Overview
Chronic myeloid leukemia(CML) is a malignant tumor formed by 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. The count is increased or the left upper abdomen mass is further examined. The Ph chromosome or bcr/abl fusion group should be a prerequisite for diagnosis.
Cause
1. Ion radiation increases the incidence of CML, and the incidence of CML in patients with ankylosing spondylitis and cervical cancer is significantly increased after radiotherapy.
2. Patients with long-term exposure to benzene can cause CML to occur, suggesting that certain chemicals are also involved in 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. CML familial aggregation is very rare, indicating that CML is an acquired leukemia.
Clinical manifestation
Common symptoms in most CML patients include: anemia, spleen discomfort, hemorrhage and fatigue, weight loss and low fever, which lasts for 3 to 4 years. Some patients are asymptomatic, and many diagnoses due to physical examination or other diseases, such as white blood cell count, increased platelet count or spleen enlargement. 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.
an examination
1. Chronic laboratory examination
(1) Blood picture The number of white blood cells is often >50×109/L, sometimes up to 500×109/L. About one-third of patients have hemoglobin <110g/L, and anemia is mostly normal cells. Platelets tend to increase, sometimes as high as 1000 × 109 / L, a small number of patients can be reduced. Blood smear examination showed granulocytes at different stages of maturation, mostly in the middle and late myelocyte stage. Myeloid cells <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 granules, the ratio of granules to red can be increased to 10:1 to 20:1, and the granulosa is increased at each stage, with the increase of middle and late granulocytes. the Lord. The ratio of eosinophils to basophils was significantly higher than normal, and megakaryocytes and platelets also increased.
(3) Neutrophil alkaline phosphatase (NAP) staining score is reduced or close to zero. NAP activity can be restored when the treatment is effective, and it decreases when the disease recurs.
(4) Cytogenetics and molecular biology examination According to the definition of WHO, Ph chromosome or BCR-ABL fusion gene must be present in all CML patients, and the banding analysis is t(9;22) (q34;11). The CCR-ABL proto-oncogene translocation of the long-armed C-ABL proto-oncogene of chromosome 9 to the breakpoint cluster region (BCR) of the long arm of chromosome 22 forms a BCR-ABL fusion gene. The protein encoded by it is mainly P210, and P210 has tyrosine kinase activity, which leads to the occurrence of CML. Ph can be found in grains, red, mononuclear, megakaryocytes and lymphocytes. If CML has clinical manifestations and the Ph chromosome or BCR-ABL fusion gene is negative, the CML diagnosis should be excluded.
(5) Serum biochemical determination Serum uric acid and lactate dehydrogenase are often increased.
2. Accelerated laboratory inspection
Meet any of the following: 1 peripheral blood (PB) or bone marrow (BM) primordial cells 10% to 19%; 2 peripheral blood basophils ≥ 20%; 3 treatment-free sustained thrombocytopenia (<100 × 109 / L) or increased (>1000×109/L); 4 clone evolution; 5 progressive spleen enlargement or increased white blood cell count.
3. Catastrophic laboratory inspection
Meet any of the following: 1 primordial blood (PB) or bone marrow (BM) primordial cells ≥ 20%; 2 bone marrow biopsy primordial cell aggregation; 3 extramedullary primordial cell infiltration.
diagnosis
Typical clinical manifestations, with Ph chromosome or positive bcr/abl fusion gene, can confirm the diagnosis.
Differential diagnosis
Leukemia-like reaction
Generally complicated by serious infections, malignant tumors, trauma and other diseases. The leukocyte reactivity is increased, and the immature cells are visible in the peripheral blood, but disappear with the treatment of the primary disease. Neutrophil alkaline phosphatase activity was strongly positive. Both the Ph chromosome and the BCR/ABL fusion gene were negative.
2. Other myeloproliferative disorders
Such asPolycythemia vera,Essential thrombocytopenia,Primary myelofibrosisEtc., these diseases may have splenomegaly and blood and bone marrow similar to CML, but both the Ph chromosome and the BCR/ABL fusion gene are negative.
3.Ph chromosome positive other leukemia
Ph chromosome can also occur in 2% of acute myeloid leukemia and 20% of adult ALL, and should be identified.
4. Other causes of splenomegaly
Schistosomiasis liver disease, kala-azar, liver cirrhosis, hypersplenism, etc. have splenomegaly, but at the same time there are primary symptoms, blood and bone marrow without CML characteristics, Ph chromosome and BCR / ABL fusion genes are negative.
treatment
Allogeneic transplantation can cure CML, but there is a risk of transplant-related death and graft-versus-host disease, and can lead to infertility. With the development of research on tyrosine kinase inhibitors and the development of a new generation of drugs, conservative treatment of drugs can make most patients have long-term disease-free survival, and a small number of long-term stable patients, even after stopping drug treatment, can be long-term without Disease survival.
1. Initial treatment of patients with chronic phase CML
(1) Tyrosine kinase inhibitor treatment ImatinibIt is the first generation of highly specific tyrosine kinase inhibitor (TKI) directed against the causative gene product, the BCR-ABL fusion protein. Its mechanism of action is to block the proliferation of Ph-positive cells by blocking the phosphorylation of ABL tyrosine kinase and its downstream molecules by substituting ATP in the BCR-ABL fusion protein structure.
The main side effects are hematological toxicity, and the disease is more severe in the late stage; common non-hematologic toxicities include edema, nausea, diarrhea, rash, bone and joint pain, tendon and liver enzyme abnormalities, etc. Most patients can be tolerated or controllable.
Hematologic and genetic remission after drug treatment needs to be closely monitored to adjust the intensity of treatment at any time. In particular, genetic remission is currently required to be reviewed every 3 months for a total of 2 years, then every 6 months for a total of 3 years. Previous examination methods include bone marrow chromosome, FISH, quantitative PCR, etc. Currently, peripheral blood BCR-ABL fusion gene quantification is recommended.
In theory, imatinib is an inhibitor of leukemia gene products and cannot eradicate disease-causing genes. Therefore, even if the patient receives molecular remission, it takes a lifetime to take the drug, and stopping the drug will lead to recurrence of the disease. Recent studies have found that a small number of low-risk patients with long-term treatment with deep molecular remission, under close monitoring by experienced medical centers, may stop drug treatment. 1 TKI first-line treatment in patients with chronic disease The preferred treatment for patients with chronic disease is tyrosine kinase inhibitor (TKI) once a day. Hematology, cytogenetics, and molecular responses should be monitored regularly during treatment, and treatment options adjusted at any time. 2 chronic phase TKI second-line treatment in chronic phase patients with TKI second-line treatment indications: imatinib intolerance can chooseDasatinibOr nilotinib; patients with poor efficacy of imatinib, imatinib or choose dasatinib or nilotinib; imatinib treatment failure, choose dasatinib or nilotidine Ni.
(2) Other patients who have failed treatment with dasatinib or nilotinib, who have detected T315I mutation, and who have progressed to AP/BP stage, can undergo allogeneic hematopoietic stem cell transplantation. For patients who are not allowed to undergo the above treatment under economic conditions, medications such as interferon, hydroxyurea or homoharringtonine can improve the condition, but ultimately the disease cannot be avoided.
2. CML advanced treatment
(1) Accelerated treatment 1 Those who have not used TKI in the past Those who have not used TKI in the past can be given imatinib orNilotinibWhen the condition returns to the chronic phase, TKI treatment can continue to be used. If the patient has a suitable source of hematopoietic stem cell donor, allo-HSCT can be considered. If necessary, BCR/ABL kinase domain mutation detection, and found that T315I mutation or second-generation TKI insensitive mutations should be performed early allo-HSCT. A unit feasible new drug test for conditional new drug clinical trials. 2 Progression of patients with imatinib during the course of treatment of imatinib should be based on BCR-ABL mutation analysis, switch to second-generation TKI, such as dasatinib 140mg, 1 time / day, or Nilotinib 400mg, 2 times / day, if patients have a suitable source of hematopoietic stem cell donors, consider allo-HSCT. Those who have the condition can simultaneously perform BCR/ABL kinase domain mutation detection, and find that T315I mutation or second-generation TKI-insensitive mutation should be performed early allo-HSCT. A unit feasible new drug test for conditional new drug clinical trials.
(2) Treatment in catastrophic period 1 For those who have not used TKI in the past, those who have not used TKI in the past should first give imatinib or dasatinib in order to make it return to the chronic phase and return to the chronic phase smoothly. allo-HSCT. Those with conditions can conduct clinical research. 2 In the process of imatinib treatment, patients with sudden changes in imatinib treatment, first bone marrow morphology, flow cytology, cytochemistry (peroxidase, TdT, etc.), cytogenetic examination Etc. Determined to be acute or acute. According to the BCR-ABL mutation analysis, a second-generation TKI, such as dasatinib or nilotinib, and/or a combination of different chemotherapy is used. After alleviation, allo-HSCT or new drug test treatment is performed.
3. Allogeneic stem cell transplantation
(1) Indications can be screened for allo-HSCT patients according to the following principles: 1 newly diagnosed CML children and young patients; 2 chronic patients, if the Sokal score is high risk and transplant EBMT risk score ≤ 2, and there are HLA matching donors You can choose first-line allo-HSCT treatment; 3 for all patients with failed first- or second-generation TKI treatment, allo-HSCT can be considered according to the age and willingness of patients; 4 patients with T315I mutation at any time during TKI treatment, allo is preferred - HSCT; 5 patients in the accelerated or blast phase.
Among the above principles, patients in Groups 1 and 2 are not absolutely suitable for transplantation, and need to combine the advantages and disadvantages of long-term medication and allograft. In theory, drug therapy has certain advantages in efficacy and safety.
It is recommended to give TKI treatment at least to complete hematologic remission before transplantation, and TKI should be discontinued for at least 2 weeks before transplantation. Those who cannot accept TKI also need to use it.Hydroxyurea/HarringtonineClass/other chemotherapy, alllo-HSCT is accepted after complete hematologic remission.
(2) Choice of donor and transplantation protocol HLA phase contract cells are still the best donors for CML patients, but with the improvement of HLA matching accuracy, graft-versus-host disease (GVHD) occurs in irrelevant donors. The rate was significantly reduced, and the long-term survival rate of patients after transplantation was consistent with the transplantation of sibling donors. Domestic research also supports this conclusion. Therefore, if CML patients have strong transplant indications, even if there are no sibling donors, consider choosing an HLA-matched unrelated donor.
(3) post-allo-HSCT monitoring Allo-HSCT post-monitoring includes: hematology, bone marrow cytogenetic karyotyping or FISH, peripheral blood BCR-ABL fusion gene quantitative monitoring is particularly important.
Prognosis
Many factors affect the chronic phase and survival of CML. Factors such as age, white blood cell count, basophil count, liver and spleen size, anemia, and platelet count are closely related to prognosis.
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