Chronic myeloid leukemia

Introduction to chronic myeloid leukemia Chronic myeloid leukemia (CML) is a malignant tumor formed by the clonal proliferation of bone marrow hematopoietic stem cells. Most patients have a slow onset, often asymptomatic in the early stage, and gradually develop fatigue, loss of appetite, abdominal fullness, night sweats and weight loss. Further examination was performed due to an increase in white blood cell count or left upper abdomen mass as a result of physical examination. Usually most CML patients are clinically in a "chronic" or "stable" phase, which can last for 3-4 years. Common symptoms include: anemia, spleen discomfort, bleeding and fatigue, weight loss and low fever. Some patients were asymptomatic and were diagnosed by routine physical examination of white blood cell count, increased platelet count, or enlarged spleen. A small number of patients have gout joint pain. In addition, there are visual impairments, neurological diseases, and abnormal penile erections. Patients in the chronic phase are less susceptible to infection and fever is rare. When the disease progresses, the patient begins to have fever, bone pain, splenomegaly, white blood cell counts continue to rise, and primordial cells in the bone marrow or peripheral blood increase. Clinically, it can be divided into chronic phase, accelerated phase and blast phase. basic knowledge The proportion of illness: 0.0005%--0.0008% Susceptible people: no specific population Mode of infection: non-infectious Complications: anemia

Causes of chronic myeloid leukemia

First, the cause of the disease

1. Ionizing radiation can increase the incidence of CML. The incidence of CML in survivors after the atomic bombing in Hiroshima and Nagasaki, patients with ankylosing spondylitis receiving spinal radiotherapy, and cervical cancer receiving radiotherapy is significantly higher than that in other populations.

2, long-term exposure to benzene and various cancer patients receiving chemotherapy can lead to CML, suggesting that certain chemicals are also related to CML.

3. The frequency of HLA antigens CW3 and CW4 in CML patients increased, indicating that it may be a susceptibility gene of CML.

4. Despite the reports of familial CML, CML familial aggregation is very rare. In addition, there is no increase in the incidence of CML in other members of monozygotic twins. The parents and children of CML patients do not have CML-characterized Ph chromosomes, indicating that CML is a kind of Acquired leukemia.

Second, the pathogenesis

1. Originated from hematopoietic stem cells CML is an acquired clonal disease originating from hematopoietic stem cells. The main evidences are:

1CML chronic phase may have red blood cells, neutrophils, acidophilic / basophils, monocytes and thrombocytosis;

The erythroid cells, neutrophils, acidophilic/basophils, macrophages and megakaryocytes of 2CML patients have Ph chromosomes;

3 In G-6-PD heterozygous female CML patients, red blood cells, neutrophils, acidophilic/basophils, monocytes and platelets express the same G-6-PD isoenzyme, fibroblasts Or other somatic cells can detect two G-6-PD isoenzymes;

4 Each of the analyzed cells has the same structural abnormality of chromosome 9 or 22;

5 Molecular biology studies The chromosome 22 breakpoint variation exists only in different CML patients, and the breakpoints are consistent in different cells of the same patient;

6 X-linked gene locus polymorphism and inactivation pattern analysis also confirmed that CML is monoclonal hematopoiesis.

2. Abnormal function of progenitor cells Relatively mature myeloid progenitor cells have obvious cell dynamic abnormalities, low cleavage index, few cells in DNA synthesis stage, prolonged cell cycle, unbalanced nucleoplasm development, mature granulocyte half-life is normal Granulocyte prolongation, using 3H suicide test confirmed that only 20% of CML colonies were in the DNA synthesis stage, while normal humans were 40%, CML original particles, promyelocytic labeling index was lower than normal, and medium and late granulocyte markers There was no significant difference between the index and the normal control. The proliferation of CML myeloid progenitor cells and peripheral blood progenitor cells was different in hematopoietic progenitor colony culture. The number of CFU-GM and BFU-E in bone marrow was usually higher than that of normal controls, but it could also be increased. Normal or decreased, and peripheral blood can be increased to 100 times of normal control. Long-term culture of bone marrow cells in Ph-positive CML patients found that Ph-negative progenitor cells can be detected in the culture medium after several weeks of culture. Mainly due to abnormal adhesion function of CML hematopoietic progenitor cells.

3. Molecular Pathology In 1960, Nowell and Hungerfor described the CML-associated Ph chromosome, which was the first non-random chromosomal abnormality associated with a specific human tumor. Rowley was first confirmed by quinine and Giemsa staining techniques in 1973. The Ph chromosome (22q-abnormal) found in CML is caused by t(9;22)(q34;q11) chromosomal translocation. In 1982, the ABL gene was cloned in the 9q34 break region. In 1983, the gene fragment located in q34 was confirmed. A gene called BCR, which is located on chromosome 22 and the 22q11 cleavage region, forms a BCR-ABL fusion gene.

(1) ABL gene: The proto-oncogene c-abl is located at q34 and is highly conserved during species development. It encodes a protein that is ubiquitously expressed in all mammalian tissues and various cell types. The c-abl is about 230 kb long. Containing 11 exons, the 5' end to the centromere, the first exon of this gene has two forms, exons 1a and 1b, thus there are two different c-abl mRNAs, first The species is called 1a-11, 6kb long, including exon 1a-11; the other is called 1b, starting from exon 1b, spanning exon 1a and the first intron, the same exon 2 -11 is connected to a length of 6 kb. The RNA transcription of these two ABLs encodes two different ABL proteins with a molecular weight of 145,000. DNA sequence analysis revealed that c-abl belongs to the non-receptor protein-tyrosine kinase family. In addition to the kinase fragment, the gene also has SH2 and SH3 fragments that are important in the interaction and regulation of signaling proteins. C-abl is characterized by a large C-terminal non-catalytic fragment that contains DNA and cytoskeleton binding. The important sequence and a region involved in the signal, the normal p145ABL shuttles between the nucleus and the cytosol It is mainly located in the nucleus and has low tyrosine kinase activity. The activity and intracellular localization of p145ABL are regulated by integrins of the cytoskeleton and extracellular matrix. Existing studies have shown that at least in fibroblasts, ABL is activated. Cell adhesion is required, so ABL may be involved in cell growth and differentiation control by transmitting integrin signaling to the nucleus to act as a bridge between adhesion and cell cycle signals.

(2) BCR gene: BCR gene is located at 22q11, 130 kb in length, with 21 exons, starting from the 5' end to the central granule, with 4.5 kb and 6.7 kb of different BCR mRNA transcription patterns, encoding a molecular weight For the 160,000 protein p160 BCR, the protein has kinase activity, and the C-terminus of p160 BCR is associated with the GTP activity of the ras-associated GTP-binding protein p21.

(3) BCR-ABL gene: The c-abl gene located at 9q34 is located on chromosome 22 and the bcr gene located at 22q11 forms a BCR-ABL fusion gene. So far, three bcr breakpoint clusters have been found in CML patients. M-bcr, m-bcr, u-bcl and 6 BCR-ABL fusion transcription modes, corresponding to M-bcr, b2a2, b3a2, b2a3, the encoded protein is p210, and corresponding to m-bcr, there is ela2, The encoded protein is p190, and corresponding to u-bcr, there is e19a2, and the encoded protein is p230.

BCR-ABL has been shown to cause CML in mouse models. The BCR-ABL fusion protein is localized in the cytoplasm and has a very high tyrosine kinase activity by altering some of the key regulatory proteins of the BCR-ABL catalytic substrate. The status of activation activates a variety of signaling pathways, such as by activating the Ras signaling pathway involved in cell proliferation and differentiation, increasing the number of progenitor cells, reducing the number of stem cells, and making stem cells part of the proliferation pool, thereby allowing immature granulocytes to expand, Another mechanism of BCR-ABL action is to alter normal integrin function. Normal hematopoietic progenitor cells adhere to the extracellular matrix, and adhesion is mediated by progenitor cell surface receptors, especially integrins. BCR-ABL interferes with 1. The function of integrins leads to defects in the cell adhesion function of CML cells, thereby releasing immature cells to the peripheral blood and migrating to the extramedullary space.

Recently, research on the pathogenesis of CML has made progress:

1 In vitro culture found that BCR-ABL prolongs the factor-independent growth time of CML progenitor cells by inhibiting apoptosis;

2 Down-regulation of BCR-ABL expression by antisense oligonucleotide may inhibit the growth of leukemia cells in mice by increasing the sensitivity of cells to apoptosis, especially reducing the formation of early progenitor colonies in CML patients and reducing CML-like cell lines. Cell proliferation;

3 expression of BCR-ABL, transformed, factor-independent, tumorigenic mouse hematopoietic cells increased sensitivity to apoptosis by up-regulating bcl-2, BCR-ABL when bcl-2 expression is suppressed Positive cells have become factor-dependent and non-tumorigenic. The above experimental results indicate that BCR-ABL inhibits apoptosis and leads to the continuous expansion of myeloid cells, which is another pathogenesis of CML.

(4) Mechanism of catastrophic changes: Cytogenetic studies have found that 80% of patients with AP or BP CML have secondary chromosomal abnormalities. The most common abnormalities are +8, +Ph, i(17), +19, +21 and -Y, about 80% of patients with acute myeloid leukemia (acute granulosis) have non-random sex chromosomal abnormalities, and their karyotype often appears as hyperdiploid, the most common abnormality is +8, and +8 often Similar to other chromosomal abnormalities such as i(17), +Ph, +19, followed by +Ph, i(17) and -Y, about 30% of patients with acute lymphocytic leukemia (urgent leaching) Sexual clonal chromosomal abnormalities, often chromosome loss, which manifest as subdiploid or structural abnormalities, common abnormalities are +Ph and -Y, +8 rare, i (17) has not been reported, -7,14q+ and acute shower Variable specificity, although studies have found that CML has N-Ras mutation and c-Myc gene expression in the blast phase, but its incidence is extremely low, Rb gene in the blast phase CML patients rarely change, Sill et al found p161NK4A gene The homozygous deletion is associated with CML acute leaching, and the CML acute molecular mechanism is still more p53 gene, 20% to 30% of patients with acute granules There are abnormalities in the structure and expression of p53 gene. The characteristics of CMLp53 gene change are: 1 major changes are gene rearrangements and mutations; 2 mainly seen in acute granulation, acute leaching is rare; 3p53 mutation is common in patients with 17P-abnormal; 4p53 Mutation can lead to acute granulocyte change of CML. Recently, there are reports on the degree of methylation of calmodulin gene, the relationship between telomere length and telomerase activity and CML blast, but its significance needs further clarification.

Chronic myeloid leukemia prevention

Avoid or reduce the exposure of harmful substances such as radioactive substances, chemicals, and chemicals.

Chronic myeloid leukemia complications Complications anemia

1. Some patients in the chronic phase may have splenic embolism, spleen rupture, and spleen hemorrhage.

2, acceleration period, blast period can be combined with infection, fever, anemia, heart failure and other complications, acute gouty arthritis can be complicated by the lung, central nervous system, some special sensory organs and penis and other circulating blood flow Obstructed, the corresponding symptoms and signs, such as shortness of breath, difficulty breathing, cyanosis, dizziness, unclear language, convulsions, coma, blurred vision, tinnitus, hearing loss and abnormal erection of the penis.

Symptoms of chronic myeloid leukemia Common symptoms Leukocytosis Bone pain Splenomegaly Lymph node enlargement Liver enlargement Low heat Weight loss Thoracic tenderness Joint pain

Chronic phase

(1) Symptoms: Most patients with CML are usually in a chronic or stable phase. This period lasts for 3 to 4 years. Common symptoms include: anemia, spleen discomfort, bleeding and fatigue, weight loss and low fever. Such as the increase in metabolism, 20% to 40% of patients with asymptomatic, due to routine physical examination found that the number of white blood cells, increased platelet count or spleen enlargement diagnosis, a small number of patients with gouty facet joint pain, in addition, visual impairment, nerve Systemic lesions and abnormal penile erections, etc., chronic phase patients are less susceptible to infection, fever is rare.

(2) Signs: mainly manifested as organ infiltration, 90% of patients with splenomegaly, varying degrees, ribs can reach the spleen extended to the pelvic cavity, hard and often have obvious incision, spleen area can touch the sense of friction when spleen embolism Or smell of friction, there may be mild to moderate hepatic enlargement, lymphadenopathy is rare, sternum often tenderness, with the lower end of the sternum stem, retinal infiltration of the fundus, visible retinal vasospasm dilatation, and can be seen in the form of flaky Bleeding spots and white infiltration centers.

2. The catastrophic period

After several months or years in the chronic phase, malignant hematopoietic stem cells are extremely proliferated, bone marrow granules + promyelocytic cells 20%, may be associated with changes in myelofibrosis caused by excessive platelet-derived growth factor, and when each patient changes rapidly It is not yet predictable that in the event of a rapid change, the condition deteriorates rapidly and the treatment is very difficult. The survival period rarely exceeds 6 to 12 months.

(1) Symptoms: There is fever of unknown cause, the spleen is further enlarged; bone infiltration, bleeding and extramedullary mass such as infiltration, such as lymphadenopathy, soft tissue mass or osteolytic lesions.

(2) Rapid change type:

1 about 65% for acute granulation: including: A. primordial granulocyte crisis, sudden sudden changes in the disease, a large number of granulocytes in the bone marrow or blood, the original granule + early granules > 90%, the disease develops rapidly, the course of disease Short, usually within 1 to 2 months of death; B. Slow-granular blast, refers to the conversion process of CML over several weeks to several months, all signs of acute leukemia, the original + early granules in the bone marrow >20%, resistant to treatment The medicine has a survival period of no more than 6 months.

2 about 30% for acute leaching: including common acute lymphoblastic leukemia (C-ALL), non-T non-B lymphocytic leukemia, pre-B-cell leukemia and B, T-cell leukemia, acute leaching after vincristine and splashing Nisson was temporarily relieved, but eventually died within 0.5 to 1 year.

35% are other rare types of acute marrow changes: including tissue cell changes, erythroleukemia, megakaryocyte changes and acute mononuclear cell changes, blood, bone marrow, cell morphology and other changes have their corresponding characteristics, and poor prognosis, Most patients die within 6 months after a sudden change.

3. Acceleration period

Between the chronic phase and the acute phase, this period begins with low fever, splenomegaly, anemia, gradual increase in anemia, white blood cells continue to rise, immature cells begin to increase, granules + early granules 10%, effective drugs Drug resistance can develop into a typical acute phase within weeks or months. The chromosome has changed in this phase, such as the acute phase, so the chromosome change is earlier than hematological and clinical changes, and can be used as disease progression and prognosis. The indicator of judgment.

Typical CML is accompanied by splenomegaly, and the number of white blood cells in peripheral blood is increased. It can be seen that immature granulocytes, eosinophils and basophils in all stages, and myeloproliferation are marked or extremely active, mainly granulocyte cell proliferation, neutral and young. Rod-shaped granulocytes are proliferated, eosinophils and/or basophils are also increased, megakaryocyte cell lines are often proliferating, neutrophil alkaline phosphatase score (ALP) is reduced, and cytogenetic examination has Ph chromosome or application. Molecular biological methods to detect BCR-ABL gene rearrangement or fusion, diagnosis is not difficult.

Examination of chronic myeloid leukemia

Chronic phase

(1) Blood: The number of white blood cells is often >50×109/L, sometimes up to 500×109/L, and about 1/3 of patients have hemoglobin <110g/L. Most of the anemia is positive pigmentation of normal cells, and platelets tend to increase, sometimes up to 1000 × 109 / L, a small number of patients can be reduced normally, blood smear examination can be seen in different stages of granulocytes, in the middle, late granulocyte stage, raw material cells <5%, primary particles + promyelocytes 10 %, eosinophilic and basophilic granulocytes, a small number of nucleated red blood cells.

(2) Bone marrow: hyperplasia is extremely active or significantly active, with granules as the ratio, the ratio of granules to red can be increased to 10:1 to 20:1, and the granules increase at each stage. Mainly, the ratio of eosinophils to basophils was significantly higher than normal, and megakaryocytes and platelets also increased.

(3) Neutrophil alkaline phosphatase (ALP): The staining score is reduced or close to zero.

(4) Cytogenetic and molecular biological examination: more than 90% of patients with chronic phase of the bone marrow are often positive for Ph chromosome, and the zoning technique proves that the chromosome 3 long arm 3 region 4 band and the 22 chromosome 1 region 1 band segment Mutual translocation, ie t(9;22)(q34;11), fluorescein chromosome in situ hybridization (FISH) is more sensitive, extracting DNA from bone marrow or peripheral blood mononuclear cells, which can be detected by Southern blotting Bcr gene rearrangement occurs at the 5th end (b3a2). If bone marrow or blood mononuclear cell RNA is extracted, bcr/abl transcript mRNA can be detected by reverse transcription polymerase chain reaction (RT-PCR). The most sensitive and specific method.

(5) Serum biochemical assay: serum uric acid, lactate dehydrogenase and lysozyme are often increased.

2. The catastrophic period

Anemia is rapidly aggravated, and the number of granulocytes in bone marrow and peripheral blood is significantly increased. The bone marrow granulocytes are 20%. If it is an acute crisis, it can reach more than 90% of the card. Thrombocytopenia. Neutrophic nucleus cells can be alkaline phosphatase. Elevated or normal, genetically examined, often aneuploid, in addition to the Ph chromosome of t(9;22)(q341;q11), also attached to other chromosome abnormalities, such as the emergence of a second Ph chromosome, or more A chromosome 8 (+8), or an arm of the long arm of chromosome 17 (ISO17q-).

3. Acceleration period

White blood cells continue to rise, immature cells begin to increase, and the original particles + early young granules 10%.

1. Bone marrow biopsy pathological section silver staining often shows reticular fiber hyperplasia, about half of patients with significant proliferation.

2. According to the condition, symptoms and signs, choose X-ray, CT, MRI, B-ultrasound, electrocardiogram and other tests.

Diagnosis and diagnosis of chronic myeloid leukemia

First, the diagnostic criteria

Typical CML, also known as chronic myeloid leukemia (CGL), must be positive for the Ph chromosome-positive BCR-ABL fusion gene, or negative for the Ph chromosome, but positive for the BCR-ABL fusion gene, and must be one of the following: 1 Peripheral blood leukocytes increased, mainly neutrophils, immature granulocytes >10%, primordial cells (I + II type) <10%, 2 myeloid hyperplasia was extremely active, with neutral mesenchymal cells and The following stages are mainly neutrophils, and the original cells (type I+II) are <10%.

1. Staging criteria Because 90% of CML has a chronic phase of about 3 years after the median period, it will inevitably enter the accelerated phase, and finally develop to the blast phase, ending with acute leukocyte disease, so it is necessary to understand the characteristics of each period, below Introduce the staging standards currently applied in China.

(1) Chronic period:

1 clinical manifestations: asymptomatic, or only low fever, fatigue, sweating, weight loss and other symptoms.

2 blood: white blood cell count is increased, mainly neutral, young, young, rod and granulocyte, primordial cells (I + II type) <10%, alkalophilic and eosinophilia, may have a small amount of childish Red blood cells.

3 bone marrow: hyperplasia is extremely active, mainly granulocyte hyperplasia, middle, young and rod-shaped granulocytes, primordial cells (I + II type) <10%.

The 4Ph chromosome and/or BCR-ABL fusion gene is positive.

5 Peripheral blood CFU-GM culture: the number of colonies and clusters was significantly higher than normal.

(2) If the acceleration period has any of the following 2 items, it can be diagnosed.

1 Unexplained fever, anemia, increased bleeding and/or bone pain.

2 spleen progressive enlargement.

3 non-drug-induced platelet progressive reduction or increase.

4 peripheral blood basophils >20%.

5 primordial cells (I+II type) in peripheral blood and/or bone marrow 10%, but <20%.

6 bone marrow pathology has significant proliferation of collagen fibers.

7 chromosomal abnormalities other than the Ph chromosome (8, 17, 19 and 22 are the most common).

8 failed treatment of traditional anti-CGL drugs.

9CFU-GM proliferation and differentiation defects, clustering increased, cluster/column ratio increased.

(3) Anyone of the following can be diagnosed during the catastrophic period.

1 Peripheral blood or bone marrow, primordial cells (type I+II), or primitive+naive lymphocytes, or primordial + naive monocytes 20%.

2 peripheral blood blasts (type I + II) + promyelocytes 30%.

3 bone marrow blast cells (type I + II) + promyelocytes 50%.

4 extramedullary primordial cells infiltrated.

The staging criteria of the International Bone Marrow Transplant Registry in 1987 were generally the same as the domestic standards.

2, CML variant

(1) chronic neutrophilic leukemia (CNL): patients with Ph chromosome negative, BCR-ABL fusion gene negative, ANL clinical manifestations and hematological changes are also different from typical CML, patients usually only mild spleen Swollen; peripheral blood leukocytes increased by (30 ~ 50) × 109 / L, the vast majority of mature neutral lobular nucleated cells, basophils usually do not increase, ALP staining scores increased; bone marrow is also mature The neutrophils are predominant, and the progression of the disease is roughly the same as that of CGL. In 2001, the new classification scheme of WH0 myeloid tumors has classified CNL into myeloproliferative diseases and no longer belongs to CML.

(2) Chronic myelomonocytic leukemia (CMML): patients with Ph chromosome negative, BCR-ABL fusion gene negative, its clinical and hematological changes are also different from typical CML, the patient's spleen usually does not enlarge, or only mild swelling Large; peripheral blood leukocyte elevation is low, rarely >100 × 109 / L, naive neutrophils <5%, and mature monocytes increased significantly, absolute number > 1 × 109 / L; granules in bone marrow Hyperplasia is obvious, mature monocytes are also slightly increased, the proportion of young red blood cells is often >15%, but the lines are basically no pathological hematopoiesis, or even light; the disease progresses faster than CGL, the treatment effect is poor, 2001 WHO myeloid tumor classification The regimen has classified CMML into myelodysplastic/myeloproliferative disorders (MD/MPD).

(3) juvenile CML (jCML): occurs in adolescent DML, most in clinical manifestations, hematological changes and cytogenetics and typical CML, only the same disease occurs in young people, but another Adolescent CML is a disease different from typical CML:

1 Its Ph chromosome is negative, the BCR-ABL fusion gene is also negative, and there are no other chromosomal abnormalities.

2 Clinically, there is often skin damage, and the disease progresses rapidly, similar to acute myeloid leukemia (AML).

3 The bone marrow and monocyte cell lines are simultaneously proliferated, and the original cells are <20%. It is suggested to be called juvenile mohocytic leukemia.

4 The increase of white blood cells is lower than that of typical CML, and the proportion of immature granulocytes is higher, but basophils are normal or only slightly increased, while monocytes are >1×109/L.

Five characteristic features of hemoglobin electrophoresis showed that 50% of patients had elevated HbF, while HbA2 decreased, and red blood cell carbonic anhydrase levels decreased.

6 platelets are often reduced, and bone marrow megakaryocytes are also reduced.

CML with the above characteristics, called jCML, is very similar to the single gamma syndrome, but the chromosome examination can identify it. In the above new WHO classification scheme, jCML has been classified into MD/MPD.

(4) Atypical CML (atypical CML, aCML): aCML and typical CML have similar abnormalities in clinical and laboratory tests, but to a lesser extent, so called aCML (including splenomegaly, white blood cell liters) High amplitude, immature neutrophil ratio and number of basophils). In addition, aCML often has anemia, peripheral blood mononuclear cells increase slightly, 1/3 of patients have elevated ALP scores, and bone marrow erythroid cells are relatively more. And with multi-lineage disease, hematopoiesis often ends with bone marrow failure as the disease progresses, and acute is rare. The main difference between aCML and typical CML is that both the Ph chromosome and the BCR-ABL fusion gene are negative, and there are often other chromosomal abnormalities. For example, the prognosis of the trisomy 8 is significantly worse than that of the CGL, and the median survival time is only 1 to 1, 5 years. In the above new WHO classification scheme, aCML has also been classified into MD/MPD.

3. Stages according to prognostic factors: Some foreign scholars have proposed some staging criteria based on poor prognostic factors or regression equation calculation results.

Grouping: Although several grouping patterns have been proposed, it has so far been recognized as the relative risk formula proposed by Sokal et al. (1984) in the International CMI, Prognostic Study Group:

Male is 1, female is 2, hematocrit is calculated in %, and the relative risk value is calculated according to the above formula. CML patients can be divided into low-risk group (<0, 8), intermediate risk group (0, 8~1, 2) ) and high risk groups (> 1, 2).

Since the above formula is mainly inferred from patients with conventional chemotherapy (mainly busulfan and hydroxyurea), the value of patients treated with IFN- is relatively poor. Recently, Hasford et al. treated patients with IFN- according to 1300 cases. The information presented a new point system.

Clinically, patients with unexplained spleen are obviously swollen, sternal tenderness, peripheral white blood cell count is significantly increased, and (or) basophilic, eosinophilic patients should be alert to the presence of CML, timely blood smears carefully observed Nuclear cell morphology, such as the occurrence of a certain number of neutral late, mesozoic cells, after the exclusion of leukemia-like reactions, can make a preliminary diagnosis of CML, so attach importance to clinical examination and blood routine examination, can be the diagnosis of CML Provide valuable information.

Bone marrow puncture shows hyperplasia or hyperactivity, and is mainly granulocyte lineage, mainly neutral mesangial cells and neutrophils in the following stages, which can be basically diagnosed as CML. According to international standards, CML should be diagnosed. Genetic and/or molecular biological evidence that the Ph chromosome and/or BCR-ABL fusion gene is detected, or at least the BCR-ABL fusion protein expressed by the latter is detected, especially in clinical or hematological atypical In cases, it is necessary to carry out this examination to improve the level of diagnosis and differential diagnosis.

Second, differential diagnosis

1, in atypical cases CML should be associated with leukemia-like differential leukemia reaction can be secondary to shock, severe infection, tuberculosis, advanced tumor or pregnancy, late, white blood cell count is less than 50 × 109 / L, neutral The cell alkaline phosphatase staining score is often increased, without the abnormality of Ph chromosome and bcr/abl fusion gene. After the primary disease is controlled, the white blood cells can return to normal, and need to be differentiated from primary myelofibrosis (MF), MF Often there are obvious splenomegaly, white blood cells and platelets can be increased, young particles appear in blood, young red blood cells, easy to be confused with CML, but MF patients with Ph chromosome negative, bone marrow biopsy reticular fibers and collagen fibers hyperplasia.

2. The clinical manifestations of Ph-positive ALL and CML without acute phase were similar. The splenomegaly was more obvious. The chromosomal karyotype of Ph-positive ALL could be restored to normal during remission, and recurred when recurred. It is difficult to reduce the Ph chromosome, and it is accompanied by additional chromosomal abnormalities. From the molecular level, it can be found that about half of the Ph-positive ALL fusion gene and its expression product are identical to CML, the breakpoint is in M-bcr, and the bcr/abl product is p210. The other half of the Ph-positive ALL has a breakpoint of about 40 kb in the M-bcr region upstream of M-bcr, and the protein product is p190. As a genetic test, primers and probes different from Ph-positive CML are needed to distinguish CML.

3, CML also needs to be identified with several related diseases of the original CML because they have elevated peripheral blood leukocytes, immature granulocytes; bone marrow hyperplasia is obvious or extremely active, mainly granulocyte system; often accompanied by splenomegaly Signs, CML and the identification of these related diseases are the detection of Ph chromosome and bcr/abl fusion gene, CML is positive, and the related diseases are negative, and other identification points are briefly listed below.

(1) Chronic neutrophilic leukemia (CNL): The proliferating cells in the bone marrow are mainly mature neutral lobular nucleated cells, and the peripheral blood neutrophil alkaline phosphatase (ALP) staining score is often increased, currently WHO CNL has been classified in the classification of myeloproliferative diseases.

(2) Atypical CML (aCML): It is essentially a disease that is completely different from typical CML, and the name is not suitable. ACML has anemia in the early stage of the disease, thrombocytopenia, and the increase of white blood cells is low, or does not increase. Peripheral blood basophils are rare or absent; bone marrow often has one or more pathological hematopoiesis; splenomegaly is not significant; late stage often manifests as bone marrow failure, acute changes <50%.

(3) Chronic myelomonocytic leukemia (CMML): CMML with myelodysplastic syndrome (MDS) in the original FAB classification has obvious pathological hematopoiesis and blastocytosis (RAEB), accompanied by peripheral blood mononuclear cells > 1×109/L, which is not easy to be confused with CML. Another type of proliferating CMML should be carefully identified. Except for the above-mentioned Ph chromosome and bcr/abl fusion gene, peripheral blood mononuclear cells are >1×109/L. The main point of identification.

(4) juvenile granulocyte monocytic leukemia (JMML): is a very rare childhood chronic myeloid leukemia, clinically often with fever, anemia, especially with skin lesions, such as facial rash, yellow tumor and milk coffee spot The peripheral blood mononuclear cells >1×109/L are the distinguishing points from CML. The above aCML, CMMIL and JMML are classified into myelodysplastic syndrome/myeloproliferative diseases (MDS/MPD) in the WHO classification.

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