Chronic myeloid leukemia: Pathogenesis, clinical manifestations, and diagnosis

INTRODUCTION — 

Chronic myeloid leukemia (CML; previously called chronic myelogenous leukemia, chronic myelocytic leukemia, or chronic granulocytic leukemia) is a myeloproliferative neoplasm that manifests uncontrolled proliferation of mature and maturing granulocytes in blood and bone marrow. CML is characterized by t(9;22), a reciprocal translocation of chromosomes 9 and 22, which results in an abnormally short chromosome 22 known as the Philadelphia (Ph) chromosome. The chromosomal translocation generates the BCR::ABL1 fusion gene, which is translated into a constitutively active tyrosine kinase protein.

CML accounts for approximately 15 percent of adult leukemias. The median age at diagnosis is in the sixties, but CML can occur at any age. Most patients present with chronic phase (CP) CML, which is a relatively indolent disorder of excessive mature and maturing neutrophils, basophils, and eosinophils, with or without splenomegaly and/or constitutional symptoms. Up to one-half of patients with CP CML are asymptomatic at diagnosis. In regions with limited access to medical care, patients often present with more advanced disease.

Infrequently, patients initially present with more aggressive stages of CML called accelerated phase (AP) and/or blast phase (BP). These advanced stages of CML manifest increasingly immature blood cells in blood and bone marrow, worsening symptoms, and additional cytogenetic abnormalities.

BCR::ABL1 is exquisitely sensitive to BCR::ABL1 tyrosine kinase inhibitors (TKIs), and they effectively control CML in most patients. TKIs have improved outcomes so that the survival of patients with CML is now comparable to that of the general population.

This topic discusses pathogenesis, clinical presentation, and diagnosis of CML.

Related topics include:

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

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

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

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

EPIDEMIOLOGY — 

CML accounts for approximately 15 to 20 percent of leukemias in adults.

The annual incidence of CML is 1 to 2 cases per 100,000, with a slight male predominance [1-3]. Cancer registry data report the median age at presentation is 66 years in the United States [4].

The prevalence of CML is steadily increasing in the Western world due to improved survival with BCR::ABL1 tyrosine kinase inhibitors. To illustrate this point, approximately 70,000 patients were living with CML in the United States in 2021, but it is estimated that there will be more than 180,000 patients living with CML by the year 2050 [5].

Exposure to ionizing radiation is the only known risk factor for the development of CML [6,7]. There is no known familial disposition to CML [8]. It is uncertain whether genetic variants predispose persons in the general population to develop CML. However, a genome-wide association study of Korean and European cohorts suggested that persons with genetic variants at two chromosomal loci (6q25.1 and 17p11.1) may be more likely to develop CML [9]. (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera", section on 'Familial PV'.)

PATHOBIOLOGY — 

The BCR::ABL1 fusion gene is an essential feature of CML that drives the dysregulated proliferation of hematopoietic cells and associated clinical manifestations.

CML is caused by reciprocal translocation between chromosomes 9 and 22 (figure 1) within a hematopoietic stem cell or progenitor cell, which results in the so-called Philadelphia (Ph) chromosome, an abnormally small chromosome 22. The chromosomal rearrangement generates the BCR::ABL1 fusion gene and production of the BCR::ABL1 tyrosine kinase. BCR and ABL1 can undergo various molecular rearrangements, and the resultant gene and protein products are described below. (See 'BCR::ABL1 rearrangements' below.)

The constitutively active BCR::ABL1 tyrosine kinase drives the uncontrolled proliferation, aberrant maturation, escape from apoptosis, and altered cell-cell interactions of the transformed cells in CML, as described below. (See 'Cell biology of CML' below.)

The BCR::ABL1 rearrangement appears to be the initiating event in CML. However, the progression of chronic phase (CP) CML to accelerated phase (AP) or blast phase (BP) appears to require the acquisition of other chromosomal or molecular changes, as described below. (See 'Disease progression' below.)

BCR::ABL1 rearrangements — Distinct BCR::ABL1 fusion proteins can be generated from the t(9;22) chromosome translocation, depending on the site of the breakpoint on chromosome 22. Most patients with CML have rearrangements that produce the p210 (210 kilodalton) protein product.

Each rearrangement includes the entire ABL1 tyrosine kinase catalytic domain, but they have different amounts of BCR sequence at the N-terminus. All BCR::ABL1 fusion proteins have tyrosine kinase activity.

In >98 percent of patients, chromosome 22 rearrangements involve breakage at one of four exons in the BCR gene (labeled e1, e13, e14, and e19) (figure 2). BCR is fused with ABL1 exon a2 to produce one of four possible transcript products, BCR::ABL1 e1a2, e13a2, e14a2, or e19a2, which are translated into the various protein products (p190, p210, or p230, respectively) [10].

Most patients with CML have a p210 rearrangement, but a small minority of patients have other rearrangements. By contrast, Ph-positive B cell acute lymphoblastic leukemia (ALL) is more often associated with the p190 protein. The various BCR::ABL1 rearrangements are associated with certain disease manifestations.

The most common protein products of the BCR::ABL1 rearrangement:

●p210 – Fusion of a breakpoint in BCR at either e13 or e14 with ABL1 at a2 is translated into a 210 kD protein, which is present in most patients of CML. Both e13 and e14 breakpoints are associated with similar survival [11]. However, compared with the e14a2 rearrangement, patients with e13a2 may respond more slowly to tyrosine kinase inhibitors (TKIs) and are less likely to achieve a deep molecular response [12].

●p190 – Fusion of a breakpoint in BCR at e1 with ABL1 at a2 results in a 190 kD protein. This rearrangement is rare in patients with CML, but it is found in 80 percent of childhood Ph-positive B cell ALL and in 60 to 70 percent of adult Ph-positive B cell ALL. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

Patients with CML that express the p190 protein may have different outcomes than those with the more typical p210 product. p190 is associated with monocytosis and a low neutrophil/monocyte ratio in peripheral blood [13,14]. In a single-institution study, the e1a2 transcript was found in only 14 of 1292 patients with CML [15]. A retrospective analysis of 14 patients with p190 reported a low response rate to TKI therapy with frequent evolution into AP or BP [15]. However, a study of 10 patients with p190 treated with second-generation (2G) TKIs reported comparable outcomes in patients with p190 and p210 [16].

●p230 – Fusion of a breakpoint in BCR at e19 with ABL1 at a2 generates a 230 kD protein product that is rare in patients with CML.

It is uncertain if CML that expresses p230 is associated with outcomes that differ from patients with p210 [17,18]. However, patients with the p230 rearrangement may require special arrangements for disease monitoring because most routine BCR::ABL1 PCR (polymerase chain reaction) assays do not detect this fusion gene.

Although patients with the p230 rearrangement can present with a high percentage of mature neutrophils, this does not establish a diagnosis of chronic neutrophilic leukemia (CNL), which is discussed below. (See 'Chronic neutrophilic leukemia' below.)

●Rare variants – Rare patients have fusion of BCR exon 1 or exon b2 with ABL1 exon 3 (e1a3 and b2a3, respectively) or BCR exon 6 to ABL1 exon 2 (e6a2).

Cell biology of CML — Acquisition of the BCR::ABL1 tyrosine kinase in a hematopoietic stem cell or progenitor cell alters the growth and development of maturing progeny cells.

BCR::ABL1 promotes the development of CML by allowing uncontrolled proliferation of transformed cells, escape from apoptosis, discordant maturation, and altered interactions with the cellular matrix [19].

●Activation of the MAP kinase (MAPK) pathway by BCR::ABL1 appears to play a central role in promoting uncontrolled proliferation. Other important mediators of BCR::ABL1 effects include JAK/STAT and stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) pathways, STAT5, MYC, and cyclin D1.

●CML displays discordant maturation, with an alteration in the balance between self-renewal and differentiation of immature cells. While the pool of self-renewing stem cells is normal, there is an expansion of committed progenitor cells [20].

●The antiapoptotic activity of BCR::ABL1 is poorly understood, but it appears to block programmed cell death upstream of mitochondrial cytochrome c release and caspase activation.

●CML cells have an altered cytoskeleton and a decreased adhesion to microenvironmental substrates. Defects in adherence may contribute to the increased circulation and unregulated proliferation of Ph-positive stem and progenitor cells in CML.

Disease progression — The progression from CP to AP and/or BP is associated with a gradual block in the ability of stem/progenitor cells to differentiate, resulting in increasing immaturity of myeloid cells, and can culminate in a process that resembles acute leukemia.

Most cases of BP resemble acute myeloid leukemias, but approximately one-third of cases have predominantly lymphoblasts, a reflection of the stem cell origin of CML. Disease progression is a complex, multistep process that is only partially understood.

●Additional cytogenetic abnormalities – Disease progression is associated with the acquisition of other chromosomal changes and/or dysregulation of differentiation-regulatory genes.

Additional cytogenetic abnormalities (ACAs) develop in >80 percent of patients in AP and BP, most commonly trisomy 8, trisomy 19, duplication of Ph, and isochromosome 17q (leading to the loss of the TP53 gene on 17p). These can be seen singly or in any combination, but any of these ACAs confers a worse prognosis [21]. Such ACAs may also be found at diagnosis in approximately 7 percent of patients, and they are associated with a lower response rate to treatment and inferior survival [22,23].

●BCR::ABL1 – Disease progression requires continued expression of BCR::ABL1, and it often manifests a rise in BCR::ABL1 activity.

The progressive failure of differentiation may be mediated through interactions of BCR::ABL1 with key transcription factors or through a separate genetic event that creates a dominant-negative transcription factor. As an example, impaired expression or activity of the myeloid transcription factor, C/EBP alpha, may contribute to myeloid BP [24,25]. Similarly, disruption of the Ikaros transcription factor may foster the development of lymphoblasts [26,27].

●Other molecular events – Some cases of advanced-phase CML are associated with the loss of tumor suppressor genes, mutations in epigenetic regulatory genes, or increased activity of certain transcription factors.

•TP53 – In BP, 20 to 30 percent of patients have deletions and rearrangements involving the TP53 tumor suppressor gene on chromosome 17p13. Another tumor suppressor gene on 17p may also be involved in disease progression.

•TET2, ASXL1, DNMT3A – Loss of function mutations in epigenetic regulator genes can be found in both CP and advanced phases of CML. The same genes are mutated in clonal hematopoiesis of indeterminate potential (CHIP) and are associated with increased stem cell self-renewal and an inferior response to TKI therapy [28,29].

•MYC – Amplification of MYC on chromosome 8 and deletion of RB1 or CDKN2A tumor suppressors is more common in patients with lymphoid BP.

•Chromosome 9 deletions – Large deletions of the derivative chromosome 9 are found in 15 to 20 percent of patients with CP CML, and they are associated with more rapid disease progression and decreased survival [30]. No specific tumor suppressor genes have been proven responsible.

CLINICAL PRESENTATION — 

Patients with CML often experience nonspecific symptoms, with or without findings related to splenomegaly, but up to one-half of patients with chronic phase CML are asymptomatic at presentation and are diagnosed because of laboratory abnormalities.

Among symptomatic patients with CML, fatigue (34 percent), weight loss (20 percent), excessive sweating (15 percent), abdominal fullness (15 percent), bone pain (7 percent), and bleeding due to platelet dysfunction (21 percent) are most common [31]. Case series reported splenomegaly in 48 and 76 percent of patients [6,31]. Splenomegaly may manifest as early satiety, abdominal discomfort, or left upper quadrant pain (often referred to as the left shoulder). Tenderness over the lower sternum, due to an expanding bone marrow, is sometimes seen. Acute gouty arthritis may also occur due to overproduction of uric acid.

Involvement of extramedullary tissues (eg, lymph nodes, skin, soft tissues) is generally limited to patients with blast phase (BP). Presentation of accelerated phase and BP are discussed in more detail separately. (See "Accelerated phase chronic myeloid leukemia: Diagnosis and treatment" and "Chronic myeloid leukemia-blast phase: Diagnosis and treatment".)

PATHOLOGIC FEATURES — 

CML manifests as an expansion of myeloid cells in blood, bone marrow, and spleen. In advanced CML, there may be extramedullary collections of leukemic cells.

All cases of CML have the BCR::ABL1 rearrangement. In most patients, this is associated with t(9;22) chromosomal translocation and an abnormally short derivative chromosome 22, called the Philadelphia chromosome (Ph) to reflect the city where it was initially described (figure 1). Rare cases have three-way or other complex chromosomal rearrangements, or small rearrangements that are below the threshold for detection with chromosomal banding techniques.

Peripheral blood — Patients with CML have leukocytosis in association with predominantly myeloid white blood cells (WBCs). Many patients also have anemia and/or thrombocytosis.

●Myeloid series – The median WBC count at presentation is approximately 100,000/microL, but it can range from 12,000 to 1,000,000/microL [32]. Virtually all WBCs are of the neutrophilic lineage, ranging from myeloblasts to mature neutrophils. There are peaks in the percent of myelocytes and segmented neutrophils (picture 1), while blasts typically account for <2 percent of WBCs in patients with chronic phase (CP) CML. A higher percentage of myelocytes than the more mature metamyelocytes ("leukemic hiatus" or "myelocyte bulge") is a classic finding in CML [33].

The mature granulocytes of CML are morphologically normal and generally exhibit no dysplastic features. However, dysplasia and increasingly immature cells can be seen in some cases of accelerated phase (AP) CML or blast phase (BP) CML. The differential count of peripheral blood and bone marrow is an important feature of determining disease phase. (See 'Disease phase' below.)

Absolute basophilia is a universal finding in blood smears from CML patients, and absolute eosinophilia is seen in approximately 90 percent of cases. Absolute monocytosis (>1000/microL) is not uncommon, although the percentage of monocytes is typically low (<3 percent) [13,34].

●Platelets – The platelet count can be normal or elevated. Platelet counts >600,000/microL are seen in 15 to 30 percent of patients [6,31]. If thrombocytopenia is present at diagnosis, other diagnostic possibilities (eg, myelodysplastic syndromes/neoplasms) should be considered.

●Erythrocytes – Normochromic, normocytic anemia is seen in 45 to 60 percent of patients [6,31]. Some patients have polycythemia.

Bone marrow — Bone marrow of patients with CML demonstrates granulocytic hyperplasia and increased immature myeloid forms, and there may be abnormalities in the erythroid series, megakaryocytes, or increased fibrosis.

●Bone marrow examination – Most patients with CML have a bone marrow examination at diagnosis. In selected cases of CP CML, the diagnosis can be established with cytogenetics and/or polymerase chain reaction (PCR) from peripheral blood alone. Bone marrow biopsy is indicated for patients who meet any of the clinicopathologic criteria for AP or BP or with a history that suggests disease progression (eg, increasing splenomegaly) unless frailty or age would preclude treatments that are used for patients with advanced-stage disease. (See 'Disease phase' below.)

The bone marrow aspirate and biopsy are evaluated for morphology (eg, fibrosis, blast count) and cytogenetic studies. Aspirate specimens provide material for chromosome banding and/or fluorescence in situ hybridization (FISH) and molecular studies, including quantitative reverse transcription polymerase chain reaction (RT-PCR); BCR::ABL1 mutation analysis can also be performed using these specimens if needed.

Bone marrow also provides important prognostic information, including the percentage of blasts and the degree of myelofibrosis [35]. As discussed above, it is possible to diagnose CML using peripheral blood alone. (See 'Peripheral blood' above.)

●Pathologic findings – Bone marrow generally reveals granulocytic hyperplasia with a maturation pattern that reflects that in the peripheral smear (picture 2). CP CML generally has approximately 2 percent blasts, while the percentage increases with advanced stages of disease. The differential count of bone marrow and blood is a key determinant of CML disease stage, as discussed below. (See 'Disease phase' below.)

Bone marrow specimens are hypercellular, with marked granulocytic hyperplasia; the maturation pattern generally reflects that of peripheral blood [36]. There is generally little or no dysplasia. Erythroid precursors are generally decreased and the myeloid:erythroid ratio is increased to as much as 20:1. Megakaryocytes may be normal in number or slightly decreased, but up to one-half of cases have moderate or marked increases of megakaryocytes. Megakaryocytes are typically smaller than normal. There may be moderate or marked reticulin fibrosis.

Cytogenetics — The cytogenetic hallmark of CML is t(9;22)(q34;q11.2) and the associated BCR::ABL1 rearrangement.

●Chromosomal findings – The t(9;22)(q34;q11.2) chromosomal abnormality of CML can be demonstrated by conventional cytogenetic analysis (karyotyping) and/or by FISH.

More than 90 percent of patients with CML exhibit t(9;22)(q34;q11.2), which generates an abnormally short chromosome 22 (the Ph chromosome). Some cases have complex chromosomal translocations, such as t(9;14;22), that mask the Ph chromosome. Others have cryptic translocations of 9q34 and 22q11.2 that cannot be identified by routine cytogenetics; these "Ph-negative" cases require FISH or RT-PCR to document the diagnosis.

In a large prospective study, 15 percent of patients lacked the Ph chromosome by cytogenetic analysis; one-half of these Ph-negative patients had complex chromosomal rearrangements, while another subset had BCR::ABL1 diagnosed by metaphase or interphase FISH or RT-PCR [31].

In patients with a high clinical suspicion of CML, karyotyping alone is not adequate to exclude the diagnosis of CML. FISH for BCR::ABL1 is mandatory in such cases.

●Molecular findings – The BCR::ABL1 rearrangement can be demonstrated by RT-PCR or by FISH.

The most common BCR::ABL1 fusion transcripts (e13a2 or e14a2) in CML generate the p210 BCR::ABL1 protein [37]. In <1 percent of cases, the e19a2 fusion transcript produces a p230 fusion protein or the e1a2 transcript produces p190. (See 'BCR::ABL1 rearrangements' above.)

RT-PCR assays from most commercial laboratories generally detect only the p210 and p190 BCR::ABL1 variants; if a patient with suspected CML is negative for BCR::ABL1 by RT-PCR, it is important to exclude the possibility of BCR::ABL1 gene fusion by FISH.

DIAGNOSIS AND CLASSIFICATION

Diagnosis — CML should be suspected in patients with unexplained leukocytosis and a left-shifted myeloid series, with or without abnormal levels of red blood cells or platelets, signs or symptoms associated with splenomegaly or bone pain, or constitutional symptoms (fatigue, sweats, weight loss).

CML is a pathologic diagnosis that requires documentation in bone marrow or peripheral blood of:

●t(9;22)(q34;q11.2) (figure 1) by chromosome banding or by fluorescence in situ hybridization (FISH)

and/or

●BCR::ABL1 by reverse transcription polymerase chain reaction (RT-PCR) (figure 3).

The diagnosis of CML can be made by genetic testing of peripheral blood granulocytes, but a bone marrow biopsy is required to fully stage the disease (ie, chronic phase [CP], accelerated phase [AP], blast phase [BP]) and because it provides valuable prognostic information. However, in selected cases, CML can be diagnosed with cytogenetic/molecular evaluation of peripheral blood alone, as discussed above. (See 'Bone marrow' above.)

Diagnostic criteria for CML are the same in the International Consensus Classification (ICC) [38] and the World Health Organization 5^th edition (WHO5) [39]. Either of these systems can be used for the diagnosis of CML, but the classification of disease phase differs between these systems. (See 'Disease phase' below.)

The ICC and WHO5 classification systems are discussed separately. (See "Classification of hematopoietic neoplasms", section on 'Myeloid neoplasms'.)

Disease phase — The disease phase of CML is determined by clinical and pathologic features. The differential count of blood and bone marrow, the presence of myeloid sarcoma (extramedullary collection of blasts), and additional cytogenetic abnormalities (ACAs) are used to define the CML disease phase.

Bone marrow aspirate and biopsy are required to classify advanced disease stages unless the clinician determines that the findings would not affect treatment because of frailty or advanced age.

The categories and labels for CML disease phases differ in the ICC and WHO5 classification systems. The ICC and WHO5 classification systems also differ from some earlier schemes. For example, the International Blood and Marrow Transplant Registry [40], MD Anderson Cancer Center [41], and European LeukemiaNet [42] systems required >30 percent blasts to diagnose BP of CML. Some clinical trials use these systems for eligibility criteria.

ICC categories — Three phases of CML are defined by the ICC [38]:

●CP – CML with none of the findings of advanced stages (below)

●AP – At least one of the following:

•Blasts 10 to 19 percent in blood or marrow

•Basophils ≥20 percent in blood

•ACAs in Ph-positive cells: second Ph, trisomy 8, isochromosome 17q, trisomy 19, complex karyotype, or abnormalities of 3q26.2

●BP – At least one of the following:

•Blasts ≥20 percent in blood or marrow

•Myeloid sarcoma

•Lymphoblasts (confirmed by immunophenotype) >5 percent indicates lymphoid BP

WHO5 categories — Two phases of CML are defined by WHO5; AP was eliminated [39].

●CP – CML with none of the findings of BP.

●BP – At least one of the following:

•Blasts ≥20 percent in blood or marrow

•Myeloid sarcoma

•Increased lymphoblasts in blood or marrow; the threshold is not defined

DIFFERENTIAL DIAGNOSIS — 

Various malignant and nonmalignant disorders can present with clinical findings that resemble those of CML.

Leukemoid reaction — A leukemoid reaction describes a high leukocyte count with neutrophilia and prominent left shift, usually in response to infection or inflammatory conditions. (See "Approach to the patient with neutrophilia", section on 'Causes of neutrophilia'.)

Leukocyte counts in leukemoid reactions generally do not rise as high as those with CML, and the blood smear may reveal toxic granulations, Döhle bodies, and/or cytoplasmic vacuoles in neutrophils (picture 3).

If the diagnosis of a leukemoid reaction cannot be made clinically, cytogenetic or molecular testing is definitive for CML.

Chronic myelomonocytic leukemia — Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy with clinical and pathologic features of both myelodysplastic syndromes/neoplasms (MDS) and myeloproliferative neoplasms (MPNs). CMML is characterized by excessive maturing monocytic cells and dysplastic neutrophils, often accompanied by anemia and/or thrombocytopenia. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

Bone marrow in CMML demonstrates prominent dysplasia, while cytogenetic testing does not demonstrate BCR::ABL1 or t(9;22).

CMML is excluded if there are cytogenetic or molecular findings of CML.

Atypical CML — Atypical CML is an MDS/MPN characterized by leukocytosis, mild monocytosis, and profound dysgranulopoiesis.

Atypical CML is a misnomer because it lacks the diagnostic cytogenetic/molecular findings of CML [43]. The name atypical CML is retained in the International Consensus Classification (ICC) [38], but the World Health Organization 5^th edition (WHO5) replaced that term with MDS/MPN with neutrophilia [39].

Patients are generally older and have high neutrophil counts with thrombocytopenia and/or anemia. Atypical CML manifests as leukocytosis (≥13 x 10⁹), cytopenias, blasts <20 percent, dysgranulopoiesis, and modest monocytosis (<10 percent). The prognosis is poor, and transformation to acute myeloid leukemia (AML) can occur.

CML is definitively distinguished from atypical CML by the detection of BCR::ABL1 and/or t(9;22).

Chronic eosinophilic leukemia — Chronic eosinophilic leukemia (CEL) is a rare MPN characterized by sustained clonal proliferation of morphologically abnormal eosinophils in blood and marrow that can also involve multiple organ systems.

The names and diagnostic criteria for CEL differ in ICC and WHO5.

●ICC calls the disorder CEL, not otherwise specified (NOS), and diagnosis requires hypercellular bone marrow with an infiltrate of aberrant eosinophils and eosinophil precursors, dysplastic megakaryocytes (with or without dysplasia in other lineages), and significant fibrosis [38].

●WHO5 calls it CEL and requires ≥4 weeks of sustained hypereosinophilia, documentation of clonality, and abnormal bone marrow morphology with megakaryocytic or erythroid dysplasia [39].

Cytogenetics in CEL may be normal, or there may be del(4q12) or rearrangement of 5q22, 12p12-13, or 8p11. Further details of the diagnosis of CEL are discussed separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

CML is definitively distinguished from CEL by the detection of BCR::ABL1 and/or t(9;22).

Chronic neutrophilic leukemia — Chronic neutrophilic leukemia (CNL) is a rare MPN that manifests as neutrophilia with predominantly mature granulocytes, hypercellular marrow, and hepatosplenomegaly.

Neutrophils in CNL may display toxic granulation and nuclear hypersegmentation. CSF3R mutations are present in >60 percent of cases, but additional mutations (eg, SETBP1, ASXL1, SRSF2) are also common. Bone marrow reveals hypercellularity with a myeloid:erythroid ratio that may exceed 20:1; in most cases, blasts are <5 percent, and there are no dysplastic features or Auer rods. The prognosis is generally poor.

Diagnostic criteria differ in ICC and WHO5.

●ICC requires leukocyte count ≥25,000/microL with ≥80 percent segmented neutrophils and bands [38].

●WHO5 applies the same threshold, but CNL can also be diagnosed with ≥13,000/microL in cases with CSF3R T618I or other activating CSF3R mutations [39].

CML is definitively distinguished from CNL by the detection of BCR::ABL1 and/or t(9;22).

Juvenile myelomonocytic leukemia — Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive MPN of infancy and childhood that manifests as infiltration of blood, bone marrow, and viscera by abnormal myelomonocytic cells. (See "Juvenile myelomonocytic leukemia".)

Children with JMML present with findings that are often indistinguishable from other childhood leukemias and MPNs. Hepatosplenomegaly is common, and most patients have pallor, bleeding/bruising, and or infection related to cytopenias. The karyotype is generally normal, but monosomy 7 may be present. Progression to acute leukemia is rare, but children may have clinical findings of inherited/germline syndromes associated with pathogenic variations that cause JMML. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

CML is rare in children, but it can be distinguished from JMML by the diagnostic cytogenetic/molecular findings.

Other Ph-positive malignancies — The Philadelphia (Ph) chromosome can be found in hematologic malignancies other than CML. Distinguishing blast phase (BP) CML from other Ph-positive acute leukemias can be especially challenging.

The Ph chromosome is found in 20 to 30 percent of adults with precursor B cell acute lymphoblastic leukemia (ALL), 5 to 10 percent of childhood ALL, and 1 percent of adult AML [44]. At least some of these patients likely have BP CML that arose after unrecognized chronic phase (CP) CML, while others are de novo acute leukemia.

Ph-positive B cell ALL is heterogeneous at the molecular level. While most patients have BCR::ABL1 e1a2 breakpoints that produce the p190 protein, one-half of adults and approximately 10 percent of children have e13/e14a2 breakpoints and the p210 variant that is more common in CML. BCR::ABL1 rearrangements are discussed above. (See 'BCR::ABL1 rearrangements' above.)

Some features can help distinguish CML BP from other Ph-positive acute leukemias. Most patients with ALL that express p190 do not have additional cytogenetic abnormalities that are typical of CML BP, lack the Ph chromosome in myeloid cells, and become Ph-negative after achieving hematologic remission. Ph-positive AML, like Ph-positive ALL and CML lymphoid BP, is characterized by frequent chromosomal deletions of the immunoglobulin heavy chain (IgH) region, which are not found in CML myeloid BP. The persistence of the Ph chromosome in myeloid cells after achieving hematologic remission with chemotherapy is more likely to represent CML presenting in BP.

PROGNOSIS

Outcomes — The prognosis of patients with CML has improved dramatically since the incorporation of BCR::ABL1 tyrosine kinase inhibitors (TKIs) into the initial treatment such that the life expectancy approaches that of the general population [45,46].

As the risk of dying from CML has decreased, the prognostic impact of comorbidities has taken on greater importance. In one large study, overall survival (OS) decreased with increasing comorbidity, as measured by the Charlson Comorbidity Index (CCI) [47]. Eight-year OS estimates were 94, 89, 78, and 46 percent for patients with a CCI of 2, 3 to 4, 5 to 6, and ≥7, respectively.

Prognostic scoring systems — A validated prognostic model for CML should be used to assess prognosis and to aid selection of initial therapy of CML.

The Sokal, Euro (Hasford), EUTOS, or ELTS (EUTOS long-term survival score) are all acceptable for assessing prognosis in CML (table 1) [48-51]. 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 provides the best discrimination for the probability of CML-specific death, and unlike the other prognostic models, was derived from survival data that reflect the treatment of CML with TKIs [51,52]. (See 'ELTS' below.)

The Sokal and Hasford scores have similar levels of performance but were derived from data sets that included some patients who were treated before the routine use of TKIs [53].

Sokal — The Sokal prognostic score is based on four clinical features: spleen size, percent blasts, age, and platelet count >700,000/microL (700 x 10⁹/L) (calculator 1) [48].

Hasford (Euro) — The Hasford (Euro) score adds eosinophilia and basophilia to the clinical features of the Sokal score (described above) (Euro score calculator) [49].

EUTOS — The EUTOS (EUTOS score calculator) is based on age, spleen size, peripheral blood blast count, and platelet count.

ELTS — The ELTS score is based on age, spleen size, peripheral blood blast count, and platelet count (ELTS score calculator) (calculator 2).

The use of prognostic scores for management of CML is described separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment", section on 'CML risk score'.)

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

●Description – Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm associated with the t(9;22)(q34;q11), resulting in an abnormally short chromosome 22 (Philadelphia [Ph] chromosome). The chromosomal rearrangement generates a BCR::ABL1 fusion gene that produces a constitutively active tyrosine kinase protein, BCR::ABL1.

●Pathobiology – BCR::ABL1 in hematopoietic stem/progenitor cells is an essential feature of CML. The BCR::ABL1 tyrosine kinase drives the aberrant growth of affected cells and causes the resultant clinical manifestations. Additional molecular events contribute to the progression of CML to advanced disease phases. (See 'Pathobiology' above.)

●BCR::ABL1 rearrangements – Based on the specific breakpoint in chromosome 22, distinct fusion proteins are generated. The most common protein in CML is p210, but the p190 or p230 forms are generated in rare patients. (See 'BCR::ABL1 rearrangements' above.)

●Presentation – Most patients present in chronic phase (CP), with nonspecific symptoms or splenomegaly, but up to one-half of patients with CP CML are asymptomatic. Occasional patients present with more advanced disease: accelerated phase (AP) or blast phase (BP). (See 'Clinical presentation' above.)

●Pathology

•Blood – Leukocyte counts vary, but the median value is 100,000/microL. Increased granulocytic cells (mature/maturing neutrophils, eosinophils, basophils), with or without abnormalities of erythroid and platelet lineages, are seen on blood smears (picture 1).

Advanced phases of CML display increasing myeloid immaturity and blast cells. (See 'Peripheral blood' above.)

•Marrow – Bone marrow displays granulocytic hyperplasia and left-shifted myeloid forms, with or without abnormalities of the erythroid or megakaryocytic lineages, or fibrosis. Blast percentage is increased in AP/BP. (See 'Bone marrow' above.)

•Cytogenetics – BCR::ABL1 is universally present. The Ph chromosome (figure 1) is found in >90 percent of patients, while others have cryptic rearrangements. Additional cytogenetic abnormalities and mutations are common in advanced-phase CML.

●Diagnosis – CML should be suspected with unexplained leukocytosis/left-shifted myeloid cells, with or without abnormal levels of red blood cells or platelets, splenomegaly, or constitutional symptoms. (See 'Diagnosis' above.)

CML is a pathologic diagnosis that requires documentation in bone marrow or peripheral blood of:

•t(9;22)(q34;q11.2) (figure 1) by chromosome banding or fluorescence in situ hybridization (FISH)

and/or

•BCR::ABL1 by reverse transcription polymerase chain reaction (RT-PCR) (figure 3).

●Disease phase – Complete staging requires a bone marrow biopsy since it is based on clinicopathologic features, but the categories differ in contemporary classification schemes. (See 'Disease phase' above.)

•International Consensus Classification (ICC) defines three phases: CP, AP, and BP. Criteria are presented above. (See 'ICC categories' above.)

•World Health Organization 5^th edition (WHO5) defines two phases: CP and BP. Criteria are presented above. (See 'WHO5 categories' above.)

●Differential diagnosis – Various malignant and nonmalignant disorders can resemble CML clinically and/or pathologically. All of these conditions are definitively excluded by demonstration of BCR::ABL1 and/or t(9;22). (See 'Differential diagnosis' above.)

●Prognosis

•With the success of BCR::ABL1 tyrosine kinase inhibitors for CML, outcomes are now most closely associated with individual comorbidities and prognostic score. (See 'Outcomes' above.)

•The Sokal, Euro (Hasford), EUTOS, or ELTS (EUTOS long-term survival score) models are validated for assessing prognosis in CML (table 1). (See 'Prognostic scoring systems' above.)

Any one of these models can be used for stratification of initial treatment, as discussed in detail separately. (See "Chronic myeloid leukemia in chronic phase: Initial treatment".)