Version May 2024
INTRODUCTION — Chronic myeloid leukemia (CML; also known as chronic myelocytic, chronic myelogenous, or chronic granulocytic leukemia) is a myeloproliferative neoplasm characterized by the dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with fairly normal differentiation. (See "Overview of the myeloproliferative neoplasms".)
CML is associated with the fusion of two genes: BCR (on chromosome 22) and ABL1 (on chromosome 9) resulting in the BCR::ABL1 fusion gene. This abnormal fusion typically results from a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), that gives rise to an abnormal chromosome 22 called the Philadelphia (Ph) chromosome. It is this derivative chromosome 22 that harbors the BCR::ABL1 fusion gene.
The BCR::ABL1 fusion gene results in the formation of a unique gene product, the BCR::ABL1 fusion protein. This protein product includes an enzymatic domain from the normal ABL1 with tyrosine kinase catalytic activity, but relative to ABL1, whose kinase activity is tightly regulated [1], the kinase activity of BCR::ABL1 is elevated and constitutive [2] due to fusion with a portion of BCR. It is this deregulated tyrosine kinase that is implicated in the pathogenesis of CML. (See "Molecular genetics of chronic myeloid leukemia".)
The clinical hallmark of CML is the uncontrolled production of mature and maturing granulocytes, predominantly neutrophils, but also basophils and eosinophils. In the absence of treatment, CML has a triphasic or biphasic clinical course as it progresses from a chronic phase to an accelerated phase and on to a terminal blast crisis. Sometimes it goes from chronic phase directly to blast crisis, particularly when the blast phase is lymphoid.
The clinical manifestations and diagnosis of CML will be reviewed here. The molecular genetics, biology, and treatment of this disorder are considered separately. (See "Molecular genetics of chronic myeloid leukemia" and "Cellular and molecular biology of chronic myeloid leukemia" and "Overview of the treatment of chronic myeloid leukemia".)
EPIDEMIOLOGY — CML accounts for approximately 15 to 20 percent of leukemias in adults [3]. It has an annual incidence of 1 to 2 cases per 100,000, with a slight male predominance [4-6]. The median age at presentation is approximately 50 years for patients enrolled on clinical studies, but the actual median age from cancer registry data may be 10 years older. Exposure to ionizing radiation is the only known risk factor [7,8].
While there is no known familial disposition to CML [9], rare families in which multiple members develop myeloproliferative neoplasms (MPNs), including CML, have been described [10]. Studies of these families suggest the presence of an autosomal dominant mutation that may predispose to acquisition of a secondary somatic mutation such as the Philadelphia chromosome translocation or JAK2 mutation. It is unknown whether specific 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 [11]. (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera", section on 'Familial PV'.)
The prevalence of CML is steadily increasing in the Western world, due to the dramatic effect of ABL1 kinase inhibitors on survival. It is estimated that there will be >180,000 patients living with CML in the United States by the year 2050 [12].
CLINICAL MANIFESTATIONS — CML has a triphasic or biphasic clinical course: a chronic phase, which is present at the time of diagnosis in approximately 85 percent of patients; an accelerated phase, in which neutrophil differentiation becomes progressively impaired and leukocyte counts are more difficult to control with treatment; and blast crisis, a condition resembling acute leukemia in which myeloid or lymphoid blasts proliferate in an uncontrolled manner [7]. The varying definitions of these disease phases are discussed in more detail separately. (See "Overview of the treatment of chronic myeloid leukemia", section on 'Pretreatment evaluation'.)
The clinical findings at diagnosis of CML vary among reported series and also depend on the stage of disease at diagnosis. Twenty to 50 percent of patients are asymptomatic, with the disease first being suspected from routine blood tests [7,13]. Among symptomatic patients, systemic symptoms such as fatigue (34 percent), malaise (3 percent), weight loss (20 percent), excessive sweating (15 percent), abdominal fullness (15 percent), and bleeding episodes due to platelet dysfunction (21 percent) are common [13].
Abdominal pain and discomfort may include left upper quadrant pain (sometimes referred to the left shoulder) and early satiety, due to the enlarged spleen with or without perisplenitis and/or splenic infarction. Tenderness over the lower sternum, due to an expanding bone marrow, is sometimes seen. Acute gouty arthritis may also present at this time, due to overproduction of uric acid. (See "Asymptomatic hyperuricemia".)
Other frequent findings include splenomegaly (present in 48 and 76 percent in two series), anemia (45 and 62 percent), white blood cell count above 100,000/microL (52 and 72 percent), and platelet count above 600,000 to 700,000/microL (15 and 34 percent) [7,13]. Involvement of extramedullary tissues such as the lymph nodes, skin, and soft tissues is generally limited to patients with blast crisis.
PATHOLOGIC FEATURES
Peripheral blood — The peripheral smear typically demonstrates leukocytosis with a median white count of approximately 100,000/microL (range 12,000 to 1,000,000/microL) [14]. The white blood cell differential typically shows virtually all cells of the neutrophilic series, from myeloblasts to mature neutrophils with peaks in the percent myelocytes and segmented neutrophils (picture 1). Blasts typically account for less than 2 percent. The presence of a greater percent of myelocytes than the more mature metamyelocytes ("leukemic hiatus" or "myelocyte bulge") is one of the classic findings in CML [15]. The granulocytes of chronic phase are morphologically normal with no evidence of dysplasia, but dysplasia can develop in more advanced disease, and particularly in accelerated phase. (See "Evaluation of the peripheral blood smear", section on 'Neutrophil series'.)
Although morphologically normal, the neutrophils in CML are cytochemically abnormal. The cytochemical reaction called leukocyte (or neutrophil) alkaline phosphatase (LAP, or NAP) when scored is low. The low LAP score is useful in excluding a reactive leukocytosis or "leukemoid reaction," typically due to infection, in which the score is typically elevated or normal. Low LAP activity was also classically used to exclude polycythemia vera (PV) in the differential diagnosis of CML, in which LAP activity is also often increased. (See "Clinical manifestations and diagnosis of polycythemia vera".)
Absolute basophilia is a universal finding in the blood smears from CML patients, and absolute eosinophilia is seen in about 90 percent of cases. Absolute monocytosis (>1000/microL) is not uncommon, although the percentage of monocytes is typically low (<3 percent). The occasional patients with CML who have an alternate breakpoint in chromosome 22, producing a p190 BCR::ABL1 fusion protein rather than the classic p210 BCR::ABL1 fusion protein, tend to have a more prominent monocytosis and a low neutrophil/monocyte ratio in the peripheral blood [16,17]. (See "Cellular and molecular biology of chronic myeloid leukemia", section on 'BCR-ABL1'.)
The platelet count can be normal or elevated. Platelet counts above 600,000/microL are seen in 15 to 30 percent of patients [7,13]. Low platelet counts or thrombocytopenia, if present at diagnosis, should make one reconsider other diagnostic possibilities, such as one of the myelodysplastic syndromes. A normochromic, normocytic anemia is seen in 45 to 60 percent of patients.
Bone marrow biopsy — Bone marrow aspiration and biopsy demonstrates granulocytic hyperplasia with a maturation pattern that reflects that seen in the peripheral smear (picture 2). Other non-specific bone marrow findings include an increase in reticulin fibrosis and vascularity. (See "Overview of angiogenesis inhibitors", section on 'Vascular endothelial growth factor'.)
There is usually a thicker layer of immature neutrophils in the paratrabecular cuff and mature neutrophils are found in the intertrabecular areas. Erythroid islands are reduced in number and size. Small megakaryocytes with hypolobulated nuclei (so-called "dwarf megakaryocytes") are present. These are smaller than normal megakaryocytes, but not as small as dysplastic "micromegakaryocytes." Markers of increased cell turnover are commonly noted with Pseudo-Gaucher cells and sea-blue histiocytes. Iron-laden macrophages are reduced or absent.
The peripheral blood and bone marrow aspirate differential count are key components of determining the disease stage. In general, peripheral blood and bone marrow blasts between 10 and 19 percent are diagnostic of accelerated phase disease, while blasts over 20 percent are diagnostic of blast crisis. Additional criteria for accelerated phase are also described, and these are discussed in more detail separately. (See "Overview of the treatment of chronic myeloid leukemia", section on 'Pretreatment evaluation'.)
Genetics — Genetic testing for the Philadelphia chromosome (figure 1), the BCR::ABL1 fusion gene (figure 2) or the fusion mRNA gene product is done by conventional cytogenetic analysis (karyotyping), fluorescence in situ hybridization (FISH) analysis, or by reverse transcription polymerase chain reaction (RT-PCR). Southern blot techniques to identify BCR::ABL1 gene rearrangements were used in the past, but are time consuming and no longer employed as a routine diagnostic test. Evaluating for BCR::ABL1 protein by Western blot analysis is also not typically done. All patients with CML have evidence of the Philadelphia chromosome (Ph) (figure 1), the BCR::ABL1 fusion gene or its product, the BCR::ABL1 fusion mRNA (figure 2) by at least one of these tests [14].
The vast majority of patients (90 to 95 percent) demonstrate the t(9;22)(q34;q11.2) reciprocal translocation that results in the Ph chromosome. Some of the remaining minority have variant translocations such as complex translocations involving other chromosome (eg, t(9;14;22)). The rest have cryptic translocations of 9q34 and 22q11.2 that cannot be identified by routine cytogenetics. These are referred to as "Ph-negative" and require FISH analysis to identify the BCR::ABL1 fusion gene, or RT-PCR to identify the BCR::ABL1 fusion mRNA.
As an example, approximately 15 percent of patients in a large prospective study lacked the Ph chromosome by cytogenetic analysis [13]. However, about one-half of such patients had complex chromosomal rearrangements masking a t(9;22) translocation; another subset was Ph-negative by karyotype but had evidence of BCR::ABL1 gene fusion by metaphase or interphase FISH analysis or RT-PCR. The clinical features of both groups of these patients are very similar to those with typical Ph chromosome-positive CML. In contrast, patients whose cells lack evidence of BCR::ABL1 gene fusion by FISH or RT-PCR do not have CML, but may have a related condition, such as a myelodysplastic syndrome or disease with overlapping MDS/MPN features. (See 'Differential diagnosis' below.)
There are several distinct BCR::ABL1 fusion proteins generated from the chromosomal translocation or molecular fusion, depending on the site of the breakpoint in the BCR gene on chromosome 22.
●The most common abnormal BCR::ABL1 fusion transcript produced is from a breakpoint in exon 13 or exon 14 (alternatively called exon b2 or b3) in the BCR gene, fused to the ABL1 gene at exon a2. These are referred to as e13a2, e14a2 or alternatively as b2a2 or b3a2. These fusions result in a BCR::ABL1 protein with 210 kilodalton molecular mass which is referred to as the p210 BCR::ABL1 protein. This p210 BCR::ABL1 protein has increased and constitutively activated tyrosine kinase activity, as discussed above.
●Less commonly, an alternative e19a2 fusion transcript is found, producing a larger fusion protein with 230 kilodalton weight (p230 BCR::ABL1). This is seen in rare CML cases (<1 percent).
●A smaller e1a2 fusion transcript, which produces the p190 BCR::ABL1 protein is also seen in a very small number of CML patients, but is more frequently associated with Ph-positive acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL). It is also often produced in small quantities by patients with the classic p210 transcript as a form of alternative splicing of the BCR gene.
●In addition, rare patients with fusion of BCR exon 1 or exon b2 to ABL1 exon 3 (e1a3 and b2a3) and BCR exon 6 to ABL1 exon 2 (e6a2) have been described.
Common RT-PCR assays available in most commercial and academic laboratories will only detect the p210 and p190 variants of BCR::ABL1. If patients with suspected CML are negative for BCR::ABL1 transcripts by RT-PCR, it is important to exclude the possibility of BCR::ABL1 gene fusion by FISH.
All the BCR::ABL1 fusion proteins exhibit dysregulated tyrosine kinase activity. (See "Molecular genetics of chronic myeloid leukemia", section on 'Distinct forms of BCR-ABL1 from alternative chromosome 22 breakpoints' and "Cellular and molecular biology of chronic myeloid leukemia", section on 'The BCR-ABL1 fusion protein'.)
Although the Ph chromosome translocation is the initiating event in CML, progression to accelerated phase or blast crisis appears to require the acquisition of other chromosomal or molecular changes [7]. Additional cytogenetic abnormalities develop in over 80 percent of patients in the accelerated and blast crisis phases, most commonly trisomy 8, trisomy 19, duplication of the Ph chromosome, and isochromosome 17q (leading to the loss of the P53 gene on 17p). These can be seen singly in addition to the Ph chromosome or in any combination. The acquisition of any of these additional karyotypic findings confers a worse prognosis [18]. These additional cytogenetic aberrations may also be found at the time of diagnosis in approximately 7 percent of patients and are associated with a lower response rate to tyrosine kinase inhibitors and inferior survival [19,20]. (See "Cellular and molecular biology of chronic myeloid leukemia", section on 'Progression to acute phase CML'.)
DIAGNOSIS — The diagnosis of CML is first suspected by identifying the typical findings in the blood and bone marrow, and then confirmed by the demonstration of the Philadelphia chromosome (figure 1), the BCR::ABL1 fusion gene or the BCR::ABL1 fusion mRNA (figure 2) by conventional cytogenetics, fluorescence in situ hybridization (FISH) analysis, or reverse transcription polymerase chain reaction (RT-PCR) [14,21]. (See 'Differential diagnosis' below and "Molecular genetics of chronic myeloid leukemia".)
Hydroxyurea can be used to reduce white blood cell counts while awaiting confirmation of a suspected diagnosis of CML in a patient with significant leukocytosis (eg, >80 x109 white cells/L). (See "Overview of the treatment of chronic myeloid leukemia", section on 'Other agents'.)
DIFFERENTIAL DIAGNOSIS — There are several other disorders that resemble CML clinically. These include a leukemoid reaction, juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, "atypical CML," chronic eosinophilic leukemia, chronic neutrophilic leukemia, other myeloproliferative neoplasms, and other Philadelphia chromosome (Ph)-positive leukemias. These are discussed below:
Leukemoid reaction — A leukemoid reaction describes a high leukocyte count with neutrophilia and prominent left shift, usually in response to infection. The peripheral blood count may be as high as 50,000/microL and can easily mimic CML. However, the following features are more commonly found in a leukemoid reaction and help to distinguish it from CML: toxic granulation in the neutrophils, a high LAP score, lack of a "myelocyte bulge," and most importantly, the presence of an obvious cause for the neutrophilia. Bone marrow examination is often not helpful. Cytogenetic or molecular testing is definitive for CML if the distinction cannot be made clinically.
Juvenile myelomonocytic leukemia — Juvenile myelomonocytic leukemia (JMML, formerly called "juvenile CML") is a rare fatal disorder of infancy and early childhood characterized by the combination of hepatosplenomegaly, lymphadenopathy, pallor, fever, and skin rash (table 1) [22-24].
Patients with JMML demonstrate clonal overproduction of maturing myeloid cells, usually with an excess of monocytic lineage cells that are hyper-responsive to granulocyte macrophage colony-stimulating factor (GM-CSF), leading to organ infiltration with relatively normal-appearing monocytes and macrophages and death from organ failure or infection [25,26]. In contrast to CML, the karyotype in JMML is normal or sometimes shows monosomy 7, and progression to acute leukemia is rare. Many patients with JMML have mutations in genes that encode elements of the GM-CSF signal transduction pathway, including PTPN11, NRAS and KRAS2, CBL, and NF1 [27-30]. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Epidemiology'.)
It is notable that children and infants can have typical CML. Because of the imprecise older term "juvenile CML" for JMML, it is important to clearly indicate if the case is truly CML by noting that it is "BCR::ABL1 positive or Ph positive." The correct diagnosis will have important treatment implications and must be communicated unambiguously.
Chronic myelomonocytic leukemia — Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm characterized by the overproduction of maturing monocytic cells and sometimes dysplastic neutrophils, often accompanied by anemia and/or thrombocytopenia [31]. Unlike CML, the bone marrow morphology in CMML demonstrates prominent dysplastic changes in at least two of the three myeloid lineages. In addition, genetic testing does not demonstrate evidence of BCR::ABL1, the Ph chromosome or their products. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Diagnosis'.)
"Atypical CML" — "Atypical CML" is a myelodysplastic/myeloproliferative neoplasm that is characterized by features of dysplasia and of myeloid proliferation at the same time. The entity is uncommon, but can cause a considerable diagnostic challenge. Patients are older adults and present with high neutrophil counts but with thrombocytopenia and/or anemia. The bone marrow shows increased cellularity due to a granulocytic proliferation without increased blasts. There is no monocytosis in the blood or marrow. The distinguishing feature of "atypical CML" is the presence of dysplasia in the neutrophils, and sometimes in the megakaryocytes and erythroid forms as well (table 2) [21,32,33].
"Atypical CML" is an unfortunate term for this disorder since it is not a type of CML that is "atypical." It is BCR::ABL1 negative and Ph negative, a finding that should be noted in the diagnosis to avoid confusion. Atypical CML can be associated with other cytogenetic changes including trisomy 8, and isochromosome 17q [34]. In one study, recurrent somatic point mutations of set-binding protein 1 (SETBP1) were identified in 17 of 70 (24 percent) cases of atypical CML; a smaller percentage of cases of myelodysplastic syndrome/myeloproliferative disorder, chronic myelomonocytic leukemia, and chronic neutrophilic leukemia; and none of 458 individuals with other hematologic malignancies [35]. In another study, activating point mutations in the colony stimulating factor 3 receptor (CSF3R) gene were identified in 8 of 18 patients with atypical CML and 8 of 9 patients with chronic neutrophilic leukemia, but only 4 of 344 patients with other leukemias [36]. (See 'Chronic neutrophilic leukemia' below.)
The prognosis of patients with atypical CML is poor, and transformation to acute myeloid leukemia (AML) can occur [37].
Chronic eosinophilic leukemia — Chronic eosinophilic leukemia (CEL) is a rare clonal chronic myeloproliferative disorder characterized by the overproduction of normal-appearing eosinophils in the bone marrow with proliferation in the blood and infiltration into the organs resulting in end-organ damage (table 3). There is only a minor tendency to progress to AML [38].
Cytogenetics in CEL may be normal or exhibit clonal abnormalities including del(4q12), rearrangement of 5q22, 12p12-133, or 8p11. Molecularly, some cases have rearrangements involving the tyrosine kinases PDGFRA, PDGFRB, FGFR1, or JAK2 [21,39,40]. Cases of CEL do not demonstrate the Ph chromosome or BCR::ABL1 gene fusion. However, some cases do respond to imatinib therapy since the underlying molecular pathogenesis is related to overactivity of an imatinib-sensitive tyrosine kinase. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Diagnosis of myeloproliferative variants'.)
Chronic neutrophilic leukemia — Chronic neutrophilic leukemia (CNL) is a rare disorder characterized by mature granulocytic proliferation in the blood and marrow, and infiltration into the organs resulting in hepatosplenomegaly. There is often toxic granulation in the neutrophils, nuclear hypersegmentation and an increased leukocyte alkaline phosphatase (LAP) score (table 4) [33,41-44]. The Ph chromosome and its products are not detected in patients with chronic neutrophilic leukemia. Although these patients do not usually progress to AML, their survival is short and usually less than two years. Effective treatment is uncertain; some patients have responded to interferon [41] and the JAK1/2 inhibitor ruxolitinib [36].
A subset of patients with CNL demonstrates point mutations in the CSF3R gene, which encodes the receptor for CSF3 (previously called G-CSF), an integral part of the regulation of neutrophil production in both steady-state and in response to stress [36,45,46]. In one study, activating point mutations of CSF3R were identified in 8 of 9 patients with CNL and 8 of 18 patients with atypical CML, but only 4 of 344 patients with other leukemias [36]. Further analysis demonstrated two classes of mutations: point mutations involving the juxtamembrane regions, and nonsense or frameshift mutations resulting in truncation of the COOH-terminal cytoplasmic tail of CSF3R. Biochemical studies showed cells carrying CSF3R truncation mutations were sensitive to the multikinase inhibitor dasatinib, while those carrying membrane proximal mutations were sensitive to the JAK inhibitor ruxolitinib. A patient with a CSF3 proximal membrane mutation demonstrated a dramatic response following treatment with ruxolitinib. Together, these findings suggest that mutations in CSF3 have a central role in the pathogenesis of some patients with CNL or atypical CML. Further studies are needed to evaluate the use of tyrosine kinase inhibitors in patients with CSF3R mutations.
It is notable that some patients with myeloma or other immunoproliferative disease with increased plasma cells can have marked neutrophilia. This may be due to the secretion of neutrophil-stimulating cytokines from the plasma cells. Such cases likely represent reactive neutrophilia and not CNL. True cases of CNL should have clonal neutrophils that might be demonstrated by a cytogenetic clone or by clonality studies such as the HUMARA analysis. Rare cases of CML have a p230 BCR::ABL1, and these may be associated with either a prominent neutrophil proliferation or a prominent thrombocytosis. The former (sometime referred to as "CML-N") may be particularly difficult to distinguish from CNL.
Other myeloproliferative neoplasms — A small number of patients present with clinical characteristics of one of the other myeloproliferative neoplasms (eg, essential thrombocythemia or polycythemia vera) but are Ph-positive by cytogenetic analysis. The majority of these patients exhibits a clinical course consistent with CML, including eventual progression to blast crisis, and must be considered CML with an atypical initial presentation [47]. The typical non-CML myeloproliferative neoplasms (polycythemia vera, essential thrombocytosis, and primary myelofibrosis) are BCR::ABL1 negative and Ph chromosome negative, and will not respond to imatinib therapy.
Sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) assays for detection of the BCR::ABL1 fusion mRNA have shown that this product can be detected at low levels in approximately 50 percent of Ph-negative patients with essential thrombocythemia; these individuals do not have a clinical course that is distinctly different from classical essential thrombocythemia [48], and should not be considered CML. The significance of BCR::ABL1 transcripts in this setting requires further investigation. (See "Molecular genetics of chronic myeloid leukemia" and "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia" and "Clinical manifestations and diagnosis of polycythemia vera".)
Although the clinical course and initial blood findings of patients with the other myeloproliferative neoplasms can sometimes overlap with those of CML, the bone marrow evaluation can be helpful in distinguishing them apart. CML has small "dwarf" megakaryocytes, and the other myeloproliferative neoplasms typically have large atypical megakaryocytes. Evaluation for the Ph chromosome by cytogenetics, BCR::ABL1 by FISH, or high levels of BCR::ABL1 transcripts by RT-PCR will usually resolve any difficult cases.
Rare cases have been reported in which patients with JAK2 V617F mutations (commonly seen in the non-CML myeloproliferative neoplasms) later develop the Ph chromosome and BCR::ABL1 [49]. These are quite unusual and are likely cases of non-CML myeloproliferative neoplasms which develop superimposed CML. The opposite sequence of events has also been reported.
Other Philadelphia chromosome-positive malignancies — The Ph chromosome is found in 20 to 30 percent of adults with acute precursor B cell lymphoblastic leukemia (ALL), 5 to 10 percent of childhood ALL, and about 1 percent of adult AML [50]. Patients with Ph-positive acute leukemia are heterogeneous when analyzed at the molecular level. At least some of these patients probably represent CML presenting in blast crisis phase, but others may represent de novo acute leukemia. Ph-positive AML, like Ph-positive ALL and CML lymphoid blast crisis, is characterized by frequent chromosomal deletions of the immunoglobulin heavy chain (IgH) region that are not found in CML myeloid blast crisis, supporting a distinct origin of this disease [51].
Often one can identify the blastic disease and recognize CML in the background in patients who have CML that is presenting in blasts crisis. For example, a patient might present with a white blood cell count of 600,000/microL and have 60 percent lymphoblasts, but 40 percent of the cells (240,000/microL) are immature with maturing neutrophils, a "myelocyte bulge," and basophilia. This is clearly CML with a lymphoid blast crisis superimposed. In such a case the Ph chromosome will be in the lymphoblasts and in the neutrophils, whereas in Ph+ ALL the clone is restricted to the lymphoid cells [52].
The Ph chromosome has been reported rarely in other hematologic malignancies, including multiple myeloma and B cell non-Hodgkin lymphoma [53,54]. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma", section on 't(9;22); BCR::ABL1'.)
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 [55,56].
This improvement over time was illustrated in a study of the Surveillance, Epidemiology, and End Results (SEER) database that analyzed the outcomes of 5138 patients diagnosed with CML before and after the general availability of TKIs [55]. Five-year overall survival (OS) rates in 2000 and 2005, according to patient age at diagnosis, were as follows:
●15 to 44 years – OS 72 versus 86 percent (HR 0.424; 95% CI 0.275-0.654)
●45 to 64 years – OS 68 versus 76 percent (HR 0.716; 95% CI 0.528-0.971)
●65 to 74 years – OS 38 versus 51 percent (HR 0.692; 95% CI 0.518-0.924)
●75 to 84 years – OS 19 versus 36 percent (HR 0.568; 95% CI 0.441-0.734)
A multicenter longitudinal study of patients treated with imatinib beginning before 2005 who achieved complete cytogenetic remission within two years demonstrated an age-adjusted mortality rate that was not significantly different from that of the general population [57].
Attempts have been made to identify patients at diagnosis who have an unfavorable prognosis [58-65]. By far the strongest single predictor of outcome in patients with CML is the stage of disease at the time of diagnosis. Patients with chronic phase at the time of diagnosis can have years of disease control with treatment while those in accelerated phase or blast crisis have a much poorer prognosis.
This observation also holds for the subgroup of patients harboring the BCR::ABL1 T315I mutation, which is resistant to the majority of the currently available TKIs. In a study of 222 such patients, median OS was 22, 28, 4, and 5 months when this mutation was detected during chronic phase, accelerated phase, blast phase, or Ph+ ALL, respectively [66].
As the risk of dying from CML has decreased, the prognostic impact of comorbidities has taken on greater importance. In one large study, the estimated OS rate at eight years decreased with increasing comorbidity as measured by the Charlson Comorbidity Index (CCI) [67]. 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. These results demonstrate that CML is usually well managed with available therapies and deaths are more often likely to occur due to other medical problems. As patients enrolled on a prospective clinical trial are typically more medically fit than the general CML population (due to eligibility requirements), the clinical outcomes for non-protocol candidates may be even more stark.
Scoring systems — A validated prognostic model for CML should be used to assess prognosis and to aid selection of a TKI for initial therapy of CML. (See "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Choosing a TKI'.)
The Sokal, Euro (Hasford), EUTOS, or ELTS (EUTOS long-term survival score) are all acceptable for assessing prognosis in CML (table 5) [58,63,68,69]. 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 treatment of CML with TKIs [69,70]. (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 [59].
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) [58].
Hasford (Euro) — The Hasford (Euro) score adds eosinophilia and basophilia to the clinical features of the Sokal score (described above) (Euro score calculator) [63].
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 (calculator 2) (ELTS score calculator).
Use of prognostic scores for management of CML is described separately. (See "Initial treatment of chronic myeloid leukemia in chronic phase", 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 5th to 6th 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 10th to 12th 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
●Definition – Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm (MPN) associated with the t(9;22)(q34;q11) chromosomal rearrangement, the so-called Philadelphia chromosome (Ph). The rearrangement creates the BCR::ABL1 fusion protein, which drives excessive accumulation of immature and maturing granulocytic cells in blood, bone marrow, liver, and spleen.
●Clinical manifestations – CML can be considered a biphasic or triphasic disease. Most patients present with chronic phase (CP) CML, which is relatively indolent, but occasional patients present with accelerated phase (AP) or blast crisis (BC), which are more advanced disease phases. (See 'Clinical manifestations' above.)
Many patients with CP CML are asymptomatic and the disease is first detected with a routine blood test; other patients may describe constitutional symptoms (fever, sweats, weight loss), abdominal discomfort, or early satiety due to an enlarged spleen. Patients who present with AP or BC CML may have infections, anemia, bleeding, prominent constitutional symptoms, or increasing splenomegaly.
●Pathologic features
•Complete blood count (CBC)/differential count – In CP CML, there is marked leukocytosis (median 80,000/microL), a left shift with circulating immature myeloid cells, blasts are typically <2 percent, and eosinophils and/or basophils are often increased. CBC may also reveal anemia, polycythemia, thrombocytosis, or thrombocytopenia. Blood counts are generally more extreme in AP and BC CML.
•Blood smear – Myeloid cells in CP CML range from myeloblasts to mature neutrophils (picture 1), but they generally are not strikingly dysplastic. AP and BC exhibit more extreme left shift and blasts are markedly increased.
•Bone marrow – Marrow in CP is generally hypercellular with an increase of granulocytic cells (picture 2) and blasts are usually <5 percent of myeloid cells. Other findings include an increased myeloid:erythroid ratio; megakaryocytes may be normal, diminished, or increased; and there may be reticulin fibrosis. AP and BC exhibit more blasts; for most patients these are myeloid blasts, but up to one-quarter have lymphoid blasts.
●Diagnosis – The diagnosis of CML requires detection of the t(9;22)(q34;q11) chromosomal rearrangement (the Ph chromosome) by karyotypic banding (figure 1) or fluorescence in situ hybridization (FISH) and/or BCR::ABL1 RNA transcripts by reverse transcription polymerase chain reaction (RT-PCR). (See 'Diagnosis' above.)
●Differential diagnosis – Disorders that may resemble CML include (see 'Differential diagnosis' above):
•Leukemoid reaction – Marked accumulation of non-malignant granulocytic cells in response to an infection or other inflammatory stimulus
•Other MPNs – Polycythemia vera, essential thrombocythemia, chronic myelomonocytic leukemia
•Other leukemias – Acute myeloid leukemia, Ph+ acute lymphoblastic leukemia/lymphoblastic lymphoma
●Prognosis – Prognosis should be assessed using either the Sokal, Euro (Hasford), EUTOS, or ELTS (EUTOS long-term survival score) models (table 5). (See 'Scoring systems' above.)
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