Introduction:
Chronic lymphocyte leukemia(chronic lymphocytic leukemia, CLL) is a tumorous disease in which lymphocytes are clonally proliferating. Lymphocytes accumulate in bone marrow, lymph nodes, blood, spleen, liver, and other organs. More than 95% of CLL is a clonal proliferation of B cells (ie, B-CLL), and less than 5% of cases are T cell phenotypes (ie, T-CLL).
Cause:
(1) Causes of the disease
The cause of CLL is unknown. There is no evidence that retroviruses and ionizing radiation can cause this type of leukemia; however, several factors are found to be closely related to the disease: hereditary (racial and familial) and gender.
1. Genetic factors include CLL or other family history of lymphoid malignancies. The incidence of immediate family members is three times higher than that of the general population. The incidence of autoimmune diseases in relatives of CLL patients also increased significantly.
2. About 50% of CLL patients with chromosomal abnormalities have chromosomal abnormalities, often involving chromosomes 12 or 4, -8, i(7), i(2p), t(13;21), 18,6q-, 14q-, Abnormalities such as -X have been reported. Chromosomal abnormalities are related to the course of the disease. Early chromosomal abnormalities account for about 20%, and advanced cases can reach 70%. CLL-affected chromosomes often involve immunoglobulin-encoding genes (such as the heavy chain gene of chromosome 14) or oncogenes (such as c-ras-Harvey on chromosome 12 and c-ras-Kirsten on chromosome 11).
(two) pathogenesis
The exact pathogenesis of CLL is unknown, and environmental factors are not significantly associated with CLL. Factors closely related to the onset of other types of leukemia, such as ionizing radiation, chemical carcinogens, and insecticides, have been reported to be unrelated to the pathogenesis of CLL. Viral infections such as HCV (hepatitis C virus) and Epstein-Barr virus are also unrelated to the pathogenesis of CLL. Although there were significantly more males than females in CLL patients, no correlation was found between sex hormones and the onset of CLL. Current research focuses on the relationship between CLL pathogenesis and genetic factors, chromosomes, cell oncogenes, and anticancer genes.
1. Genetic factors The incidence of CLL is higher in Caucasians and blacks, and lower in Asian yellows, and the incidence is not changed by ethnic migration. It is suggested that certain genetic factors of different races are associated with the pathogenesis of CLL. In addition, it has been reported that B-cell type CLL occurs in many people in the same family. The first-generation children of CLL have three times more risk of developing CLL or other malignant lymphoproliferative diseases than ordinary people, and most of them are young at the time of onset. It is suggested that genetic factors play an important role in the pathogenesis of familial CLL, but there is no significant correlation between HLA single phenotype and CLL. No genetic factors have been found with CLL, even in patients with single-oval twin CLL, no common genetic abnormalities have been found so far.
2. The cytogenetic study of chromosome CLL is difficult, because its lymphocytes are not easily stimulated by mitogens and proliferate, and it is difficult to obtain dividing cells. In recent years, by improving the stimulation of CLL cell division technology, chromosome R banding and in situ hybridization are applied. The (FISH) method improves the success rate of CLL chromosome research. About 50% of CLL patients were found to have cloned chromosomal abnormalities, while the remaining normal karyotypes may be normal T cell karyotypes and no CLL abnormal karyotypes were detected.
(1) Chromosome 13 abnormality: Nearly 50% of CLL patients have a long arm loss of chromosome 13. Most of the missing sites were deleted in 13q12.3 and 13q14.3. 13q12.3, and the deletion site was breast cancer susceptibility gene (BRCA2). Deletion at 13q14.3, the deletion site can affect the tumor suppressor gene RB-1 (retinal gene), DBM (related to preventing lymphocyte malignant transformation), LEV1, LEV2 and LEV5 (related to the pathogenesis of CLL).
(2) Chromosome 12 abnormality: The trisomy abnormality of chromosome 12 is rarely detected in CLL at the early stage, and CLL with chromosome 13 trisomy is found in the clinical progression of CLL or conversion to lymphoma (Richter syndrome). There are many complex changes in cells and atypical or young lymphocyte morphology. It is suggested that the trisomy 12 chromosome abnormality is related to the deterioration of CLL. The mechanism of the trisomy of chromosome 12 may be manifested by the influence of certain genes located between 12q13 and 12q22, such as the mdm gene.
(3) Abnormal chromosome 11: Nearly 10% to 20% of CLL patients have chromosome 11 translocation or deletion, and those with abnormal chromosome 11 have a milder onset age (<55 years), and the course of disease often shows invasiveness. Abnormal chromosome 11 may affect 11q13, and it has been recognized that this site includes the tumor suppressor gene - MEN-1 (multiple endocrine neoplasia syndrome type I). The most common chromosome 11 deletion is between 11q14-24, especially between 11q22.3-23.1, where there may be a tumor suppressor gene RDX (multiple neurofibromatosis type II tumor suppressor gene congener) and AIM (hereditary ataxia - hair cell vasodilator mutant gene), the function of these two genes is related to the activation of the tumor suppressor gene p53. The p53 gene regulates the cell cycle and maintains gene stabilization. Its expression products can block abnormal cells from entering the cell cycle, which is convenient for abnormal cells to repair DNA. For example, cells cannot repair damaged cells by themselves. DNA will self-apoptosis.
(4) Chromosome 6 abnormality: including the short arm of the chromosome 6 and the abnormality of the long arm. Short-arm abnormalities of chromosome 6 have not yet been found to have specific gene function changes. Patients with abnormal 6q21-q24 often show a clinical progression of juvenile lymphocytosis and invasive disease. In addition, TNF-α (tumor necrosis factor α), and LY-α (lymph) are located on the long arm of chromosome 6, and these two factors are involved in promoting proliferation of CLL cells and inhibiting proliferation of normal lymphocytes and bone marrow cells.
(5) Abnormal chromosome 14: often expressed as a translocation. It is rare in CLL patients, and t(11;14)(q13;q32) translocation is more common in lymphoma patients: rare in CLL. 14 q32 contains the immunoglobulin a heavy chain isoform switch gene, while 11q13 has the cyclin D1 gene (cyclic D1) t (11; 14), which is common in coat-type non-Hodgkin's lymphoma. T (14:18) CLL patients are rare, common in low-grade follicular lymphoma.
3. Special genetic changes
(1) p53 gene: The p53 gene is an important tumor suppressor gene located at the 17p13.1 site and encodes a 53-kD nucleic acid phosphoprotein. The mutation or defect may be the cause of the disease in nearly half of the tumor patients. Short arm loss on chromosome 17 is only seen in 10% to 15% of CLL patients. In addition, 10% to 15% of CLL patients have p53 gene mutations, patients with p53 gene mutations are mostly progressive, with high proliferation rate of leukemia cells, short survival time, clinical characteristics of resistance to first-line treatment drugs, seen in half of Richter Syndrome and B cell lymphocytic leukemia suggest that p53 gene mutation may be acquired in the course of certain CLL patients.
(2) Multiple drug resistance gene (MDR): MDR-1 gene expression is increased in about 40% of CLL patients, and MDR-1 is located in 7q21.1, encoding a 170kD transmembrane glycoprotein. The expression of MDR-1 is increased in B cells of CLL patients but not in normal B cells. In addition, the expression of MDR-1 gene is also increased due to treatment or other factors. The abnormal expression of MDR gene is more likely to promote the progression of CLL patients. Not the primary cause of CLL.
(3) bcl-2: The bcl-2 gene is located on chromosome 18q21, and most CLL patients have increased expression due to bcl-2 gene rearrangement. About 5% of CLL patients with bcl-2 gene rearrangement are IGk or lambda light chain genes located on chromosomes 2 and 8, and bcl gene translocations on chromosome 18. However, in addition to gene rearrangement, increased expression of bcl-2 in CLL leukemia cells is associated with hypomethylation of its gene locus. There may be some genes that are not yet known to be involved in the action of CLL cells against apoptosis.
4. Cytokine CLL cells have the ability to secrete a variety of cytokines, such as TNF-α, TGF-β (transfer growth factor β), IL-7 (interleukin-7), IL-5, IL-2, etc. It has the effect of directly or indirectly stimulating CLL leukemia cell proliferation or preventing apoptosis of CLL cells, and inhibiting the proliferation of normal lymphocytes and bone marrow hematopoietic cells. Therefore, cytokines are associated with the pathogenesis and disease progression of CLL patients.
Cellular dynamics studies showed that the number of 3H-labeled white blood cells in the peripheral blood of CLL patients was small, suggesting that most white blood cells were in the resting phase (G0 phase) without proliferation, and that almost all CLL leukocytes expressed high levels of anti-aging. The death protein bcl-2, and the low level of apoptotic protein bax, the imbalance of bcl-2/bax ratio, resulting in impaired apoptosis, consistent with the accumulation of a large number of mature small lymphocytes in clinical, constitute the main pathological basis of CLL.
symptom:
1. About 1/4 of the patients with general symptoms are asymptomatic and accidentally found due to blood tests. Fatigue, decreased physical activity and weakness are common symptoms. It occurs more often before the patient develops anemia or lymph nodes and hepatosplenomegaly. Other rare symptoms include chronic rhinitis caused by infiltration of nasal mucosa in CLL cells, multiple neuropathy in sensorimotor nerves, and allergies to mosquito bites. During the progression of the disease, the patient may have symptoms of weight loss, recurrent infection, bleeding, or severe anemia. In addition, CLL patients are mostly elderly, and can be combined with lung, heart and cerebrovascular disease.
2. CLL patients with 80% lymph node enlargement have a painful lymphadenopathy at the time of diagnosis. The most common sites are the neck, supraclavicular and axillary lymph nodes. Typical CLL lymph nodes are hypertonic, but may be tender when combined. High lymphadenopathy can cause local compression symptoms and affect organ function. For example, oropharyngeal lymph node enlargement can cause upper airway obstruction. Abdominal lymphadenopathy can cause urinary tract obstruction and hydronephrosis, and obstructive bile duct causes obstructive jaundice. However, mediastinal lymphadenopathy in CLL patients rarely causes superior vena cava syndrome. If this syndrome occurs, it is highly suspected to have a lung tumor.
3. Hepatosplenomegaly About half of CLL patients have mild or moderate hepatosplenomegaly at diagnosis, often accompanied by fullness and bloating. In some patients, the spleen may exceed the umbilical level and even extend to the pelvic cavity. A small number of splenomegaly may be associated with hypersplenism, resulting in anemia and thrombocytopenia. Some CLL patients may have hepatomegaly. Hepatic dysfunction in the liver is mostly mild, mostly without jaundice. However, if the abdominal lymph nodes enlarge the biliary tract, obstructive jaundice can be produced.
4. Extranodal involvement in organ examination of CLL patients often found organ infiltration, but abnormalities in organ function are rare. For example, more than half of patients had autoimmune findings of leukemia cell infiltration in the renal interstitial, but rare renal failure. In some organs and tissues accompanied by leukemia cell infiltration can produce symptoms, such as in the back of the eye, pharynx, epidermis, prostate, gonads and lymphoid tissue, leukemia cell infiltration can cause exophthalmos, upper airway obstruction, scalp nodules, urethra Obstruction and other symptoms. Pulmonary X-rays of pulmonary interstitial infiltrates show nodular or miliary changes that can cause pulmonary dysfunction. Pleural infiltration can produce bloody or chyle-like pleural effusions. Leukemia cell infiltration can cause thickening of the digestive tract mucosa, resulting in ulcers, bleeding, and malabsorption. CLL central nervous system infiltration is rare, can produce headache, meningitis, cranial nerve palsy, unresponsiveness, coma and other symptoms.
5. Rare clinical performance
(1) Conversion to invasive lymphoma/leukemia: 10% to 15% of patients are converted to invasive lymphoma/leukemia. The most common conversion to Richter syndrome is manifested as progressive liver, spleen, lymph node enlargement, fever, abdominal pain, weight loss, progressive anemia and thrombocytopenia, and peripheral blood lymphocytes rapidly increase. Lymph node biopsy pathology is large B cells or immunoblastic lymphoma. Through immunophenotypic, cytogenetics, immunoglobulin heavy chain gene rearrangement, DNA sequence analysis and other studies, it is proved that the large lymphocytes of patients with 1/2 Richter syndrome are derived from a single clone of CLL. Patients with Richter syndrome have a poor response to systemic chemotherapy and generally have a survival period of 4 to 5 months. CLL can also be converted to young lymphocytic leukemia, acute lymphocytic leukemia, plasma cell leukemia, multiple myeloma, Hodgkin's lymphoma and the like.
(2) Autoimmune diseases: About 20% of CLL patients can be combined with autoimmune hemolytic anemia with positive Coombs test, and half of them have obvious clinical manifestations. 2% CLL patients with immunological thrombocytopenia. The severity of clinical CLL was not associated with a combination of immunological anemia and thrombocytopenia. Patients with autoimmune hemolysis and thrombocytopenia generally respond well to adrenocortical hormone. If the adrenal cortex hormone is ineffective, try a large dose of intravenous gamma globulin, splenectomy or spleen area irradiation.
(3) pure red blood cellsAplastic anemia: It has been reported that CLL combined with pure red blood cell aplastic anemia can be as high as 6%, the clinical manifestations are severe anemia, bone marrow erythrocytes and peripheral blood reticulocytes are reduced, but not accompanied by granulocyte and thrombocytopenia. Adrenal cortex hormones have a short-term effect. Most patients are effective for chemotherapy, which increases hemoglobin values and is associated with a reduction in CLL. Cyclosporin A is also effective with or without adrenocortical hormone in CLL patients with pure red blood cell aplastic anemia, but often only the amount of hemoglobin is elevated, and the condition of CLL is not improved.
6. Patients with secondary malignant tumors may develop secondary malignancies due to autoimmune deficiency or chemotherapy. The most common are lung cancer and malignant melanoma, other tumors haveHodgkin's lymphomaAcute myeloid leukemia,Chronic myeloid leukemia,Multiple myelomaWait.
diagnosis:
1. Domestic diagnostic criteria Comprehensive domestic report for nearly 15 years and reference to foreign literature, CLL diagnostic criteria are summarized as follows.
(1) Clinical manifestations:
1 may have fatigue, physical decline, weight loss, hypothermia, anemia or bleeding.
2 may have lymph nodes (including head and neck, armpits, groin), liver, splenomegaly.
(2) Laboratory inspection:
1 Peripheral blood leukocytes>10×109/L, lymphocyte ratio 50%, absolute value>5×109/L, the morphology is mainly mature lymphocytes, and naive lymphocytes and atypical lymphocytes are seen. The above abnormality lasts for ≥ 3 months.
2 myeloproliferation is active or significantly active, lymphocytes ≥ 40%, mainly mature lymphocytes.
3 Immunophenotyping: B-CLL: CD5, CD19, CD20 positive; mouse rosette test positive; sIg weakly positive, showing kappa or lambda monoclonal light chain; CD10, CD22 negative. T-CLL: CD2, CD3, CD8 and/or CD4 positive; sheep rosette test positive; CD5 negative.
(3) Exclude other diseases: 1 excluding lymphoma with leukemia and young lymphoblastic leukemia; 2 exclude viral infection, tuberculosis, typhoid, infectious mononucleosis and other patients with lymphocytosis.
B-cell chronic lymphocytic leukemia (B-CLL) can be divided into three types according to different proportions of lymphocytes, immature lymphocytes and atypical lymphocytes in peripheral blood and bone marrow: 1 typical CLL: more than 90% are similar mature Small lymphocytes; 2CLL with young lymphocytosis (CLL/PL): immature lymphocytes >10%, but <50%; 3 mixed type: different proportions of atypical lymphocytes, large cell volume, nuclear/mass ratio Decreased, the cytoplasm showed different degrees of basophilic staining, with or without azure particles.
2. International Diagnostic Criteria International CLL Working Conference (IWCLL) and National Cancer Institute (NCI) CLL Collaboration Group standards.
(1) The absolute value of peripheral blood lymphocytes increased by >5×109/L. After repeated examination, it lasted for at least 4 weeks (NCI), or 10×109/L, and persisted (IWCLL).
(2) Mainly mature small lymphocytes, morphological classification: 1 typical CLL: atypical lymphocytes ≤ 10%. 2LL/PL: Peripheral blood lymphocytes account for 11% to 54%. 3 atypical CLL: There are different proportions of atypical lymphocytes in peripheral blood, but young lymphocytes <10%.
(3) B-CLL immunophenotyping: SMIg+/-, showing kappa or lambda monoclonal light chain; CD5, CD19, CD20, CD23, FCM7+/-, CD22+/-.
(4) At least one bone marrow puncture and biopsy were performed. The smear showed active or significant hyperplasia, lymphocytes >30%; biopsy showed diffuse or non-diffuse infiltration.
Diagnostic Review: Patient age is an important parameter in the diagnosis of CLL because 95% of CLL occurs after age 50. In the medical history, the painless mass of the neck and/or the left upper abdomen has a suggestive value, and blood routine should be checked accordingly. If the total number of white blood cells is increased, the absolute number of lymphocytes is ≥5×109/L, and it persists. It should be highly suspected of CLL, and a basic diagnosis can be made after excluding other causes of lymphocytosis. Further blood microscopy under the microscope, such as mature small lymphocytes accounted for more than 60% can be diagnosed. Bone marrow smears are generally consistent with blood smears and have an auxiliary diagnostic effect. Bone marrow pathological sections can understand the extent of the lesion, and provide a reference for the choice of treatment plan and prognosis judgment while verifying the diagnosis. Because B-CLL leukemia cells have a more specific immunophenotype, it is helpful for differential diagnosis in atypical cases. Various imaging examinations are mainly used to understand the extent of the disease, not the basis for diagnosis.
As can be seen from the above analysis, medical history and physical examination can provide diagnostic clues, while hematological tests have decisive value, and immunological examinations have an auxiliary effect.
Identification
Adult benign lymphocytosis is seen in several reasons:
1 virus infection: especially hepatitis virus, cytomegalovirus, EB virus infection, infectious mononucleosis. Clinically, it is often characterized by lymph nodes, mild swelling of the liver and spleen, and can be identified by corresponding virological examination;
2 bacterial infection: brucellosis, typhoid fever, paratyphoid fever and other chronic infections, have their corresponding pathogenic diagnosis and corresponding clinical manifestations, can be identified;
3 autoimmune diseases, drugs and other allergic reactions;
4 hyperthyroidism and adrenal insufficiency;
5 after splenectomy.
2. The clinical manifestations of juvenile lymphocytic leukemia are obviously swollen. The cells of young lymphocytes are larger than those of CLL cells, and the cytoplasm is light blue with a distinct nucleolus. Under the electron microscope, the surface surface fluff was more than that of CLL cells, and the expression level of immunoglobulin on the cell surface was high.
3. Hairy cell leukemia is mostly B cell source, T cell source is very rare, and CLL is two different diseases. Clinically, the spleen is highly swollen with typical hair cells in the blood, which contains acid phosphatase isoenzyme 5, which is characterized by resistance to tartrate acid phosphatase staining. The specific identification is shown in Table 1.
4. Small lymphocytic lymphoma Small lymphocytic lymphoma and CLL are the closest in clinical and biological performance. The prognosis and treatment are similar. Therefore, the latest clinical standards such as Real and WHO classify the two into one category. From the lymph node pathological examination can not distinguish between the two, but small lymphocytic lymphoma does not necessarily infiltrate the bone marrow, the proportion of bone marrow lymphocytes <40%, even if there is bone marrow infiltration, nodular infiltration, and CLL is mostly diffuse.
5.non-Hodgkin's lymphomaWhen leukemia non-Hodgkin's lymphoma is converted to lymphoma leukemia, its cell body is large, the nucleus is folded, the cell surface is highly expressed immunoglobulin, and CD5 is negative. All of these characteristics are easily distinguished from CLL.
6.Dermal T-cell lymphoma Often accompanied by extensive skin infiltration, the nucleus of the brain is cerebral. It is a non-Hodgkin's lymphoma derived from helper T cells (CD4).
7. Large-granulocyte lymphocytic leukemia (LGL) Generally, lymphocytes are larger than CLL cells, and have abundant border-clear translucent cytoplasm with azolla granules of varying sizes, oval or irregular nuclei. The tissue is derived from NK/T cells, and the immunophenotypes derived from T suppressor cells (CD8) are CD3, CD4-, CD8, CD16, CD56-, CD57/-, with TCR gene rearrangement; those derived from NK cells, CD3-, CD4-, CD8-, CD16, CD56-, CD57/-. No clonal gene abnormalities. The clinical condition of T-cell LGL is inert and chronic, often accompanied by pancytopenia and splenomegaly. Some patients with LGL in NK cells may have acute fulminant onset, and some may have a chronic course.
complication:
1. One of the main causes of death and deterioration of CLL patients is infection, which can affect about 40% of patients. Hypogammaglobulinemia is one of the leading causes of infection and disease progression. In addition, there are granulocyte deficiency, T cell dysfunction, and the like. The most common is bacterial infection, which accounts for about 15% of viral infections (especially herpes virus infections). Fungal infections are rare.
2. CLL patients with secondary tumors 9% to 20% may have secondary tumors. The most common secondary tumors are soft tissue sarcoma and lung cancer. Patients with CLL are 10 times more likely to develop multiple myeloma than the average person, but neither originated from the same malignant B cell clone. The risk of CLL secondary to acute myeloid leukemia does not increase.
treatment:
Western medicine treatment
CLL is a disease with a good prognosis, although there is no cure case report, but its 5-year survival rate can reach 50%. 20% of patients are diagnosed at an advanced stage with an average survival of about 2 years. The purpose of treatment is to reduce complications and improve the quality of life; it is generally believed that early patients may not be treated, how to determine the timing of treatment is very important, there are many criteria for judging, consider the following aspects:
1 disease staging: patients with general stage III, IV (or C) are considered for treatment. Patients with anemia (especially in the presence of autoimmune hemolytic anemia) and thrombocytopenia require treatment.
2 lumps: simple mild to moderate lymphadenopathy can not be treated; lymph node enlargement caused by dysfunction (including nerve compression symptoms, lymphatic reflux disorder leading to physical changes, etc.) need treatment. Only patients with splenomegaly and no lymphadenopathy have a better prognosis; therefore, treatment of patients with splenomegaly and symptoms should be individualized.
3 infection: There is no definite evidence that alkylating agents or corticosteroid treatment can reduce the incidence of infection.
4 lymphocyte count: weekly blood lymphocyte count <40 × 109 / L or lymphocyte doubling time longer than 1 year can not be treated. Peripheral blood lymphocyte counts >200 × 109 / L and no other disease is not necessarily treated immediately.
Therefore, CLL treatment indications can be summarized as: 1 anemia; 2 thrombocytopenia; 3 spleen progressive enlargement or spleen pain; 4 lymph nodes, symptoms; 5-week blood lymphocyte count doubled within 6 months; 6PLL transition; 7Richter transition.
CLL treatment mainly includes chemotherapy, radiotherapy, glucocorticoids, splenectomy, bone marrow transplantation and biological treatment.
Chemotherapy CyclophosphamideAnd chlorambucil (tumorine) is the standard first-line treatment. Benzoyl mustard (Ukrainol) is an aromatic derivative of nitrogen mustard and has been the main drug for the treatment of CLL since 1952. Oral medication, the usual dose of 0.03 ~ 0.3mg / (kg · d); or the total dose of 0.4 ~ 0.8mg / kg, divided into 4 days medication, repeated every 4 to 6 weeks. The two effects are similar, generally no bone marrow suppression, the most common side effect is nausea, a small number of rashes due to allergies; there are reports of oral secondary tumors may be taken every day. The complete response rate is up to 15% and the partial response rate is 65%. Jaksic and Brugiatelli et al reported that daily oral administration of large doses of chlorambucil (15 mg) to relieve or develop intolerable toxicity can achieve better results than CHOP regimen combined with chemotherapy.
The effect of cyclophosphamide (CTX) is basically the same as that of chlorambucil (tumorine). The usual dose is 2~3mg/(kg·d) or the total dose is 2~3 weeks 20mg/kg, orally or intravenously. Cyclobutyric acid (CTX) is still effective in the ineffective phenylbutyrate mustard (CTX), and is often used in patients who cannot tolerate chlorambucil or chlorambucil (tumorine). . The side effects are similar to those of chlorambucil (tumorine), and hemorrhagic cystitis may occur in cyclophosphamide (CTX).
2. The most commonly used combination chemotherapy is chlorambucil (tumorine) + prednisone (MP regimen), commonly used dose of chlorambucil (tumoren) 30mg/m2, day 1, prednisone 80mg / d, for 5 days for a course of treatment, repeated every 2 weeks. Benzoate mustard (tumoren) can be divided into 2 days, according to the clinical response can be increased or decreased by 4mg / (m2 · d) per month. When the white blood cell count is less than 10×109/L, the chlorambucil must be reduced to maintain the white blood cell count at (5-10)×109/L. The efficacy of chlorambucil (tumorine) + prednisone is better than that of single-cancer, which is effective in 80% of patients.
COP regimen (cyclophosphamide (CTX),Vincristine,Prednisone) Effective for newly diagnosed patients and partially refractory patients. Dosage: cyclophosphamide (CTX) 300mg / (m2 · d) × 5 days; VCR 1-4mg / m2, day 1; prednisone 40mg / (m2 · d) × 5 days; repeat 1 course every 3 weeks . Approximately 25% of patients achieved complete remission and 50% had majority remission; the overall median survival was 4 years. Prolonged treatment time to 12 to 18 months can prolong survival and compare with MP regimen. The COP regimen is more neurotoxic and myelosuppressive.
On the basis of the COP protocol, doxorubicin (Doxorubicin) (2 mg/m2, day 1, CHOP regimen) was added to treat advanced patients, and the median survival time was extended from <2 years to >4 years, but the results were Similar to patients treated with COP regimen for 18 months.
In addition, M2 regimen, CMP regimen (cyclophosphamide, oxyfluorfen, prednisone), ACP regimen (cytarabine, cyclophosphamide, prednisone), DHAP regimen (Dexamethasone, high-dose cytarabine, cisplatin), MOPP regimen (nitrogen mustard, vincristine, carboplatin, prednisone) have certain effects.
3. Penstatin (DCF) Penstatin (DCF) is an adenosine deaminase inhibitor commonly administered at a dose of 4 mg/m2 administered intravenously every week or every 2 weeks. The effective rate is about 25%, and the main side effect is severe infection.
4. There are two methods of fludarabine: 126mg / (m2 · d) × 5 days, 28 days with a course of treatment, 4 to 6 courses of treatment; 220mg / m2 of the first day, followed by 30mg / (m2 · d) Continuous infusion for 2 days, repeated 4 weeks apart. The initial treatment rate was 83% (complete remission rate 75%), and the retreatment patients were 12% to 57% effective. Early patients have better outcomes. The main side effect is myelosuppression and infection (the main cause of infection is a decrease in CD4 positive cells), and another possible complication is tumor lysis syndrome. The combination of fludarabine and prednisone does not improve the efficacy and is prone to Listeria infection.
5.2-chlorodeoxyadenosine (2-chlorodeoxyadenosine, 2-CDA) 2-CDA is another steroid that is resistant to adenosine deaminase. The usual dose is 0.1g/(kg·d), continuous infusion for 7 days; or 0.1mg/(kg·d), input for 2 hours, for 5 days; oral administration is also effective. The effective rate is 44%, and the rapid decline of peripheral blood lymphocytes after the start of treatment is effective. The main side effects are myelosuppression (especially thrombocytopenia) and infection (related to a decrease in peripheral blood CD4 positive cells).
6. Monotherapy of glucocorticoids is especially suitable for those with autoimmune hemolytic anemia or thrombocytopenia. CLL alone should avoid single-agent applications. The most commonly used is prednisone, dose 30 ~ 60 mg / (m2 · d), gradually reduced to a minimum amount to maintain. At the beginning of treatment, transient lymphocytosis may occur due to redistribution of lymphocytes. Peripheral blood lymphocytes may be observed for 4 to 6 weeks, and lymph nodes and spleen may be reduced in some cases. The main side effects are diabetes, osteoporosis, high blood pressure, infection, etc.
7. Bone marrow transplantation
(1) Allogeneic bone marrow transplantation: Allogeneic bone marrow transplantation is mainly applied to patients with advanced stage and chemotherapy, and HLA-matched sibling donor transplantation is the main. The median time from self-diagnosis to transplantation was 3 years, and pretreatment was based on high-dose CTX+ total body irradiation (TBI). About 75% of patients can achieve remission, and about 40% of patients can develop acute GVHD (II-IV degree). The median disease-free survival period was 4 years, and the survival rate at 80 months after transplantation was about 30%.
(2) Autologous hematopoietic stem cell transplantation: including autologous bone marrow and peripheral blood stem cells, the pretreatment regimen is also dominated by large doses of CTX + TBI; some cases can be purified by monoclonal antibodies (CD19, CD20, CD10, etc.). Due to the small number of cases treated, it is difficult to draw a positive conclusion.
8. Splenectomy Some patients with stage Rai stage IV and severe thrombocytopenia have effective splenectomy. However, the spleen hyperfunction patients who had been treated with chemotherapy had no obvious improvement in platelet count after spleen.
9. Radiotherapy and radiotherapy is the earliest treatment method for CLL, which can improve the condition, but the effect is maintained for a short time, and often accompanied by bone marrow suppression. However, it is still an effective method for local treatment of CLL.
(1) Systemic Radiotherapy (TBI): The value of TBI is still controversial. Early studies suggested that some patients achieved complete remission after exposure to 100-400 cGy (5-10 cGy per day, 5 times a week), and serum immunoglobulin improvement was observed. . No recent cases of complete remission have been observed, and 73% of cases have significant hematologic toxicity. The use of TBI with cyclophosphamide (CTX)/prednisone did not improve efficacy.
(2) Local irradiation: This is an important treatment for improving nervous system symptoms, bone pain, organ involvement, and local mass. If irradiated with 200cGy lymph nodes or masses, it can be rapidly reduced, but chemotherapy is needed to maintain efficacy. Irradiation in the spleen area is also beneficial for patients who are weak and unable to undergo splenectomy. However, the mediastinal irradiation should be too toxic to be cautious.
10. Biological treatment
(1) Interferon α-(α-IFN): Early CLL is effective in the treatment of recombinant interferon alpha, which can reduce lymphocyte count with less side effects. Therapeutic effects of high-dose interferon alpha in patients with advanced disease are limited and may increase the risk of illness. Interferon can improve the effects of chemotherapy and rebuild natural killing activity.
(2) Monoclonal antibodies: less reported, infusion of CD5 murine monoclonal antibody may have short-term effects; its application due to its target cell surface antigen and allergic reaction. The field of application is promising for patients with partial or non-clonal complete remission to eliminate minimal residual disease.
(3) Cytokines: The application of hematopoietic growth factors makes it possible to perform large doses of radiotherapy/chemotherapy in the absence of transplantation. The application of interleukins is under investigation and may have some effect.
11. Leukocyte separation A large number of leukocyte separations can reduce enlarged organs and increase hemoglobin and platelet levels. It is optional for patients with bone marrow failure who are not eligible for standard chemotherapy.
The above content is for reference only, please consult the relevant physician or relevant medical institution if necessary.
prevention:
Prognosis
The clinical course of CLL is highly heterogeneous, with a median survival of 2 to 20 years. Many clinical and laboratory characteristics (such as clinical stage, bone marrow histopathology, peripheral blood lymphocyte count, lymphocyte doubling time, lymphocyte morphology, cytogenetic abnormalities, etc.) can affect its prognosis. This requires hematologic oncologists to look for prognostic indicators, of which the clinical staging system is the most valuable prognostic parameter. There are currently two recognized CLL staging criteria: the staging and improved inclusion based on clinical signs and blood counts. Staging of the involvement of the lymphatic system. In 1987, Rai divided CLL into three groups based on its original staging criteria: low-risk group (0 phase, median survival time > 150 months), intermediate-risk group (I and II, median survival time was about 90) Months), high-risk group (stages III and IV. Median survival time is approximately 19 months).
CLL can be transformed in three directions with a poor prognosis.
1. CLL patients with young lymphoblastic leukemia (PLL) and CLL/PLL transitions of about 10% can switch to PLL. This transition can be slow or progressive. 80% of CLL patients may have a lower proportion (<10%) of young lymphocytes, which may not change throughout the course of the disease. About 15% of patients can coexist with small lymphocytes and young lymphocytes, and the proportion of young lymphocytes ranges from 10% to 50%. This part of the patient was diagnosed as CLL/PLL, and the lymph nodes and spleen were enlarged. The proportion of young lymphocytes in 80% of CLL/PLL patients remained stable, and there was no significant difference in survival and typical CLL duration.
Other CLL/PLL patients can switch to PLL, which is characterized by a decrease in the proportion of leukemia cells that can form rosettes with rat erythrocytes, increased peripheral venous cells in the peripheral blood, progressive splenomegaly; t(6;12) chromosomal changes in some cases (This chromosomal change is common in PLLs). Patients who have undergone a change in chemotherapy have a poor response and a shorter survival period with an average survival of 9 months.
2. Richter's transformation of Richter syndrome includes fever, weight loss, rapid lymphadenopathy, hepatosplenomegaly, abdominal and central nervous system symptoms, and clinical deterioration. This transition can occur at any time during the course of the CLL, and the median time from the diagnosis of CLL to the transition is 2 years. The retroperitoneal lymph nodes are enlarged and the spleen is common; the bone marrow often infiltrates the immature cells and can cause bone destruction. Lymph node biopsy can be diagnosed, and the affected lymph nodes often show a larger class of primordial cells: cytoplasm rich, basophilic, and clear and irregular nucleoli. The treatment response was poor, with a median survival of 4 months; however, it has also been reported that combined chemotherapy can achieve long survival.
3. ALL transforms CLL to ALL, and the original cells can express strong Ig, Ia and TdT. The expression of the C-myc gene and the μ chain gene is increased.
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