Accelerated phase chronic myeloid leukemia: Diagnosis and treatment

INTRODUCTION — 

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm associated with the Philadelphia chromosome, t(9;22)(q34;q11). This chromosomal rearrangement creates the BCR::ABL1 fusion gene, which encodes BCR::ABL1, a constitutively active tyrosine kinase. Up to 90 percent of patients with CML present with chronic phase (CP) CML, a relatively indolent disorder that responds well to treatment with a BCR::ABL1 tyrosine kinase inhibitor (TKI). Others present with more advanced stages: accelerated phase (AP) or blast phase (BP).

AP CML is distinguished from CP and BP CML by the percentage of myeloblasts, percentage of basophils, additional chromosomal abnormalities, and other clinicopathologic features.

Some patients initially present with AP CML (de novo AP CML), while others progress to AP while receiving a TKI (transformed AP). The distinction between de novo AP CML and transformed AP CML affects treatment decisions and prognosis.

This topic discusses the diagnosis and management of AP CML.

Treatment of CP CML, blast crisis CML, and use of hematopoietic cell transplantation for CML are discussed separately.

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

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

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

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

PRETREATMENT EVALUATION — 

Pretreatment evaluation of a patient with CML should include history and physical examination, performance status (table 1), and laboratory and clinical studies that distinguish AP CML from chronic phase (CP) and blast phase (BP) CML.

Patients with transformed AP CML (ie, AP CML that arose while undergoing treatment for CP CML) must also have molecular analysis for BCR::ABL1 mutations. (See 'Mutation testing' below.)

Initial evaluation, diagnosis, and differential diagnosis of CML are discussed separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Pretreatment evaluation'.)

Clinical and laboratory

●History – History should include:

•B symptoms (ie, unexplained fevers, drenching sweats, weight loss), anorexia, abdominal pain/fullness, bone pain

•Comorbid conditions (eg, cardiac dysrhythmias, heart failure, pancreatitis, liver disease, diabetes mellitus)

•Adherence to and tolerance for BCR::ABL1 tyrosine kinase inhibitor (TKI), if used previously

●Physical examination – Note splenomegaly, hepatomegaly, and stigmata of bleeding/bruising

●Performance status (table 1)

●Laboratory

•Complete blood count (CBC) with differential count

•Serum chemistries, including electrolytes, glucose, kidney function tests, and liver function tests

•Hepatitis B serology

●Clinical tests

•Electrocardiogram (EKG)

•Chest radiograph

●Molecular testing – Quantitative reverse transcription polymerase chain reaction (qRT-PCR) for BCR::ABL1 in blood or bone marrow, to establish a baseline for subsequent response monitoring.

●Bone marrow examination

•Morphology – Including the percentage of blasts, promyelocytes, and basophils; diagnostic criteria for distinguishing AP CML from CP and BP CML are described below. (See 'Diagnosis' below.)

•Karyotype – Giemsa-stained chromosome banding analysis (CBA) to confirm the presence of t(9;22) (q34;q11)/Philadelphia chromosome (Ph) and identify additional chromosomal abnormalities (ACAs) in Ph-positive cells.

Fluorescence in situ hybridization (FISH) is not an adequate substitute for CBA because it will not detect ACAs, but FISH should be performed if Ph is not detected by CBA.

Mutation testing — BCR::ABL1 kinase domain mutations inform the choice of a TKI, as described below. (See 'Mutation-guided' below.)

Mutation testing is not required for patients who present with de novo AP CML.

Transplant eligibility — For patients who may require allogeneic hematopoietic cell transplantation, it is important to determine eligibility and initiate a donor search. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

All patients with transformed AP CML (except those who are frail) should be referred promptly for evaluation.

For patients with de novo AP CML, many experts await the response to initial therapy before referring them for evaluation. (See 'de novo versus transformed AP' below.)

DIAGNOSIS — 

AP CML should be considered in patients whose CML progresses while receiving a tyrosine kinase inhibitor (TKI) for chronic phase (CP) CML, or in patients newly presenting with circulating immature myeloid cells, basophilia, splenomegaly, or constitutional symptoms.

Diagnosis of CML requires documentation of the Philadelphia (Ph) chromosome and/or BCR::ABL1, but classification of the stage of CML differs among contemporary systems. We favor the International Consensus Classification (ICC) [1]:

The ICC criteria for AP CML are:

●Blasts ≥20 percent in blood or marrow

●Basophils in blood ≥20 percent

●Persistent thrombocytopenia <100 x 10⁹/L, unrelated to therapy

●Major route clonal chromosome abnormalities (CCA) in Ph-positive cells: second Ph chromosome, trisomy 8, isochromosome 17q, trisomy 19, complex karyotype, or abnormalities of 3q26.2

Some clinicians and hematopathologists favor the European LeukemiaNet (ELN) or the World Health Organization 5^th edition (WHO5) classification systems for CML:

●ELN criteria are like those of the ICC, except the blast criterion differs: blasts 15 to 29 percent or blasts plus promyelocytes >30 percent in blood or marrow with blasts <30 percent [2].

●WHO5 eliminated AP CML as a distinct category; instead, it simply distinguishes CP from blast phase CML [3].

The diagnosis and classification of CML are discussed in greater detail separately. (See "Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis".)

MANAGEMENT — 

Our approach to CML management is consistent with guidelines from the European LeukemiaNet [2] and the United States National Comprehensive Cancer Network [4].

de novo versus transformed AP — We distinguish between de novo AP CML and transformed AP CML because this influences management and prognosis.

●de novo AP CML – This refers to patients who present with AP CML and have not previously received a tyrosine kinase inhibitor (TKI; ie, treatment-naïve). Management of de novo AP CML is described below. (See 'Treatment of de novo AP CML' below.)

●Transformed AP CML – AP that arises while being treated with a TKI for chronic phase (CP) CML is described as transformed AP CML. Transformed AP CML generally has a less favorable prognosis than de novo AP CML, and it often arises in association with the acquisition of a BCR::ABL1 kinase domain (KD) mutation.

For patients with transformed AP CML, it is important to assess adherence with the prior TKI regimen, as poor adherence is a possible cause of disease progression. It is important to ask about adherence to the TKI dose and schedule and use of other medications or herbal supplements that may impair the metabolism of the TKI.

Management of transformed AP CML is described below. (See 'Treatment of transformed AP CML' below.)

Treatment of de novo AP CML — For patients who present with de novo AP CML, we suggest initial treatment with a second-generation (2G) TKI (ie, dasatinib, nilotinib, bosutinib), rather than other TKIs or allogeneic hematopoietic cell transplantation (HCT).

The 2G TKIs are generally well tolerated and efficacious for de novo AP CML. By comparison, ponatinib is considerably more toxic, responses to imatinib are generally slower, there is limited long-term experience with asciminib, and allogeneic HCT is associated with substantial toxicity and possible treatment-related mortality (TRM).

●Selection of a TKI – The choice of a 2G TKI is based on the TKI toxicity profile (table 2) and the individual's comorbidities. Adverse effects (AEs) of 2G TKIs are generally modest but differ among individual TKIs. (See 'Second-generation tyrosine kinase inhibitors' below.)

If testing for BCR::ABL1 KD mutation was performed, the choice of TKI is guided by the mutation profile (table 3), toxicity profile (table 2), and comorbidities.

●Response monitoring – Hematologic, cytogenetic, and molecular responses (table 4) are monitored, as discussed below. (See 'Response monitoring' below.)

•Adequate responses – The TKI is continued indefinitely in patients who meet and sustain response milestones.

We do not pursue a trial of TKI discontinuation for patients with AP CML, even for those with a robust and prolonged molecular response, because there are insufficient data in patients with AP CML to justify such a trial.

•Inadequate responses – Patients who do not meet treatment milestones should be assessed for treatment adherence. Mutation testing should be performed, whether previously done, and fitness for allogeneic HCT should be assessed promptly.

Management of an inadequate response is like that for transformed AP CML, as discussed below. (See 'Treatment of transformed AP CML' below.)

●Outcomes – No prospective studies have directly compared a TKI versus early allogeneic HCT in patients with de novo AP CML.

A single-center study reported that treatment with dasatinib or nilotinib was associated with 90 percent complete cytogenetic response (CCyR) among 21 patients with de novo AP CML [5]. In studies that included both de novo and transformed AP CML, treatment with a 2G TKI was associated with two- to four-year survival in approximately two-thirds of patients [6-8]; however, outcomes with de novo AP CML are probably more favorable than outcomes of the transformed AP CML in these studies.

Treatment of transformed AP CML — Treatment for transformed AP CML is guided by the patient's suitability for allogeneic HCT (algorithm 1), which depends on age, medical fitness, and an available donor, as discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)

Transplant-eligible — For transplant-eligible patients with transformed AP CML, we suggest treatment with a suitable TKI followed by allogeneic HCT, rather than a TKI alone.

The choice of approach is individualized according to medical fitness, age, and patient preference. For transformed AP CML, the possibility of long-term disease control and cure with allogeneic HCT generally outweighs the AEs and risk of TRM. By contrast, 2G TKIs or ponatinib have less potential for long-term disease control. Nevertheless, some patients who have an excellent response to a TKI may choose to continue the TKI alone because they place greater weight on the avoidance of transplant-related toxicity than on the potential benefits of allogeneic HCT.

●Prior to transplantation – During the search for a transplant donor, a TKI is selected based on BCR::ABL1 KD mutation status (table 3), TKI toxicity (table 2), comorbidities, and prior TKI exposure. Mutation testing is particularly important for transformed AP CML because disease progression usually reflects resistance to the prior TKI. (See 'Tyrosine kinase inhibitor selection' below.)

We generally proceed to allogeneic HCT as soon as the disease can be brought under control with a TKI. Treatment with a TKI does not compromise transplant outcomes or increase transplant-related toxicity [9-15].

●Outcomes – Outcomes with allogeneic HCT for AP CML vary because of different eligibility criteria and the small number of patients in most studies.

•Analysis of 168 patients with AP CML in a registry study reported no difference in overall survival (OS) between allogeneic HCT and treatment with a TKI alone [16]. However, conclusions are limited by the inclusion of both de novo and transformed AP CML and differences in definitions of AP, choices of TKI, and patient populations.

•A multicenter study of transplantation in 28 patients with advanced phase CML (ie, both AP CML and blast phase [BP] CML) reported 59 percent three-year OS [17]. A single-center study reported 45 percent long-term survival after allogeneic HCT for 40 patients with advanced phase CML [18]. A registry study reported 37 percent five-year OS among 14 patients with advanced phase CML; nonrelapse mortality was 12 percent, but this included patients with AP CML and CP CML [19].

Not transplant-eligible — For patients with transformed AP CML who are not candidates for allogeneic HCT (eg, not medically fit, no suitable donor, or the patient declines), we select a TKI according to BCR::ABL1 mutation analysis, TKI toxicity profile (table 2), comorbidities, and prior TKI exposure, as described below. (See 'Tyrosine kinase inhibitor selection' below.)

TYROSINE KINASE INHIBITOR SELECTION — 

The following should be considered when selecting a BCR::ABL1 tyrosine kinase inhibitor (TKI) for AP CML:

●Mutation status – BCR::ABL1 kinase domain (KD) mutation testing should be performed on all patients with transformed AP CML. We do not routinely perform mutation testing in patients who present with de novo AP CML.

The selection of a TKI based on mutation status is discussed below. (See 'Mutation-guided' below.)

●Adverse effects – Each TKI is associated with characteristic adverse effects (AEs) (table 2). The selection of a TKI based on toxicity profile is discussed below. (See 'Toxicity-guided' below.)

●Comorbid conditions – A history of heart disease, lung conditions, diabetes, pancreatitis, and other comorbid illnesses should be considered when choosing a TKI. (See 'Toxicity-guided' below.)

●Prior TKI – Selection of a TKI depends in part on prior therapy, as discussed below. (See 'Prior tyrosine kinase inhibitor(s)' below.)

Mutation-guided — It is essential to consider BCR::ABL1 KD mutations (table 3) when choosing a TKI for AP CML:

●T315I mutation – For the T315I mutation, we suggest either ponatinib or asciminib rather than other TKIs. The choice of ponatinib versus asciminib is guided by the TKI toxicity profile and comorbidities.

We simultaneously evaluate eligibility for allogeneic hematopoietic cell transplantation (HCT) and initiate a donor search in case the TKI response is inadequate or not sustained. For transplant-eligible patients with an inadequate or unsustained response to ponatinib or asciminib, we proceed promptly to allogeneic HCT.

●Other KD mutations – For KD mutations other than T315I, we select a TKI based on the expected resistance patterns of various KD mutations (table 3), toxicity (table 2), and comorbidities.

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

●No KD mutation – The choice of TKI in patients with no KD mutation is influenced by the toxicity profile (table 2), comorbidities, and prior TKIs. (See 'Prior tyrosine kinase inhibitor(s)' below.)

Comorbidity-guided — Certain comorbid conditions (table 2) influence the choice of a TKI:

●Cardiovascular disease – We favor dasatinib or bosutinib (and avoid nilotinib) for patients with arrhythmias; cardiovascular, cerebrovascular, or peripheral arterial disease; or hyperglycemia.

●Diabetes mellitus – We favor dasatinib or bosutinib (and avoid nilotinib) for patients with arrhythmias, coronary artery disease, or hyperglycemia.

●Pancreatitis – We favor dasatinib (and avoid nilotinib and bosutinib) for patients with pancreatitis.

●Lung diseases – We favor nilotinib or bosutinib (and avoid dasatinib) for patients with lung disease or who are at risk for pleural effusion.

Toxicity-guided

●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 the correction of electrolyte imbalances and discontinuation of other medications that might affect the QTc interval.

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

Prior tyrosine kinase inhibitor(s) — The selection of a TKI is influenced by prior TKI therapy. Progression to AP CML while taking a TKI, by definition, indicates resistance to that agent (assuming the patient adhered to the TKI and was not taking drugs or other substances that would interfere with its activity).

●Prior imatinib – We consider a 2G TKI (dasatinib, nilotinib, bosutinib) or asciminib acceptable, with the choice guided by mutation status (table 3), toxicity (table 2), and comorbidities.

●Prior 2G TKI or asciminib – The choice of a TKI is guided by mutation status (table 3), toxicity (table 2), comorbidities, and prior TKI(s).

INDIVIDUAL TYROSINE KINASE INHIBITORS

Second-generation tyrosine kinase inhibitors — Each second-generation (2G) tyrosine kinase inhibitor (TKI) is associated with characteristic adverse effects (AEs), some of which may not be manifest for months or years.

All TKIs are also associated with certain common AEs (eg, cytopenias, rash, nausea, muscle cramps, edema, diarrhea, fatigue) early in treatment, but most of the early AEs are modest and self-limited. The management of early AEs is discussed separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Management of toxicity'.)

Dasatinib — Dasatinib should be avoided in patients with lung disease or who are at risk for pleural effusion. Treatment with dasatinib is associated with cytopenias, pleural effusion/fluid retention, QTc prolongation, and bleeding (table 2).

●Administration – For AP CML, dasatinib should be taken 140 mg once daily, with or without a meal; note that the recommended dose for AP CML differs from that in chronic phase (CP) CML. Patients should be screened by electrocardiogram (EKG) for QTc interval at baseline, and hypokalemia or hypomagnesemia should be corrected before dasatinib administration.

Caution is advised in patients who require anticoagulants, drugs that inhibit platelet function, antiarrhythmic agents, and medications or supplements that may prolong QTc (table 5), as described separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Dasatinib'.)

●AEs – Most AEs are mild, but patients may experience QTc prolongation, fluid retention (grade ≥3 in 4 percent), exacerbation of heart failure, pleural effusions, or bleeding from platelet dysfunction (table 2). Severe central nervous system (CNS) and gastrointestinal hemorrhages have been reported in approximately 1 and 4 percent of patients, respectively; most cases were associated with severe thrombocytopenia, anticoagulants, and/or inhibitors of platelet function.

●Outcomes – In a trial that randomly assigned 317 patients with AP CML to dasatinib 140 mg once daily versus dasatinib 70 mg twice daily, response rates were comparable in both arms, but there was less toxicity with the single daily dose (ie, 20 versus 39 percent pleural effusions); most patients probably had transformed AP CML because resistance or intolerance to imatinib was a study entry criterion [6]. With median follow-up of 15 months, the rates of complete hematologic response (CHR), major cytogenetic response (MCyR), and complete cytogenetic response (CCyR) were 50, 41, and 32 percent, respectively.

Treatment with dasatinib (70 mg twice daily) in 174 patients with AP CML (resistant or intolerant to imatinib) was associated with 64 percent major hematologic response (MHR), 45 percent CHR, and 32 percent CCyR after a 14-month follow-up [20,21].

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labels recommend dasatinib 140 mg daily for AP CML.

Nilotinib — Nilotinib is a 2G TKI, and it is the only TKI that must be taken twice daily. Nilotinib is associated with cytopenias, hepatotoxicity, QTc prolongation, pancreatitis, and long-term cardiovascular (CV) complications, and it should be avoided in patients with heart disease or diabetes mellitus (table 2).

●Administration – 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.

Dosing of nilotinib for AP CML follows:

•Tablet – Nilotinib tablets taken 190 mg twice daily (approximately 12 hours apart) with no restriction related to food.

•Capsule – Nilotinib capsules taken 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'.)

Prior to initiating nilotinib treatment, serum lipase and amylase should be tested, baseline QTc interval measured, potassium and magnesium levels corrected, and other medications that may prolong QTc avoided.

●AEs – Treatment with nilotinib has been associated with reversible and usually asymptomatic elevations in unconjugated bilirubin, lipase, and amylase. Most AEs are mild and self-limited, but pancreatitis and a low incidence of sudden deaths (possibly due to dysrhythmias) have been reported. Later effects include occlusive cardiac, cerebral, and peripheral artery disease; liver disease; and hyperglycemia.

●Outcomes – Treatment of 119 patients with AP CML with nilotinib (400 mg twice daily; escalated to 600 mg twice daily for inadequate response) was associated with 79 percent one-year overall survival (OS), 47 percent hematologic response (26 percent CHR), and 29 percent MCyR (16 percent CCyR) [22]. Grade ≥3 AEs included thrombocytopenia (35 percent), neutropenia (21 percent), and increased lipase (18 percent). With longer follow-up, 66 percent of patients who achieved MCyR sustained that response at 24 months [7]. Another study of 46 patients with imatinib-resistant AP CML reported similar rates of hematologic and cytogenetic response (33 and 22 percent, respectively) [23].

The FDA and the EMA approved nilotinib for AP CML.

Bosutinib — Bosutinib should be avoided in patients with liver or kidney dysfunction, diarrhea, and heart failure. Treatment is associated with cytopenias, diarrhea, abnormal liver function, and fluid retention.

●Administration – Bosutinib 500 mg once daily; note that the recommended dose for AP CML differs from that in CP CML.

●AEs – Treatment is associated with diarrhea, nausea, and abdominal pain; the most common grade ≥3 AEs are diarrhea and abnormal liver function tests; there is a low incidence of cardiac and vascular AEs with bosutinib treatment with ≥4-year follow-up [24].

●Outcomes – In one report, 57 percent of 14 patients with AP CML attained or maintained baseline overall hematologic response, and 40 percent attained or maintained MCyR [8].

The FDA and the EMA recommend bosutinib 500 mg once daily for AP CML.

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 kinase domain (KD) mutations, including T315I.

●Administration – Asciminib 80 mg is taken once daily (or 40 mg twice daily at approximately 12-hour intervals). Food 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, CV toxicity, and hypersensitivity.

●Outcomes – There are limited studies of asciminib for AP CML. Studies of asciminib for CP CML are discussed separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment" and "Treatment of chronic phase chronic myeloid leukemia after failure of the initial tyrosine kinase inhibitor".)

Asciminib was associated with CHR in 7 of 8 patients with AP CML and with CCyR and major molecular response (MMR) in 1 of 6 patients [25]. Asciminib was active in patients who had resistance to or unacceptable AEs from TKIs, including patients with T315I in whom ponatinib had failed. AEs were primarily asymptomatic elevations in lipase or amylase and grade <3 rash, fatigue, nausea, headache, or arthralgias.

Ponatinib — Ponatinib is associated with significant CV risks and complications, but it is effective against the BCR::ABL1 T315I mutation.

●Administration – Ponatinib 45 mg should be taken once daily, with or without food. We do not reduce the ponatinib dose in patients with AP CML because it is uncertain if this will compromise response and/or reduce AEs. However, some experts reduce ponatinib to 30 mg for AP CML for BCR::ABL1 <1 percent [26]. Many clinicians co-administer aspirin to mitigate CV complications of ponatinib, but this has not been proven to be beneficial.

●AEs – Treatment with ponatinib is associated with CV AEs in more than one-fifth of patients, and arterial thrombosis in 8 percent of patients, and liver toxicity/failure is possible [27].

●Outcomes – A phase 2 study (PACE) reported outcomes with ponatinib in 83 patients with AP CML (resistant or intolerant to dasatinib or nilotinib), including patients with BCR::ABL1 T315I mutations [28]. At five years, progression-free survival and OS were 22 and 49 percent, respectively. Other outcomes included MHR (61 percent), MCyR (49 percent), CCyR (31 percent), and MMR (22 percent). In the PACE study, grade ≥3 thrombocytopenia, neutropenia, and anemia occurred in 44, 37, and 22 percent, respectively. The most common nonhematologic toxicities were abdominal pain (42 percent), rash (38 percent), constipation (29 percent), dry skin (32 percent), and fatigue (38 percent) [28]. CV, cerebrovascular, and peripheral vascular events occurred in 7, 4, and 5 percent, respectively; most of these patients had at least one other risk factor (eg, hypertension, diabetes, hypercholesterolemia, obesity). Of the patients who continued ponatinib after a vascular event, 36 percent had subsequent events. Overall, severe AEs led to the discontinuation of therapy in 11 percent of patients; two patients died, including one death that was thought to be related to ponatinib (fungal pneumonia).

Ponatinib is approved for the treatment of AP CML in which no other TKIs are indicated, and for patients with BCR::ABL1 T315I mutation by the FDA and the EMA.

RESPONSE MONITORING — 

Response to a tyrosine kinase inhibitor (TKI) is evaluated by the timely achievement of hematologic, cytogenetic, and molecular milestones (table 4) [4]. Response is assessed by serial measurement in peripheral blood of BCR::ABL1 by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The qRT-PCR assay should be standardized and have a sensitivity of ≥4.5-log reduction from the baseline.

Optimal responses are:

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

●Six months: BCR::ABL1 IS ≤1 percent and/or 0 percent Ph-positive cells.

●Twelve 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 3-log molecular response, this should be confirmed by repeating qRT-PCR in one to three months. Further details and definitions of hematologic, cytogenetic, and molecular milestones are presented separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'Response monitoring'.)

Patients whose response constitutes a Warning (table 4) require close monitoring. Therapy should continue if subsequent testing reveals an optimal response, while those who do not achieve an optimal response (ie, persistent Warning or Failure) are managed like blast phase CML, as discussed separately with a change of TKI and possible transplantation. (See "Chronic myeloid leukemia-blast phase: Diagnosis and treatment".)

PROGNOSTIC FACTORS — 

Features that have been associated with outcomes in patients with AP CML include:

●de novo versus transformed AP CML – The distinction between de novo and transformed AP CML has prognostic importance, but it also guides the approach to initial treatment. (See 'Treatment of de novo AP CML' above and 'Treatment of transformed AP CML' above.)

●Major route additional chromosomal abnormalities (ACAs) versus minor route ACAs – Major route ACAs (ie, second Philadelphia chromosome, trisomy 8, isochromosome 17q, trisomy 19) are associated with an adverse impact on survival [29-31]. The impact of minor route ACAs is currently less well defined, but some caution is warranted with some of these ACAs [32,33].

●Increased blasts – AP CML that was diagnosed because of increased blasts is associated with a worse prognosis than AP CML that was diagnosed on the basis of other criteria (eg, basophils, ACAs) [34,35].

●Rate of response to treatment – Early response is predictive of long-term outcome. In a retrospective study, among 75 patients with AP CML, those who achieved BCR::ABL1 <10 percent at three months had better overall survival and event-free survival (both 95 percent) compared with those who did not (79 and 59 percent, respectively) [36].

●Molecular abnormalities – Mutations of certain genes are found with high frequency in AP CML, but their prognostic importance is presently uncertain. As examples, single-nucleotide variations and small insertions or deletions (indels) in RUNX1 and ASXL1, plus IKZF1 exon deletions; mutations of epigenetic regulators; and gene fusions involving RUNX1, MLL (KMT2A), and CBFB are common in AP CML [37,38].

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.)

●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), the Philadelphia chromosome (Ph). Most patients present with chronic phase (CP) CML, but others present with accelerated phase (AP) or blast phase (BP) CML.

●Evaluation – Clinical evaluation, medical fitness, and bone marrow examination with morphology, cytogenetics, and molecular testing are performed. Patients with transformed AP CML should have BCR::ABL1 kinase domain (KD) testing; this is not required, but it can be performed for de novo AP CML. (See 'Pretreatment evaluation' above.)

●Diagnosis – AP CML should be considered in patients with disease progression who are receiving a tyrosine kinase inhibitor (TKI) for CP CML, or in patients newly presenting with circulating immature myeloid cells, basophilia, splenomegaly, or constitutional symptoms.

AP is diagnosed in a patient with CML and any of the following (see 'Diagnosis' above):

•Blasts ≥20 percent in blood or marrow

•Basophils ≥20 percent in peripheral blood

•Persistent thrombocytopenia <100 x 10⁹/L, unrelated to therapy

•Major route clonal chromosome abnormalities in Ph-positive cells

●Management – Distinguishing de novo AP CML from transformed AP CML (ie, AP that arose during TKI treatment for CP CML) has important prognostic and treatment implications. (See 'de novo versus transformed AP' above.)

•de novo AP CML – We suggest a second-generation (2G) TKI (ie, dasatinib, nilotinib, bosutinib), rather than other TKIs or allogeneic hematopoietic cell transplantation (HCT) (Grade 2C). (See 'Treatment of de novo AP CML' above.)

Selection of a TKI is based on the TKI toxicity profile (table 2) and comorbidities. If BCR::ABL1 KD testing was performed, the choice is also informed by the mutation status (table 3).

•Transformed AP CML – Guided by suitability for allogeneic HCT (ie, medical fitness, age, suitable graft donor):

-Transplant-eligible – For transplant-eligible patients with transformed AP CML, we suggest treatment with a TKI followed by allogeneic HCT, rather than a TKI alone (Grade 2C). (See 'Transplant-eligible' above.)

Prior to transplantation, the patient is treated with a TKI selected according to BCR::ABL1 mutation status (table 3), toxicity profile (table 2), comorbidities, and prior TKI(s).

-Not suitable for HCT – For transformed AP CML in transplant-ineligible patients, we select a TKI according to mutation status (table 3), toxicity profile (table 2), comorbidities, and prior TKI(s).

●TKI selection – Informed by the following features:

•BCR::ABL1 mutation status (see 'Mutation-guided' above):

-T315I – For T315I mutations, we suggest either asciminib or ponatinib (Grade 2C), chosen by toxicity profile (table 2), prior treatment, and comorbidities.

-Other KD mutations – For other KD mutations or no KD mutation, we select a 2G TKI or asciminib based on the mutation status (table 3), toxicity (table 2), comorbidities, and prior TKI(s).

-No KD mutation – The choice of TKI in patients with no KD mutation is guided by toxicity (table 2), comorbidities, and prior TKI(s).

•Comorbidities – Diabetes or heart, lung, liver, or pancreas disease may influence the choice of TKI. (See 'Comorbidity-guided' above.)

•Toxicity profile – Each TKI is associated with characteristic adverse effects (AEs), and the selection may be influenced by toxicity profile and the individual's comorbidities. (See 'Toxicity-guided' above.)

●Response monitoring – Response to a TKI is evaluated by the timely achievement of hematologic, cytogenetic, and molecular milestones (table 4), as described above. (See 'Response monitoring' above.)