimal responses are:

●3 months: BCR::ABL1 (International Scale [IS]) ≤10 percent and/or ≤35 percent Philadelphia chromosome-positive metaphase cells

●6 months: BCR::ABL1 (IS) ≤1 percent and/or 0 percent Philadelphia chromosome-positive cells

●12 months: BCR::ABL1 (IS) ≤0.1 percent

After BCR::ABL1 is ≤0.1 percent, it should be measured every three months for the first two years and then every three to six months thereafter. At very low levels, the level of transcripts can fluctuate several-fold with successive tests. However, if there is a 1-log increase in BCR::ABL1 after achieving a major molecular response (MMR; ie, MR 3), this should be confirmed by repeating qPCR in one to three months.

Measurement of molecular response by qPCR has greater sensitivity than cytogenetic assays, and qPCR is the only tool that can monitor responses after a patient has achieved a complete cytogenetic response (CCyR).

It is not necessary to serially assess bone marrow for cytogenetic or molecular response. We generally reserve additional bone marrow biopsies for patients exhibiting resistance to a TKI, progression of CML, or development of dysplasia or cytopenias. However, for patients who have additional cytogenetic abnormalities that are detected in Philadelphia chromosome-negative cells, it may be necessary to monitor the progression of that clone with serial cytogenetic studies, as described below. (See 'Additional chromosomal abnormalities' below.)

Our approach to monitoring disease in patients in chronic phase is consistent with those proposed by the European LeukemiaNet (table 3 and algorithm 2) [86] and the National Cancer Center Network (NCCN) [87].

Definitions of response

Clinical and cytogenetic responses

●Hematologic response – Hematologic response is assessed by the white blood cell (WBC) count, differential, platelet count, and improvement in splenomegaly [86,88]:

•Complete hematologic response (CHR) is defined by normalization of all peripheral blood counts, WBC count <10,000/microL, platelet count <450,000/microL, no circulating immature myeloid cells (eg, blasts, promyelocytes, myelocytes), and no clinical findings of disease, including the disappearance of a palpable spleen [89].

●Cytogenetic response – Cytogenetic response is assessed by chromosome banding of ≥20 bone marrow cell metaphases:

•CCyR: No Philadelphia chromosome-positive metaphases detected

•Major cytogenetic response: 0 to 35 percent Philadelphia chromosome-positive metaphases

•Minor cytogenetic response: >35 percent Philadelphia chromosome-positive metaphases

We consider that fluorescence in situ hybridization (FISH) is not a preferred method for monitoring cytogenetic response because it will not detect the emergence of additional chromosomal abnormalities and the risk of false-positive or false-negative findings given the limited number of cells that are typically analyzed by interphase FISH [90]. Although FISH <1 percent generally corresponds to CCyR, endpoints for cytogenetic response with FISH have not been defined [91,92].

Molecular response

●Molecular response – Molecular response is assessed by qPCR of BCR::ABL1, which compares the level of BCR::ABL1 transcripts with other control genes (eg, BCR, ABL1, or GUSB) [52,93]. The results should be expressed using the IS, which assumes a standardized baseline value of 100 percent for all patients and should have a sensitivity of ≥4.5-log. Molecular response can be described as:

•Early molecular response (EMR): BCR::ABL1 ≤10 percent at three and/or six months.

•Major molecular response (MMR): BCR::ABL1 ≤0.1 percent.

•Undetectable BCR::ABL1: The level of sensitivity of the assay should be provided in the report (eg, MR 4, MR 4.5). To illustrate this concept, a value of MR 4 corresponds to the detection of one CML cell among 10,000 (ie, 10⁴) normal cells.

Molecular response can also be described by the log reduction below the standard 100 percent baseline value of the IS:

•MR2 – BCR::ABL1 ≤1 percent (ie, ≥2 log reduction from the standardized baseline); this level roughly corresponds to CCyR.

•MR3 – BCR::ABL1 ≤0.1 percent (ie, ≥3 log reduction); MR 3 is equivalent to MMR.

•MR4 – BCR::ABL1 ≤0.01 percent (ie, ≥4 log reduction).

•MR4.5 – BCR::ABL1 ≤0.0032 percent (ie, ≥4.5 log reduction); this is the current limit of most commercially available assays.

TYROSINE KINASE INHIBITOR TOXICITY

Monitoring for toxicity — All patients taking a tyrosine kinase inhibitor (TKI) are monitored for toxicity by history, physical examination, laboratory studies, and specialized evaluations, as needed.

●Clinical

•History should assess common early toxicities, including nausea, muscle cramps, rash, edema, fatigue, and diarrhea.

Other potential adverse effects (AEs), which vary with the specific TKI, include bleeding/bruising; chest pain, shortness of breath, palpitations, claudication, or other cardiovascular symptoms; cough or dyspnea that may suggest pleural effusion, pulmonary hypertension, or interstitial lung disease; jaundice, abdominal pain, persistent nausea/vomiting, bleeding, or other findings that suggest liver disease, pancreatitis, or gastrointestinal bleeding.

A complete list of medications should be reviewed for potential interactions with TKIs. For patients taking nilotinib or dasatinib, it is important to review medications that may prolong the QTc interval (table 5) or that can act as inhibitors or inducers of cytochrome P450 3A (table 6); cardiovascular risk factors should also be evaluated.

•Physical examination should focus on the following:

-Imatinib – Peripheral and periorbital edema and rash

-Nilotinib – Jaundice, hepatomegaly, and abdominal tenderness that may suggest liver disease or pancreatitis; pallor or reduced pulses of extremities, carotid bruit, cardiac dysrhythmia, and edema that may suggest cardiovascular disease

-Dasatinib – Chest auscultation and cardiac exam, bleeding/bruising, edema, cardiac dysrhythmia, fluid retention, tachypnea, and other findings consistent with cardiovascular disease or pleural effusion

-Bosutinib – Abdominal pain, jaundice, and other findings associated with liver disease

-Asciminib – Abdominal pain that may suggest pancreatitis, heart failure

●Laboratory

•Hematology – Complete blood count (CBC) with differential count every two weeks for the first two months of TKI therapy, monthly for the next six months, and then as needed.

•Chemistries – Kidney and liver function tests and uric acid every two weeks for the first two months, then as clinically indicated.

We also obtain:

-Potassium, phosphate, and magnesium for patients taking nilotinib and dasatinib.

-Lipase and amylase in the first several months of treatment for patients taking nilotinib, dasatinib, and bosutinib.

●Other testing – We do not suggest routine imaging or other studies, except as follows:

•ECGs to evaluate the QTc interval for patients taking nilotinib or dasatinib.

•Chest radiograph for patients with a cough or dyspnea who are taking dasatinib.

Management of toxicity — Management of toxicity is crucial for long-term adherence to a TKI regimen.

Most patients with CML require TKI therapy for the remainder of life, so maintaining treatment adherence requires effective management of both short-term and long-term toxicity. Persistent low-grade toxicities can adversely affect quality of life (QoL) and are barriers to long-term treatment adherence. Clinicians may underestimate the impact of grade 1 to 2 AEs, so the importance of reporting AEs should be emphasized at the initiation of TKI therapy and repeatedly during treatment.

Key principles — All TKIs are associated with common toxicities (eg, rash, nausea, fatigue, edema, fatigue, myalgias/arthralgias) in the first months of therapy, as discussed below. (See 'Common early toxicities' below.)

In addition, each TKI is associated with specific AEs, as discussed with the individual agent. (See 'Individual tyrosine kinase inhibitors' above.)

TKI-associated AEs typically:

●Arise in the first year of treatment, although some (eg, cardiovascular AEs with dasatinib or nilotinib) may not emerge for many months or years.

●Are mostly mild to moderate in intensity (ie, grade ≤2).

●Resolve spontaneously or can be controlled by dose adjustments.

We attempt to ameliorate AEs with symptomatic management, avoiding medications that may exacerbate the toxicity, and judiciously adjust the TKI dose or briefly interrupt treatment, if needed. However, dose reductions should be undertaken with careful monitoring of molecular response to avoid administering a subtherapeutic dose. Extended interruptions of TKI treatment should be avoided because they may affect disease outcomes.

Once a deep molecular response is achieved, it may be possible to reduce the dose or temporarily discontinue the TKI to ameliorate low-grade AEs and/or lessen long-term complications, while still maintaining the remission. In a multicenter study, remission was sustained after 12 months of half-dose TKI therapy (ie, imatinib 200 mg daily, dasatinib 50 mg daily, or nilotinib 200 mg twice daily) in 162 of 174 patients (93 percent) who had taken a TKI for ≥3 years and achieved at least major molecular response (MMR; ie, <0.1 percent BCR::ABL1 ratio) for ≥12 months [94]. The rate of recurrence was unrelated to the specific TKI or duration of TKI therapy but was lower in patients who entered the study with molecular response (MR) 4 (2 percent recurrence rate) than in those with MR 3 (19 percent); remission was regained within four months of full-dose therapy in all patients. Importantly, AEs (eg, lethargy, diarrhea, rash, nausea) improved during the three months of de-escalation but not thereafter.

For severe or intractable TKI-associated toxicity, switching to an alternative TKI is discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

TKI-associated AEs affect treatment adherence [95], and poor adherence to treatment may worsen clinical outcomes. A study that electronically monitored imatinib adherence in 87 patients with stable complete cytogenetic response reported that treatment adherence was an independent predictor of MMR; patients with ≥90 percent adherence had a significantly higher rate of MMR at six years (95 versus 28 percent), whereas no patient who took ≤80 percent of the prescribed dose attained an MMR [96].

TKI-associated AEs impair the QoL in patients with CML. A survey-based study of 448 patients with CML treated with imatinib for a median of five years reported that patients >60 years old had health-related QoL (HRQoL) scores similar to an age-matched general population, but younger patients reported significantly worse HRQoL than control patients [97]. Other studies reported that one-third to one-half of patients taking TKIs experienced symptoms that affected mood, general well-being, enjoyment of life, or interfered with daily functioning [98,99]. Randomized trials have reported no difference in QoL between patients taking imatinib and either nilotinib or dasatinib [100,101]. (See 'Nilotinib' above and 'Dasatinib' above.)

Common early toxicities — Nausea, muscle cramps, rash, and edema can occur with all TKIs in the first months of therapy, although some are more common or severe with particular TKIs (table 4). Most early toxicities can be managed with symptomatic care, avoidance of medications that may exacerbate the toxicity, and temporarily reducing or holding the TKI.

Common early AEs include:

●Nausea – Mild nausea is common with all TKIs but is generally most severe or persistent with imatinib and bosutinib; the incidence of nausea is decreased when these TKIs are taken with food (except nilotinib and asciminib, which should not be taken with food).

Antiemetics may be beneficial for persistent, severe TKI-associated nausea or vomiting. (See "Approach to the adult with nausea and vomiting", section on 'Treatment'.)

●Muscle cramps – All TKIs can cause muscle cramps, which most often affect calves, feet, and hands.

Mild cramps are most common with imatinib (approximately one-half of patients) but can be more severe (grade ≥3) in approximately 2 percent of patients [102]. There is no universally effective treatment for cramps, but electrolyte abnormalities should be corrected. Anecdotally, some patients benefit from calcium or magnesium supplements.

Other symptomatic management is described separately. (See "Nocturnal muscle cramps", section on 'Management'.)

●Rash – A mild, maculopapular rash occurs in up to one-half of patients treated with TKIs, which generally resolves with continued treatment [103-106]. Management of a more persistent or troublesome rash is described separately. (See "Exanthematous (maculopapular) drug eruption", section on 'Management'.)

●Edema – Fluid retention can typically be managed by symptomatic care (eg, leg elevation, judicious use of diuretics). Periorbital edema is common with imatinib and does not respond to diuretic therapy. Liver, kidney, and/or cardiac function should be evaluated for more severe fluid retention, pleuro-pericardial effusion, or ascites. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Initial testing'.)

●Diarrhea – Diarrhea is most common with imatinib and bosutinib but generally resolves within weeks. Treatment with antidiarrheal agents (eg, loperamide) or temporary dose reductions may be necessary to control diarrhea in some patients. It is important to question patients about possible lactose intolerance, which can exacerbate TKI-induced diarrhea.

●Fatigue – Fatigue is a common symptom associated with TKI therapy. There are no specific remedies for TKI-associated fatigue. Careful dose reductions when patients achieve a deep molecular response may be useful for lessening symptomatic fatigue. Other causes of fatigue (eg, hypothyroidism, sleep disturbance) should be considered as contributing factors.

Hematologic

●Cytopenias – Mild to moderate cytopenias are common early in the course of treatment with all TKIs [107].

Early, mild cytopenias are an "on-target" effect that reflects the mechanism of action, rather than an allergic or AE of TKIs [62]. At diagnosis, circulating blood cells are dominated by progeny of the Philadelphia chromosome-positive clone, which are effectively eliminated by the TKI. Early cytopenias appear to reflect the slow recovery of normal, Philadelphia chromosome-negative hematopoiesis; consequently, discontinuing or reducing the dose of the TKI may not solve the problem.

•For most patients, the TKI can be continued with the expectation of improvement in blood counts as normal hematopoiesis recovers.

•In a minority of patients, severe or symptomatic cytopenias (eg, infection, bleeding) may require a dose reduction or temporarily holding the TKI. This is usually followed by a gradual improvement in counts that permit restoration of the TKI dose, but occasionally, longer-term treatment with a lower dose of the TKI is needed to maintain adequate blood counts.

•Rarely, critical cytopenias develop:

-Neutropenia or thrombocytopenia – For persistent, severe neutropenia or thrombocytopenia, treatment with growth factors to stimulate recovery of normal hematopoiesis is safe and usually effective.

Myeloid growth factors can ameliorate severe neutropenia, but there is less experience with platelet-stimulating agents for severe thrombocytopenia. If hematopoietic growth factors are used to support normal hematopoiesis, an effort should be made to continue the TKI to prevent regrowth of the CML clone. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Granulocyte colony stimulating factors' and "Clinical applications of thrombopoietic growth factors".)

-Anemia – For persistent symptomatic anemia, we check the reticulocyte count, ferritin, iron saturation, vitamin B12, and folate and correct any nutritional deficiencies detected. Transfusion support may be used if the patient is symptomatic. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

We do not treat TKI-associated anemia in CML with erythropoiesis-stimulating agents (ESAs) because such treatment was associated with a higher rate of thrombosis in patients with CP CML and did not improve rates of survival or cytogenetic response [108]. The United States Centers for Medicare and Medicaid Services (CMS) and the US Food and Drug Administration do not support the use of ESAs in patients with CML. (See "Role of ESAs in adults with non-hematologic cancers".)

•Should critical cytopenias persist, a switch to a different TKI can be considered because count suppression can sometimes be less severe using an alternative TKI. Management with an alternative TKI is discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

●Other hematologic toxicities – Other TKI-associated toxicities include:

•Bleeding – Bleeding is generally caused by thrombocytopenia and should be managed as described above.

Gastrointestinal or other bleeding occurs in up to one-quarter of patients receiving dasatinib; it is less common with other TKIs [109-112]. Bleeding or bruising may be exacerbated by a qualitative platelet defect associated with dasatinib; such patients often have normal platelet counts and normal coagulation studies but impaired platelet aggregation with arachidonic acid and/or epinephrine [113]. The bleeding is typically mild to moderate and usually responds to a drug holiday. Dasatinib should be used with caution in patients who require anticoagulants or medications that inhibit platelet function [74].

•Follicular lymphoid hyperplasia – Reversible follicular lymphoid hyperplasia has been reported in patients taking a TKI, but the incidence is not well-defined. A case series reported nine patients who developed progressive cervical lymph node enlargement while taking dasatinib [114]. Lymph node biopsy demonstrated follicular lymphoid hyperplasia without evidence of extramedullary blastic transformation of CML. Discontinuation of dasatinib resulted in a complete disappearance of nodal enlargement in all patients by two months.

For patients who develop follicular lymphoid hyperplasia, we suggest holding the TKI and observing the patient for clinical improvement. A decision to again administer the same TKI after resolution should be made on a case-by-case basis.

Other toxicity

●Cardiovascular – There is a substantial risk of cardiovascular (CV) and arterial thrombotic AEs in patients taking nilotinib, a slight increase of CV risk with dasatinib, and considerably less risk with the other TKIs used for the initial treatment of CP CML. Older patients and those with pre-existing CV risk factors (eg, hypertension, diabetes, hyperlipidemia, smoking) are at greatest risk, irrespective of the TKI that is used, and the incidence ratio is highest in the early years of TKI therapy [115-117]. CV risks with individual TKIs are discussed above. (See 'Individual tyrosine kinase inhibitors' above.)

Because most patients with CML are long-term survivors, it is important to perform a thorough baseline evaluation for CV risk factors and regular assessment and management of CV risk factors, including hypertension, lipids, and advice about smoking cessation. (See 'Pretreatment evaluation' above and 'Monitoring for toxicity' above.)

Suggestions for management of specific CV AEs include:

•QTc prolongation and dysrhythmias – Cardiac dysrhythmias, including prolonged QTc interval and palpitations, are most common with dasatinib and nilotinib, but they can occur with any TKI. All patients who receive nilotinib or dasatinib should have a baseline ECG to measure pretreatment QTc interval, correction of electrolyte abnormalities, avoidance of other medications that may prolong QTc interval (table 5), and dose adjustment as needed. An ECG should be performed seven days after initiation of nilotinib or dasatinib, following dose adjustments, and periodically during treatment. (See 'Nilotinib' above and 'Dasatinib' above.)

•Arterial thrombotic events – Coronary artery disease, cerebrovascular accident, and peripheral artery disease are most common with nilotinib and less frequent with dasatinib. Nilotinib or dasatinib should be permanently discontinued for symptomatic or progressive vascular disease. Although a benefit is not proven, many clinicians offer low-dose aspirin for general CV prophylaxis in patients taking nilotinib or dasatinib. Acceptable alternatives include switching to imatinib or bosutinib or considering a trial of treatment-free remission (TFR), for appropriate patients.

•Hypertension – The incidence of hypertension is increased with all TKIs but is most common with imatinib. Management should follow general principles. (See "Overview of hypertension in adults", section on 'Treatment'.)

The CV and arterial thrombosis risks with the third-generation TKI, ponatinib, are discussed separately. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor", section on 'Ponatinib'.)

●Pulmonary – Pulmonary complications with dasatinib generally occur early, but they can occur later and with any TKI. Patients with dyspnea, dry cough, or other symptoms suggestive of pleural effusion or another pulmonary process should have a chest radiograph and other testing, as clinically warranted.

•Pleural effusion – In some studies, up to one-third of patients treated with dasatinib developed pleural effusions (most often exudative). Other causes of pleural effusion (eg, disease progression, heart failure, renal dysfunction, infection) should be investigated. Some patients have required thoracentesis, insertion of a chest tube, pleurodesis, and/or interruption or reduction of TKI dose. In a study that compared various dasatinib doses, treatment with 100 mg once daily was associated with a lower incidence of pleural effusion without affecting short- or long-term efficacy [118]. Dasatinib-associated pleural effusion is discussed in more detail separately. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Dasatinib'.)

•Pulmonary arterial hypertension – Rare cases of pulmonary arterial hypertension have been reported among patients taking dasatinib [119,120]. Dasatinib should be permanently discontinued in patients diagnosed with pulmonary arterial hypertension. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Dasatinib' and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

•Interstitial lung disease – Interstitial lung disease has been reported in patients receiving dasatinib. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Dasatinib'.)

Further description of pulmonary complications of TKIs is provided separately. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Bcr-Abl tyrosine kinase inhibitors'.)

●Gastrointestinal – Nausea, vomiting, and diarrhea are common early AEs with all TKIs but especially with imatinib and bosutinib. (See 'Common early toxicities' above.)

•Liver function – Abnormal liver function tests are most common with bosutinib and nilotinib. Alcohol and medications that may cause liver damage should be avoided, and dose adjustments should be made if needed. Additional details are provided separately. (See "Hepatotoxicity of molecularly targeted agents for cancer therapy", section on 'Specific agents'.)

•Pancreatitis – Lipase and amylase should be obtained monthly (or as clinically indicated) for the first months in patients taking nilotinib. (See 'Monitoring for toxicity' above.)

For clinically significant symptoms or abnormal lipase/amylase, the TKI dose should be reduced or suspended until improvement; if symptoms or laboratory abnormalities do not improve, the patient should be treated with an alternative TKI. (See "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

•Gastrointestinal bleeding – Management of gastrointestinal bleeding due to thrombocytopenia or a qualitative platelet disorder is described above. (See 'Hematologic' above.)

●Other toxicities

•Hypophosphatemia – Hypophosphatemia has been reported in patients taking nilotinib or larger doses of imatinib [49,121,122]. It is unknown whether hypophosphatemia results in long-term metabolic changes in bone. One report noted increased trabecular bone volume in patients receiving long-term imatinib, which may be due to the promotion of osteoblast maturation and/or inhibition of osteoclast maturation and function via inhibition of platelet-derived growth factor [123].

•Gynecomastia – In one series, gynecomastia was noted in 7 of 38 males receiving imatinib and was associated with reduced levels of free testosterone [124].

•Cancer – TKIs do not appear to be associated with an increased risk of second malignancy. Analysis of 1445 patients treated with a TKI for CML or other hematologic malignancy and followed for a median of 107 months reported rates of second cancers comparable to those in the Surveillance, Epidemiology, and End Results (SEER) database [125].

SPECIAL SETTINGS

Additional chromosomal abnormalities — Detection of additional cytogenetic abnormalities (ACAs; ie, cytogenetic abnormalities in addition to t(9;22)) at diagnosis may affect response to initial treatment and influence the protocol for response monitoring. The impact of ACAs may vary with the nature of the abnormality and whether it is detected in the same cells that carry the Philadelphia chromosome (Ph) versus a separate clonal population.

ACAs are reported in 5 to 10 percent of patients at the time of diagnosis of CP CML [126]. However, the prognostic significance of ACAs at diagnosis of CP CML is uncertain, perhaps related to the specific cytogenetic abnormality [127-131]. It has been proposed that the more common abnormalities ("major route abnormalities") can be classified as a good prognosis (eg, trisomy 8, -Y, extra copy of Philadelphia chromosome) or poor prognosis (eg, i(17)(q10), -7/del7q, 3q26.2) [132]. ACAs are known to be associated with adverse outcomes for patients with CP CML who were previously treated with interferon (IFN) alfa and other agents and for patients with CML in accelerated phase or blast phase [127].

Monitoring of the response to therapy is influenced by whether the ACA is present in the same cell as t(9;22)/BCR::ABL1 (ie, Philadelphia chromosome-positive) or in Philadelphia chromosome-negative cells; metaphase cells from the initial marrow aspirate are needed to make this distinction (see 'Pretreatment evaluation' above):

●ACA in Philadelphia chromosome-positive cells – If the ACA is present in the same cell as t(9;22)/BCR::ABL1, cases can be monitored with quantitative polymerase chain reaction (qPCR) on the blood (as described above) because the ACA will disappear as the Philadelphia chromosome-positive cells disappear. (See 'Response monitoring' above.)

●ACA in Philadelphia chromosome-negative cells – If the ACA is present in Philadelphia chromosome-negative cells, monitoring of the ACA clone will require serial bone marrow evaluations or monitoring of peripheral blood with a fluorescence in situ hybridization (FISH) probe that can detect the specific abnormality. In addition, the response of CML to initial therapy must be monitored by qPCR.

Pregnancy — Tyrosine kinase inhibitors (TKIs) are contraindicated in females who seek to become pregnant and in the first trimester of pregnancy because of increased rates of miscarriage and fetal abnormalities [133,134]. The safety of TKIs in the second and third trimesters is not well-defined. TKIs are not known to affect fertility in males or increase the rate of miscarriage or fetal abnormalities in female partners of males taking a TKI [135-139].

Conception while on a TKI and treatment with a TKI during the first trimester is strongly discouraged because of the risk of fetal abnormalities; otherwise, there is no consensus regarding optimal monitoring and management of CML during pregnancy [140,141]. We monitor BCR::ABL1 by qPCR monthly and initiate treatment if BCR::ABL1 increases to ≥1 percent. (See 'Definitions of response' above.)

Our approach follows:

●First trimester – For females who require treatment in the first trimester, we suggest leukapheresis and/or IFN alfa rather than TKI therapy because of their more favorable balance of benefit versus toxicity. IFN alfa is safe during pregnancy; some experts consider hydroxyurea safe in this setting [140,142-147]. Low-dose aspirin and/or low molecular-weight heparin may be used for thrombocytosis [148,149].

●Later pregnancy – In the second or third trimester, the potential benefit of a TKI to the mother must be weighed against risks to the fetus; IFN alfa, leukapheresis, or other approaches may be preferable in this setting.

●Nursing – Females should not breastfeed while taking a TKI because it can pass into human breast milk and may impair the growth and/or development of the infant [150,151].

●Males – We do not discontinue TKIs for male patients attempting conception. Our approach is consistent with European LeukemiaNet 2020 guidelines and opinions of other experts [6,152,153].

More than one-third of patients were of reproductive age at the time that CML was first diagnosed, according to a population-based registry study [154]. A study of 180 females exposed to imatinib during pregnancy reported that one-half of pregnancies with known outcomes were normal, but 10 percent had fetal abnormalities that ended in spontaneous abortion [133]. Among 46 females who received dasatinib during pregnancy, one-third delivered a normal infant, but elective or spontaneous abortion occurred in 39 and 17 percent, respectively, 11 percent had an abnormal pregnancy, and there were fetal abnormalities in 15 percent [134].

Among males, some clinical studies have suggested reduced spermatogenesis with TKIs, but there are multiple reports of successful pregnancy and no increased risk for congenital abnormalities among offspring from partners of male patients receiving TKIs [45,134,155-160]. As an example, among 17 males treated with bosutinib, the outcome of 14 pregnancies was known; nine patients had full-term, healthy babies, four had an induced abortion, and one had a spontaneous abortion [155]. Among males treated with dasatinib, 91 percent of 30 female partners delivered infants who were normal at birth [134].

Children — CML is rare in children, and it accounts for <3 percent of all pediatric leukemias [161-163]. We urge participation in a clinical trial, whenever possible.

There are no evidence-based guidelines for pediatric CML, and risk stratification tools that are used for the treatment of adults have not been validated in children. Outside of a clinical trial, some experts follow guidelines designed for the treatment of adult patients.

Imatinib, bosutinib, nilotinib, and dasatinib are approved by the US Food and Drug Administration (FDA) for the treatment of children. Safety and efficacy of other TKIs in children are poorly defined. CML risk scores have not been validated in children and should not be used to stratify treatment. A study that evaluated 90 children with CML reported high discordance between the Sokal, Euro, and EUTOS methods [164].

Children may require decades of treatment, and it is important to monitor children for long-term adverse effects (AEs), such as delayed growth, altered bone metabolism, thyroid abnormalities, and effects on puberty and fertility [165]. Growth should be monitored closely, and an endocrinologist should be consulted for impaired longitudinal growth in children [166-170].

Studies of TKIs for treatment of pediatric CML include:

●Imatinib – A French study included 44 children (aged 10 months to 17 years) with CP CML who were treated with imatinib (260 mg/m²) [171]. With median follow-up of 31 months, the rate of complete hematologic response (CHR) was 98 percent, and estimated progression-free survival (PFS) at 36 months was 98 percent. After 12 months, rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were 61 and 31 percent, respectively. Early molecular response (ie, BCR::ABL1 10 percent [International Scale (IS)] at three months) correlated with better PFS and higher rates of CCyR and MMR at 12 months [172].

An Italian study of 47 children with CP CML reported that higher-dose imatinib (340 mg/m²) was effective and well-tolerated [173,174]. CCyR was achieved in 92 percent at 6 months, and at 12 months MMR (≤0.01 percent BCR::ABL1 IS) and molecular response 4 were achieved in 67 and 33 percent of patients, respectively.

●Dasatinib – Dasatinib (60 mg/m² to 120 mg/m²) was tolerated in a study of children with newly diagnosed, relapsed, or refractory CML [175].

There are no reports of TKI discontinuation in children.

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)")

SUMMARY AND RECOMMENDATIONS

●Description – Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm associated with t(9;22)(q34;q11) and BCR::ABL1, which produces a constitutively active BCR::ABL1 tyrosine kinase that is sensitive to BCR::ABL1 tyrosine kinase inhibitors (TKIs).

Chronic phase (CP) CML can progress from an indolent disorder to accelerated phase (AP) or blast phase (BP).

●Pretreatment evaluation – Includes clinical evaluation, laboratory studies, and bone marrow examination. (See 'Clinical and laboratory' above.)

●CML risk score – CML risk category (eg, Sokal, Euro, EUTOS, or ELTS [EUTOS long-term survival] score) (table 2) informs treatment selection. (See 'CML risk score' above.)

●Goals – Achieving remission, maintaining long-term disease control, and avoiding progression to AP/BP, while limiting treatment-related toxicity are goals for all patients with CP CML. For selected patients, treatment-free remission (TFR) is a goal. (See 'Goals of care' above.)

●Initial therapy – We recommend initial treatment of CP CML with a TKI, rather than cytotoxic agents, interferons, or hematopoietic cell transplantation (Grade 1A). (See 'Initial therapy' above.)

●TKI selection – Guided by CML risk score, toxicity (table 4), comorbidities, availability, cost, and patient preference (algorithm 1):

•High-risk CML – We suggest a second-generation (2G) TKI (eg, nilotinib, dasatinib, bosutinib), rather than imatinib, asciminib, or ponatinib (Grade 2C). (See 'High-risk CML' above.)

If a suitable 2G TKI is not available, asciminib or imatinib is acceptable.

•Low- or intermediate-risk CML – TKI choice is influenced by the importance assigned to achieving TFR (algorithm 1):

-If TFR is a goal – When TFR is a goal, we suggest a 2G TKI rather than imatinib, asciminib, or ponatinib (Grade 2C). Eligibility, monitoring, and outcomes of TFR trials are described above. (See 'If treatment-free remission is an important goal' above.)

If a suitable 2G TKI is not available, asciminib or imatinib is acceptable.

-If TFR is not important – When TFR is not a high priority, treatment with imatinib, a 2G TKI, or asciminib is acceptable, with the choice guided by toxicity and comorbidities. (See 'When treatment-free remission is not an important goal' above.)

●Dose, toxicities, and outcomes – Initial dose, toxicities, and outcomes with individual TKIs are presented above. (See 'Individual tyrosine kinase inhibitors' above.)

●Monitoring – Monitor response with serial measurement of BCR::ABL1 by quantitative polymerase chain reaction (qPCR) in peripheral blood, cytogenetics, and hematologic parameters (algorithm 3). (See 'Response monitoring' above.)

●Toxicity – Managing TKI toxicity is crucial for treatment adherence and achieving optimal outcomes. Monitoring and managing toxicity are described above. (See 'Tyrosine kinase inhibitor toxicity' above.)

Early cytopenias, rash, nausea, fatigue, and/or muscle cramps are common with all TKIs, but each agent also has "defining" adverse effects:

•Imatinib – Muscle cramps, fatigue, edema, nausea, diarrhea

•Nilotinib – Cardiovascular (CV; eg, coronary, cerebral, and peripheral vascular) toxicity, prolonged QTc interval, hyperglycemia, pancreatitis

•Dasatinib – Pleural effusion, pulmonary hypertension, prolonged QTc interval, platelet dysfunction

•Bosutinib – Diarrhea, abnormal liver function, rash

•Asciminib – CV toxicity, pancreatitis, hypertension, hypersensitivity

●Pregnancy – TKIs are contraindicated in female patients who seek to become pregnant, in early pregnancy, and while nursing. There are no restrictions for male patients who wish to father a child while on TKI therapy. Management of CML in pregnancy is discussed above. (See 'Pregnancy' above.)