Introduction:
Chronic myeloid leukemia(chronic myelocytic leukemia, CML) is a proliferative disease of hematopoietic stem cell cloning. The bone marrow is characterized by myeloid hyperplasia, peripheral blood leukocytosis and splenomegaly.
Cause:
(1) Causes of the disease
Ionizing radiation can increase the incidence of CML. The incidence of CML in survivors after Hiroshima and long-term atomic bombing, in patients with ankylosing spondylitis receiving spinal radiotherapy, and cervical cancer receiving radiotherapy is significantly higher than in other populations. Long-term exposure to benzene and various cancer patients undergoing chemotherapy can lead to CML, suggesting that certain chemicals are also involved in CML. The increased frequency of HLA antigens CW3 and CW4 in CML patients suggests that it may be a susceptibility gene for CML. Despite the reports of familial CML, CML familial aggregation is very rare, and 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 an acquired Leukemia has nothing to do with genetic factors.
(two) 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 Thrombocytopenia; erythroid cells, neutrophils, acidophilic/basophils, macrophages, and megakaryocytes in both CML patients have Ph chromosome; 3 in G-6-PD heterozygous female CML patients, red blood cells, Neutrophils, eosinophils/basophils, monocytes, and platelets express the same G-6-PD isoenzyme, and fibroblasts or other somatic cells can detect both G-6-PD The enzymes of each of the analyzed cells have the same structural abnormality of chromosome 9 or 22; 5 molecular biology studies the breakpoint mutation of chromosome 22 exists only in different CML patients, and the breakpoints in different cells of the same patient Consistent; 6 application of X-linked locus polymorphism and inactivation pattern analysis also confirmed that CML is monoclonal hematopoiesis.
2. Abnormal progenitor cells have obvious cell dynamics abnormalities in the mature myeloid progenitor cells, with low cleavage index, few cells in the DNA synthesis phase, prolonged cell cycle, unbalanced nucleoplasm development, and mature granulocyte half-life is normal. Granulocyte elongation. The 3H suicide test confirmed that only 20% of CML colonies were in the DNA synthesis stage, while normal humans were 40%. The CML primary and promyelocytic labeling index was lower than that of normal people, while the middle and late myelocyte marker index was normal. There is no significant difference compared to the photo. Hematopoietic progenitor colony culture showed that the proliferation ability of CML myeloid progenitor cells and peripheral blood progenitor cells was different. The number of CFU-GM and BFU-E in bone marrow was usually higher than that of normal controls, but it could be normal or decreased, while peripheral blood could be elevated. Up to 100 times the normal control. Long-term culture of bone marrow cells in Ph-positive CML patients revealed that Ph-negative progenitor cells were detected in the culture medium after several weeks of culture, which has been confirmed to be mainly due to abnormal adhesion 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. In 1973, Rowley used quinine and Giemsa staining techniques to demonstrate for the first time that the Ph chromosome (22q-abnormal) found in CML was caused by t(9;22)(q34;q11) chromosomal translocation. The ABL gene was cloned in the 9q34 break region in 1982. In 1983, it was confirmed that the gene fragment located in q34 translocated to chromosome 22 and a gene called BCR in the 22q11 fragmentation region formed 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 trend is from the 5' end to the centromere. The first exon of this gene has two forms, exons 1a and 1b, and thus there are two different c-abl mRNAs. The first one is called 1a-11 and is 6 kb long, including exons 1a-11. The other, called 1b, starts from exon 1b, spans exon 1a and the first intron, and is adjacent to exon 2-11, and is 6 kb in length. RNA transcription coding of these two ABLs Two different ABL proteins with a molecular weight of 145,000. DNA sequence analysis found. C-abl is a non-receptor protein-tyrosine kinase family. In addition to the kinase fragment, this gene also has SH2 and SH3 fragments that are important in the interaction and regulation of signaling proteins. C-abl is characterized by a A large C-terminal non-catalytic fragment containing an important sequence of DNA and cytoskeleton binding and a region involved in the signal. Normal p145ABL shuttles between the nucleus and the cytosol, mainly localized to the nucleus, and has a 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 activation requires cell adhesion, so ABL may transmit integrin signaling to the nucleus. Thus acting as a bridge between adhesion and cell cycle signals, involved in cell growth and differentiation control.
(2) BCR gene: The BCR gene is located at 22q11, 130 kb in length, with 21 exons, starting from the 5' end to the central granule. There are two different BCR mRNA transcription patterns of 4.5 kb and 6.7 kb, encoding a protein p160 BCR with a molecular weight of 160,000, which has kinase activity. 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, which are M-bcr, m-bcr, u-bcl and 6 BCR-ABL fusion transcription modes, and b2a2, b3a2, b2a3 corresponding to M-bcr. The encoded protein is p210, 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 in vivo. The BCR-ABL fusion protein is localized in the cytoplasm and has extremely 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 β1. 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, the pathogenesis of CML has progressed: 1 In vitro culture, BCR-ABL prolongs the factor-independent growth time of CML progenitor cells by inhibiting apoptosis; 2 After down-regulating BCR-ABL expression by antisense oligonucleotides It is possible to inhibit the growth of leukemia cells in mice by increasing the sensitivity of cells to apoptosis, especially to reduce the formation of early progenitor cells in CML patients and reduce the cell proliferation of CML-like cell lines; 3 expressing BCR-ABL, transformed, Factor-independent, tumorigenic mouse hematopoietic cells increase sensitivity to apoptosis by upregulating bcl-2. When bcl-2 expression is inhibited, BCR-ABL positive cells 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 with other chromosomes Abnormalities such as i(17), +Ph, and +19 occur simultaneously, followed by +Ph, i(17), and -Y. About 30% of patients with acute lymphoblastic leukemia (acute lymphocytosis) have secondary clonal chromosomal abnormalities, often chromosome loss, which is characterized by subdiploid or structural abnormalities. Common abnormalities are +Ph and -Y, + 8 rare, i (17) has not been reported, -7, 14q + and acute lymphoblastic specific. Although studies have found that CML has a mutation in N-Ras gene and an increase in c-Myc gene expression in blast crisis, its incidence is extremely low. The Rb gene is rarely altered in patients with blast crisis. Sill et al. found that the homozygous deletion of the p161NK4A gene is associated with CML acute leaching. The most important molecular mechanism of CML is the p53 gene. 20% to 30% of patients with acute granulosis have abnormalities in p53 gene structure and expression. The characteristics of CMLp53 gene change are: 1 major changes are gene rearrangement and mutation; 2 mainly seen in acute granules, acute leaching is rare; 3p53 mutations are common in patients with 17P-abnormalities; 4p53 mutations can lead to acute granulocyte changes in CML. Recently, there have been reports on the relationship between the degree of methylation of the calmodulin gene, the change of telomere length and telomerase activity and the rapid change of CML, but its significance needs to be further clarified.
symptom:
Chronic phase
(1) Symptoms: Usually, most CML patients are clinically in a “chronic” or “stable” phase, which lasts for 3 to 4 years. Common symptoms include: anemia, spleen discomfort, bleeding and fatigue, weight loss and low fever. 20% to 40% of patients are asymptomatic, 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.
(2) Signs: mainly manifested as organ infiltration. 90% of patients have splenomegaly, varying degrees, and the spleen can reach the spleen and the spleen extends to the pelvic cavity. When the spleen is embolized, the spleen area may touch the friction or smell the friction sound. There may be mild to moderate hepatic enlargement, and lymphadenopathy is rare. The sternum often has tenderness, with the lower end of the sternum stem. Retinal infiltration of the fundus, visible retinal vasospasm dilatation, and visible flaky hemorrhage and white infiltration center.
2. After a few months or years in the blast phase of 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. It is not predictable when each patient will change rapidly. In the event of a sudden change, the condition deteriorates rapidly and the treatment is very difficult. The survival period rarely exceeds 6 to 12 months.
(1) Symptoms: fever of unknown cause, further enlargement of spleen; infiltration of bone pain, hemorrhage and extramedullary mass, 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 of CML over several weeks to several months, all signs of acute leukemia. The original + early juvenile in the bone marrow is >20%. Resistant to treatment, the survival period is no more than 6 months.
2 about 30% for acute lymphoblastic: including common acute lymphoblastic leukemia (C-ALL), non-T non-B lymphocytic leukemia, pre-B-cell leukemia and B, T-cell leukemia. Acute diarrhea can be temporarily relieved by vincristine and prednisone, but eventually died within 0.5 to 1 year.
35% are other rare types of acute myeloid changes: including tissue cell changes, erythroleukemia, megakaryocyte changes, and acute monocyte changes. Changes in blood, bone marrow, and cell morphology have their corresponding characteristics, and the prognosis is poor. Most patients die within 6 months after the sudden change.
3. The acceleration period is between the chronic phase and the acute phase. In this period, the phenomenon of hypothermia and splenomegaly begins to appear in the clinic. The anemia gradually increases, the white blood cells continue to rise, the immature cells begin to increase, and the original granules + early granules ≥10%. The original effective drug appeared to be resistant. It can evolve into a typical acute phase in weeks or months. Chromosomes have changed in this phase, such as the acute phase, so chromosome changes are earlier than hematological and clinical changes, and can be used as indicators of disease progression and prognosis.
The typical CML is accompanied by splenomegaly, and the number of white blood cells in the peripheral blood is increased. It can be seen that immature granulocytes, eosinophils and basophils are increased in each stage. Myeloid hyperplasia is marked or extremely active, mainly granulocyte cell proliferation, moderately young and rod-shaped granulocytes are proliferated, eosinophils and/or basophils are also increased, and megakaryocyte cell lines often proliferate. Neutrophil alkaline phosphatase score (ALP) is reduced. Cytogenetic examination of Ph chromosome or application of molecular biology methods to detect BCR-ABL gene rearrangement or fusion, diagnosis is not difficult.
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. At the same time, there must be one of the following two: 1 peripheral blood leukocytes increased, mainly neutrophils, immature granulocytes > 10%, primordial cells (I + II type) < 10%. 2 Myeloid hyperplasia was marked to be extremely active, with neutral neutrophils and neutrophils in the following stages, and the original cells (I+II type) <10%.
1. Staging criteria Because 90% of CML has a moderate period of about 3 years after the chronic phase, 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. The following describes 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 granulocytes increased, and the original cells (type I+II) <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 Ph chromosomes (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) Any of the following in the blast phase can be diagnosed.
1 Peripheral blood or bone marrow, primordial cells (type I+II), or primitive+naive lymphocytes, or primordial + naive monocytes ≥20%.
2 peripheral blood blasts (I+II type) + 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): The patient's Ph chromosome is negative and the BCR-ABL fusion gene is negative. The clinical manifestations and hematological changes of ANL are also different from typical CML. Patients usually have mild spleen enlargement; peripheral blood leukocytes increase by (30-50)×109/L, and most of them are mature neutral scores. Leaf nucleus cells, basophils usually do not increase, ALP staining scores increase; bone marrow is also dominated by mature neutrophils, and the progression of disease is roughly the same as CGL. In 2001, the new classification scheme for WH0 myeloid tumors has classified CNL into myeloproliferative diseases and is no longer attributed to CML.
(2) Chronic myelomonocytic leukemia (CMML): The patient's Ph chromosome is negative and the BCR-ABL fusion gene is negative. The clinical and hematological changes are also different from the typical CML. The patient's spleen usually does not enlarge, or only slightly enlarges; the peripheral blood leukocyte rise is relatively low, rarely >100×109/L. Naive neutrophils <5%, and mature monocytes increased significantly, the absolute number >1 × 109 / L; granulocyte hyperplasia in the bone marrow, mature monocytes also slightly increased, the proportion of young red blood cells often >15%, However, the lines are basically pathologically hematopoietic, or even light; the disease progresses faster than CGL, and the treatment effect is poor. The 2001 WHO Myeloid Tumor Classification Program has classified CMML into myelodysplastic/myeloproliferative disorders (MD/MPD).
(3) juvenile CML (jCML): occurs in adolescent DML, most of the clinical manifestations, hematological changes and cytogenetics and typical CML, only the same disease occurs in young people. However, another juvenile 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 is called jCML. It is very similar to the monomeric gamma syndrome, but it can be identified by chromosome examination. 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 examinations, 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, ALP scores increase in 1/3 of patients, bone marrow erythroid cells are relatively more, and multi-lineage morbid hematopoiesis often ends with bone marrow failure as the disease progresses. The acute is rare. The main difference between aCML and typical CML is that both Ph chromosome and BCR-ABL fusion gene are negative, and there are often other chromosomal abnormalities. For example, the prognosis of trisomy 8 is significantly worse than 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 calculations (Table 1).
Grouping: Although several grouping patterns have been proposed, it has been recognized so far that Sokal et al. (1984) are in the international CMI. The relative risk formula presented by the prognostic study group:
Male is 1, female is 2, and hematocrit is calculated in %. According to the above formula, the relative risk values can be divided into low-risk group (<0.8), intermediate-risk group (0.8-1.2) and high-risk group (>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-α is relatively poor. Recently, Hasford et al. proposed a new integration system based on data from 1300 patients treated with IFN-α.
Diagnostic evaluation: Patients with unexplained splenomegaly, sternal tenderness, increased peripheral white blood cell count, and/or basophilic and eosinophilic patients should be alert to the presence of CML and timely blood smears. Careful observation of nucleated cell morphology, such as the emergence of a certain number of neutral late, mesozoic cells, after the exclusion of leukemia-like reactions, can make a preliminary diagnosis of CML. Therefore, attaching importance to clinical examination and blood routine examination can provide valuable information for the diagnosis of CML.
Bone marrow puncture shows hyperplasia or hyperactivity, and is mainly granulocyte cell line, which is mainly neutral mesenchymal cells and neutrophils in the following stages, which can be basically diagnosed as CML. According to international standards, diagnostic CML should have cytogenetic 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 cases, this aspect is more necessary to improve the level of diagnosis and differential diagnosis.
diagnosis:
1. In atypical cases, CML should be differentiated from leukemia-like leukemia. The leukemia response can be secondary to shock, severe infection, tuberculosis, advanced tumor or middle or late pregnancy. The number of white blood cells is less than 50×109/L, neutral. The cell alkaline phosphatase staining score is often increased, without the abnormality of the Ph chromosome and bcr/abl fusion gene. After the primary disease is controlled, the white blood cells can return to normal. It is still necessary to identify with primary myelofibrosis (MF). MF often has obvious splenomegaly, white blood cells and platelets can be increased, and young and young red blood cells appear in blood samples, which is easily confused with CML. However, MF patients were negative for Ph chromosome, and bone marrow biopsy reticular fibers and collagen fibers proliferated.
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 returned to normal during remission and reappeared when recurred. The Ph chromosome of CML is difficult to reduce, and it is accompanied by additional chromosomal abnormalities. From the molecular level detection, it was found that about half of the Ph-positive ALL fusion gene and its expression product were identical to CML. The breakpoint is at M-bcr and the bcr/abl product is p210. The other half of the Ph-positive ALL had a breakpoint of about 40 kb in the M-bcr region upstream of M-bcr and the protein product was p190. When using genetic testing, primers and probes that are different from Ph-positive CML are used to distinguish them from CML.
3. CML also needs to be identified with several related diseases of the original CML because they have elevated peripheral blood leukocytes and immature granulocytes; bone marrow hyperplasia is marked or extremely active, mainly granulocyte lineage; often accompanied by splenomegaly Signs. The key point for the identification of CML and these related diseases is the detection of the Ph chromosome and the bcr/abl fusion gene, which is positive for CML and negative for related diseases. Below is a brief list of other identification points.
(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. CNL has been classified into myeloproliferative diseases in the current WHO classification.
(2) Atypical CML (aCML): It is essentially a disease that is completely different from typical CML, and the name is not appropriate. aCML has anemia and thrombocytopenia in the early stage of the disease, and the increase of white blood cells is low or not increased; peripheral blood basophils are rare or absent; bone marrow often has one or more pathological hematopoiesis; splenomegaly is not significant; It manifests as bone marrow failure, <50% of acute changes.
(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, 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 >1×109/L are the main identification points.
(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 . Its 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.
complication:
1. Some patients in the chronic phase may have splenic embolism, spleen rupture and spleen hemorrhage.
2. Accelerated period of blast crisis can be combined with infection, fever, anemia, heart failure and other complications. Acute gouty arthritis can be complicated by the circulation of blood vessels in the lungs, central nervous system, certain special sensory organs and penis, and the corresponding symptoms and signs, such as shortness of breath, difficulty breathing, cyanosis, dizziness, and unclear language. Hemorrhoids, coma, blurred vision, tinnitus, hearing loss, and abnormal erection of the penis.
treatment:
The efficacy of CML includes hematologic remission, cytogenetic remission (ie, Ph cell disappearance rate), and molecular biological remission (ie, BCR-ABL fusion gene conversion rate) due to the three different degrees of remission and survival of CML patients. The period is significantly related, so the main purpose of modern CML treatment is how to improve the remission rate of the latter two, and strive for patients to obtain long-term disease-free survival.
1. Routine treatment of CML treatment or recurrence often have high uric acid disease, therefore, should be given sterol 300mg / d before oral administration, and adequate rehydration to maintain urine output; if patients have a large number of cell lysis risk factors, then don't worry The amount of alcohol administered and the number of doses should be increased, and the urine volume should be maintained at 150 ml/h. Allergic dermatitis can occur due to allopurinol, so it should be stopped after the number of white blood cells drops to normal, the spleen is significantly reduced, and there is no obvious hyperuricemia.
2. Single drug chemotherapy
(1)Busulfan(Maliland): It is the first chemotherapy drug widely used in CML treatment. Its efficacy was confirmed by random comparison in 1968. The usual dose is 4 ~ 6mg / d, orally. Due to the obvious aftereffect of the drug, when the white blood cell count drops to about 30×109/L, the dose should be reduced or discontinued. Most patients need to maintain treatment, maintenance dose can be reduced to 2mg, oral, 2 times / week, about 95% of patients with chronic phase is effective, white blood cell count decreased, spleen shrinkage, hematocrit increased, general condition returned to normal.
The treatment of busulfan (Maliland) often does not make the Ph chromosome disappear. The purpose of busulfan (Maliland) treatment is to control the chronic phase and reduce mortality.
The main side effects of this drug are a syndrome similar to adrenal insufficiency and pulmonary fibrosis characterized by severe myelosuppression, skin pigmentation, fatigue, fever and diarrhea.
(2)Hydroxyurea: A comparison of randomized control series in 1993 confirmed that hydroxyurea (HU) was superior to busulfan (Maliland). The median survival group was significantly better than the BUS group (58 months and 45 months, respectively), and the 5-year survival rates were 44% and 32%, respectively. Because of its low toxicity, it can prolong the chronic phase of CML and facilitate the patient's hematopoietic stem cell transplantation. It has become the preferred chemotherapeutic drug for CML. According to the white blood cell count, the initial dose is 1-4 g / d, orally; when the white blood cell drops to 20 × 109 / L, it is changed to l ~ 2g / d, the maintenance amount is 0.5 ~ 2.0g / d; when the white blood cell count drops to 5 When it is ×109/L, it should be suspended. The side effects of HU are light, and there may be skin papules, giant bone marrow cells, increased red blood cells, increased menstrual flow, and baldness, but less bone marrow suppression and no pulmonary fibrosis. Some patients may have a reduced positive rate of Ph chromosome. Recently, studies have found that hydroxyurea (HU) can delay the occurrence of bone marrow fibrosis in patients with CML, and has a reversal effect on patients with early mild fibrosis.
(3) Indirubin and its derivatives, indomethacin: Indigo and Jiayi are new drugs for the treatment of CNL after more than 20 years of research by the Institute of Hematology, Chinese Academy of Medical Sciences. Single use of indirubin 100 ~ 300mg / d, divided into 3 to 4 times orally, the total effective rate was 95.8%. Oral sputum alone 75 ~ 150mg / d, 3 times orally, the total response rate was 80.6%. Compared with BUS and HU, its spleen effect is significantly better than the former. Recently, studies have confirmed that the long-term efficacy of hyperthyroidism is similar to that of HU. Hyperthyroidism combined with hydroxyurea (HU) can significantly prolong the chronic phase of patients and reduce the 5-year blast rate of patients. Some patients may have a reduced positive rate of Ph chromosome. The main side effects are different degrees of bone and joint pain, nausea, anorexia, abdominal pain, diarrhea and other digestive tract reactions, and rarely occur during treatment.
(4) Others: cyclophosphamide, bismuth (6-mercaptopurine), oxyfluorfen (melphalan), chlorambucil (tumorine), dibromomannitol, urafenidine 520), colchicine, dibromodusol, carbopol, and cephalosporin in the treatment of chronic CML patients, although these drugs are effective for CML, but no drug is better than BUS or HU. Recently, there was a long-term treatment of high-triosperidin 2.5mg/(m2·d), intravenous infusion, and days 1 to 14, which resulted in complete cytogenetic remission in 6% of patients with CML.
3. Interferon treatment In 1983, Talpaz et al reported that 51 patients with CML CP were treated with natural interferon (IFN) alone, 71% (36) of them received hematologic remission, and 7 (14%) of Ph chromosome disappeared. Subsequent observations on the efficacy of natural and recombinant interferon in the treatment of CML indicate a hematologic response rate of 61% to 80% (median 64%), and 29% to 65% of patients have varying degrees of cytogenetic remission and are now CML The preferred treatment for the drug.
Although there has been some consensus on the treatment of CML with interferon (IFN) to date: 1 natural interferon is similar to recombinant human interferon in the treatment of CML; 2 continuous drug is better than intermittent drug, high dose is better than small dose, blood of the initial case Complete remission was significantly higher than re-treatment, and the accelerated phase was worse than the chronic phase; 3 intramuscular or subcutaneous injection was better than intravenous injection. However, there are still many problems to be resolved: A. Whether interferon (IFN) can prolong the survival of CML patients: The results of a series of randomized controlled trials of recently published interferon (IFN) treatment of CML are inconsistent, the Italian Collaboration Group and the UK MCR The results showed that the interferon (IFN) treatment group had significantly longer survival than the hydroxyurea (HU) (or busulfan (BUS)) treatment group, and there was a significant difference between the two, while the results of the German CML study group found that they survived. There is no difference in the period (Table 2); B. The optimal dose and time of administration of interferon (IFN): There is no consensus so far, but the initial dose of interferon (IFN) should be 5MU/(m2·d). ), after 2 to 3 weeks, the dose is increased to 9 ~ 12 MU / d, or to achieve significant hematological efficacy [ie WBC count (2 ~ 4) × 109 / L, platelet count close to 50 × 109 / L] maximum tolerance The amount and the patient's symptoms of toxicity need to be reduced. The shortest time for cytogenetic remission is expected to be 6 months, usually until the disease progresses or the intolerable drug toxicity; C. The relationship between interferon (IFN) type and curative effect: It is generally considered that different kinds of Interferon-a has no difference in clinical efficacy, interferon gamma is unclear, interferon alpha combined with interferon gamma can not improve efficacy; D. interferon (IFN) combined with other chemotherapeutic drugs such as hydroxyurea, low-dose cytarabine 20mg / ( M2·d)×10 days have been clinically observed in stage II, indicating that the efficacy is better than IFN alone.
Early common side effects of interferon (IFN) in the treatment of CML include fever, chills, flu-like symptoms, headache, etc., lasting for several days to 2 months; late stage may have persistent fatigue, loss of appetite, weight loss, and a few cases may have Anemia, thrombocytopenia, liver and kidney dysfunction, alopecia, sometimes bones, muscle pain and hypothyroidism, depression, etc., severe cases may have angina, inattention, memory loss and lethargy and other neurological toxicity. The above symptoms can be alleviated or disappeared when the dose is reduced, and the above-mentioned side effects can be relieved by administering a small dose of an antipyretic analgesic such as acetaminophen (paracetamol).
4. Imatinib (ST1571, Gleevec) In June 1998, imatinib (STl57l) (also known as CGP57148 or Gleevec) began Phase I clinical trials in a total of 83 patients with chronic CML who failed interferon therapy. The treatment was divided into 14 dose groups of 25-1000 mg/d. The results confirmed that the lowest dose with the highest clinical efficacy was 300 mg/d, and 53 patients (98%) who received the dose of 300 mg/d or more were completely obtained. Hematologic remission, 31% of patients were significantly cytogenetic remission. Inspired by this result, 58 patients with chronic granule blast or Ph acute leukemia were treated with a dose of 300-1000 mg/d, 55% (21/38) of CML granules and 70% (14/20). Patients with Ph ALL received hematologic efficacy. Subsequently, 454 patients with CP CML, 181 AP CML, and 229 patients with CML acute granulosis entered the phase II clinical trial. The complete hematologic remission rates were 91%, 69%, and 29%, respectively. Significant cytogenetic remission rates were 55%, 24% and 16%. The drug was approved by the US FDA on May 10, 2001 and is currently undergoing Phase III clinical trials worldwide.
ImatinibThe mechanism of action of (ST1571) is to inhibit the tyrosine kinase activity of the BCR-ABL fusion gene. So far, the optimal clinical dose of imatinib (STl571) is not very clear. The recommended starting dose of CP CML is 400mg/d, and the recommended starting dose of accelerated phase (quick period) is 600mg/d. Increase to 800mg/d. Since the half-life of imatinib (STl571) is 14 to 16 h, it can be administered once/d. The main side effects are myelosuppression, nausea, muscle spasm, bone pain, joint pain, rash, diarrhea, edema, fluid retention and impaired liver function.
5. Combined chemotherapy with cytarabine, anthracyclines, thioguanine (6-TG),Cyclophosphamide,Asparaginase,巯嘌呤(6-MP),Etoposide(VP-16) and Buillian (Maliland) and other drugs with different combinations of chemotherapy regimens for CML, the rate of Ph chromosome reduction is higher than conventional monotherapy. However, most studies have shown that life expectancy is not significantly prolonged (Table 3). Recently, combined chemotherapy and interferon-a therapy have been used to improve survival rate and cytogenetic response rate, but the results have not been satisfactory so far.
6. Hematopoietic stem cell transplantation (SCT)
(1) Autologous stem cell transplantation (ASCT): The results of ASCT in patients with CP CML showed that ASCT for purifying stem cells during CP phase can significantly prolong the survival of CML.
In recent years, people have used combination chemotherapy to mobilize Ph-peripheral blood stem cells, interferon alpha alone or in combination with hydroxyurea to treat CML and other "in vivo purification" and long-term bone marrow cell culture, 4-HC and ASTA-Z drugs, interferon, antisense "In vitro purification" methods such as oligonucleotides were used to screen Ph-peripheral blood stem cells. Although the Ph negative rate was improved after ASCT, the survival rate of purified stem cell transplant patients was not significantly improved. Recently, McGlare et al. summarized the effects of ASCT in the treatment of CML reported by 8 BMT centers in Europe and America. Of the 200 patients, CP142, AP30, BP or the second chronic phase (CP2), with a median age of 42 years. The median time from diagnosis to transplantation was 15 months, 123 stem cells were derived from bone marrow, 73 were derived from peripheral blood, 21 bone marrow was purified by 10 days in vitro, 23 bone marrow was purified by interferon gamma, and median after transplantation. After 48 months of follow-up, the 5-year survival rate of patients with CP stage transplantation was 95%±5%, and that of AP stage was 27%±10%. All patients who were transplanted after sudden change died within 2 years and half of transplantation. Prognostic analysis showed: Ages >40 years and long-term diagnosis to transplantation are unfavorable factors, while stem cell sources (bone marrow or peripheral blood) and "in vitro purification" have no effect on survival.
(2) Allogeneic stem cell transplantation (Allo-SCT): Allogeneic bone marrow transplantation (Allo-BMT) is the only means to cure CML. The survival rate of CP transplantation is better than that of AP or BP, and the recurrence rate is low. The 3-year survival rates of CP, AP, and BP were 55% to 70%, 10% to 30%, and 0 to 20%, respectively, and the recurrence rates were 20%, 50%, and 75%, respectively. Patients who underwent BUS before BMT had poor outcomes, with a 3-year disease-free survival (DFS) of 45%, compared with 61% of those who received HU. IFN-a treatment had no effect on the efficacy of BMT treatment. Various pretreatment regimens such as Cy+TBI and busulfan (BUS)+Cy had no significant effect on the efficacy. The main cause of transplant-related death in Allo-BMT is GVHD. Although T-cell Allo-BMT can reduce the incidence of GVHD, the recurrence rate is significantly increased, suggesting that graft-versus-leukemia (GVL) effect is an important factor in the efficacy of Allo-BMT in the treatment of CML.
Although Allo-BMT has achieved satisfactory results in the treatment of CML, only 20% to 25% of patients have HLA-matched sibling donors. In recent years, the study of CML for Allo-BMT with irrelevant donors has achieved gratifying results. The 2-year DFS is 31%, but the graft failure rate is as high as 16%, and the incidence of grade III and IV acute GVHD is about 54%. Serious chronic GVHD is also as high as 52%.
Recently, studies have shown that the application of ex vivo peripheral blood stem cell transplantation is faster than Allo-BMT, post-transplant myeloid lineage and immune reconstitution. The short-term efficacy of the two is similar, and the long-term efficacy has yet to be determined. In addition, related/independent umbilical cord blood transplantation and non-myeloablative hematopoietic stem cell transplantation have also been reported.
In order to better guide the clinical selection of appropriate patients for peripheral blood and bone marrow transplantation, the European Peripheral Blood and Bone Marrow Transplant Group proposed a prognostic score system based on data from 3142 patients (Table 4). According to the credit system, patients with scores of 0, 1, 2, 3, 4, 5, and 6 had a 5-year disease-free survival rate of 72%, 70%, 62%, 48%, 40%, 18%, and 22, respectively. %, transplant-related mortality rates were 20%, 23%, 31%, 46%, 51%, 71%, and 73%.
Treatment of patients with relapse after allogeneic transplantation included the second transplantation, rIFN-α and donor leukocyte infusion (DLI can re-acquire CR in about 75% of patients, and the 8-year survival rate of patients with hematologic relapse can reach 60 %, the 8-year survival rate of patients with cytogenetic recurrence is about 80%, and the median time for cytogenetics and molecular biology is 4-6 months. Those who have relapsed in cytogenetics/hematology are the first in transplantation. Patients with subchronic phase (CPI), post-transplant remission time of more than 1 year, no chronic GVHD after transplantation, and chimeric hematopoiesis are more effective.
7. Acute phase of treatment Acute myeloid cell changes can be treated with a primary AML regimen, but the CR rate is <20%, and the complete remission period is only a few weeks or months. 25% to 35% of patients with acute changes are acute leaching or double phenotype leukemia, although about 60% of patients with VDLP are effective, about 1/3 of patients can return to CP2, but their overall survival rate is only 4 ~ At 6 months, the DFS of hematopoietic stem cell transplantation for 3 years can reach 15% to 20%.
(1) Screening and amplification of "benign" progenitor cells: It has been confirmed that Ph-hematopoietic progenitor cells can be enriched in bone marrow CD34 and HLA-DR-components of CML patients, so that non-leukemia dryness can be screened accordingly. Progenitor cells are used for transplantation after in vitro expansion. Another method is to perform functional screening of cells based on the different responses of "normal" cells and leukemia cells to cytokines, and long-term culture with a stem cell-deficient matrix to facilitate "beneficial" cell growth. It can be predicted that with the continuous improvement of enrichment and amplification methods, enrichment of Ph-cells for in vitro expansion for transplantation is one of the future treatment directions of CML.
(2) Antisense oligonucleotides: antisense oligonucleotides designed with BCR/ABL as targets can reduce the transcription level of BCR/ABL and the growth of CML cells cultured in vitro (possibly by inducing apoptosis) ), now mainly used as a "purification" of CML stem cell transplantation. Preliminary reports of successful engraftment of bone marrow and partial cytogenetic remission after in vitro purification of BCR/ABL and C-MYB antisense oligonucleotides have been used. Antisense oligonucleotides combined with chemotherapy drugs have been shown to significantly delay the onset of leukemia in SCID mouse animal experiments.
(3) Gene therapy: a BCR/ABL antisense gene constructed with a retroviral vector has been combined with aMethotrexateThe so-called "double gene therapy strategy" of (MT) X drug resistance gene, the results of in vitro experiments show that the method can be used for CML autologous stem cell transplantation in vitro purification and post-transplant chemotherapy to further eradicate minimal residual disease.
(4) Immunomodulatory therapy: There are reports of immunogenic P210 BCR/ABL fusion fragments and binding to major histocompatibility antigen-like allele complex polypeptides, and BCR/ABL-expressing cells have also been established. Peptide-specific CD4 T cell lines, in vitro experiments demonstrated that peptide-specific CD4 T cells can be used to degrade the P210 b3a2 product. These results suggest that CML can be treated with human T cell-mediated recognition of tumor-associated antigens. In addition, interleukin-2 activates NK cells and cytotoxic T cells. CML patients' own NK cells can inhibit the growth of CML progenitor cells. Therefore, self-activated NK cells can be expanded in vitro for self-stem cell transplantation purification and CML immunotherapy. Recently, it has been found that dendritic cells obtained from in vitro culture of bone marrow of CML patients can stimulate their own cells and have anti-proliferative effects, while anti-normal bone marrow activity is extremely low, suggesting that the method can be used for adoptive immunotherapy of CML.
9. Choice of treatment strategy With the increasing number of CML treatment methods, how to develop an optimal individualized treatment plan according to the patient's specific situation has become a problem faced by every hematologist. Several CML treatments have been proposed. Selection mode; recently, the American Society of Hematology organized CML experts from around the world to analyze the valuable literature of CML treatment published so far, and propose a CML treatment guideline: 1 First, according to the patient's age and physical condition, whether there is related or unrelated bone marrow The donor decides whether to perform stem cell transplantation; 2 if a non-transplantation regimen is chosen, a detailed dosing regimen should be made. For example, with rIFN-a, the dose must be combined with the course of treatment with hydroxyurea or cytarabine. ; 3 should develop a systematic plan to observe the degree of cytogenetic efficacy and onset time and molecular biological efficacy; 4 Once the diagnosis and treatment opinions are clearly defined, changes that involve treatment efficacy and patient wishes must be reviewed.
(two) prognosis
There are no reliable prediction methods, but a large number of studies have confirmed that age, spleen size, platelet count, proportion of primordial cells in peripheral blood or bone marrow, and proportion of basophils are factors influencing prognosis. In 1984, Sokal proposed a formula for predicting the risk ratio (RR), with age (year), spleen (cm in the midline of the rib), number of platelets (109/L), and number of promyelocytes in the blood (%) as variables. The formula is as follows:
RR={0.0116 (age-43.4)+0.0345 (spleen-7.51)+0.188[(platelet count/700)2-O.563]+0.087 (original grain-2.10)}
RR<0.8 is low risk, RR<0.8~1.2 is medium risk, and RR>1.2 is high risk. Data indicate that the median survival of the low-risk group is 60 months, the intermediate-risk group is 46 months, and the high-risk group is 32 months. However, for patients receiving IFN treatment, the judgment of this formula is not certain, and the response to IFN treatment is an important factor affecting prognosis.
prevention:
Avoid or reduce the exposure of harmful substances such as radioactive substances, chemicals, and chemicals.
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