Secondary leukemia

Introduction to secondary leukemia Secondary leukemia is an identifiable acute leukemia subtype that is secondary to chemotherapy, radiation therapy, or acute leukemia with a positive history of environmental or occupational exposure. basic knowledge The proportion of illness: 0.003% Susceptible people: no specific population Mode of infection: non-infectious Complications: sepsis, shock, cerebral hemorrhage, multiple lung infections

Cause of secondary leukemia

(1) Causes of the disease

More and more studies have shown that the occurrence of secondary leukemia is closely related to the primary disease treatment plan, the type of primary disease, the duration of the disease, and the occurrence of secondary acute myelocytic leukemia (SAML). The risk depends on the treatment plan:

1 Chemotherapy (with or without radiotherapy) is highly dangerous, and the risk of radiotherapy alone is the lowest.

2 Whole body irradiation is more dangerous than high dose local irradiation.

3 There is a positive correlation between the intensity of treatment of patients or experimental animals and the risk of leukemia. The relationship between the risk of secondary leukemia and the type of primary disease is still not estimated. The main primary disease types are reported as:

1 Hematological diseases: including Hodgkin's disease (HD), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL) and bone marrow Proliferative diseases, etc., also include the above-mentioned diseases after hematopoietic stem cell transplantation.

2 non-blood diseases: breast cancer, ovarian cancer, testicular cancer, etc., the cause of secondary leukemia is related to the following factors.

Ionizing radiation

Ionizing radiation has a clear increase in the risk of AML in humans and experimental animals. The incidence of leukemia caused by nuclear radiation below 400 cGy caused by the nuclear explosion in Hiroshima is about 2 cases/(106 person-years·kg). The incidence of leukemia in patients with ankylosing spondylitis treated with ~1500cGy spinal cord is the same; the epidemiological investigation of patients undergoing clinical radiology and receiving radiotherapy and the results of small-dose chronic irradiation in leukemia in experimental animals indicate that radiotherapy and secondary The relationship between leukemia and leukemia is direct and close. Recently, studies on Hodgkin's disease have shown that patients receiving radiotherapy have a lower incidence of secondary leukemia than chemotherapy alone; high-dose local radiotherapy is secondary to leukemia caused by systemic radiotherapy. The incidence is much lower; high-dose radiotherapy has a lower incidence of secondary leukemia than low-dose multiple radiotherapy, which has been confirmed by experimental results of small-dose chronically irradiated experimental animals for secondary leukemia, high-dose irradiation on bone marrow Cells have a lethal effect, while small doses of radiation are more likely to cause non-fatal bone marrow damage and mutations.

2. Chemotherapy drugs

(1) alkylating agents: including nitrogen mustard (nitrogenmus-tards), chlorambucil (tumorine), cyclophosphamide, melphalan (melphalan), busulfan, procarbazine (methyl benzamidine) ), nitrosourea alkylating agents such as carmustine (BCNU), lomustine (CCNU), semustine (MeCCNu), etc., alkylating agents are the strongest leukemia-producing drugs, which cause leukemia The mechanism is that DNA acts in different ways, causing DNA replication to stop, gene mutation, chromosome loss, and at the same time, leading to partial cell death. 85% of patients with secondary leukemia have been treated with alkylating agents, and various alkylating agents have caused The incidence of leukemia varies, with 65% of patients with secondary leukemia receiving cyclophosphamide, melphalan, and chlorambucil. Studies have shown that melphalan may cause leukemia than cyclophosphamide. Strong, this indicates a difference in mutagenic effects between alkylating agents.

(2) Topoisomerase II inhibitor:

1 podophyllotoxin: the most representative of etoposide (VP16) and teni-poside (VM26), podophyllotoxins are a class of non-invasive DNA topoisomerase II ( A strong inhibitor of Topo II, which acts on TopoII to covalently bond TopoII with DNA to form a stable "drug-enzyme-DNA" ternary complex, preventing TopoII from religating DNA double strands, resulting in DNA deletion and heavy Plaque, chromosome breaks and sister chromatid exchange, experiments have shown that VP-16-induced secondary leukemia lacks the basis of dose-dependent and dose accumulation, the occurrence of leukemia and treatment options and the interaction of patients' own factors and drugs More likely.

2 anthracyclines: such as doxorubicin, epirubicin (epimycin), mitoxantrone and aclarithromycin, etc., these drugs form a stable topoisomerase II-DNA complex, Inhibition of DNA repair leads to DNA single-strand and double-strand breaks and prevents DNA and RNA synthesis. They are the main drugs for the treatment of ALL, NHL, and testicular cancer. It is often necessary to use a combination of alkylating agents or radiation therapy. Therefore, it is not clear. Whether the use of ring drugs alone causes secondary leukemia. In recent years, with the successful treatment of acute promyelocytic leukemia (APL), more than 10 cases of secondary leukemia after APL treatment have been reported, considering the use of anthracyclines. It is related to drugs such as VP-16.

3. Other drugs, bismorphomorph and Razoxane, are epidemic inhibitors, which can inhibit the synthesis of DNA and cause leukemia. Long-term application has found that it causes leukemia. Many cases have been reported in China.

4. Non-therapeutic substances include benzene and benzene derivatives, gasoline, organic solvents, insecticides, hair dyes, arsenic, paints, etc. The incidence of secondary leukemia in people exposed to benzene for a long time is 20% higher than that of the control group. Times, the median onset time is 9.7 years, and there is a complete blood cell reduction in the first 6 months to 6 years after the occurrence of acute leukemia.

(two) pathogenesis

The pathogenesis of secondary leukemia has not yet been elucidated, and many studies have demonstrated that multiple effects lead to the development and progression of secondary leukemia.

1. DNA sequence and DNA regulation abnormalities All alkylating agents and ionizing radiation are strong mutagens, and their mutagenic effects may be related to their carcinogenicity and cytotoxicity. Studies have shown that secondary leukemia involves many genes, oncogene activation Inactivation of tumor suppressor genes and inhibition of apoptosis are important mechanisms of leukemia. Due to the increased genetic risk of DNA, the risk of leukemia increases, which can cause many types of chromosomal abnormalities, including chromosome breaks, complex rearrangements, and chromosome parts. Or all lost, due to the action of chemical carcinogens and radiation, the expression of oncogenes located in the chromosomal inheritance region is increased, and the regulation of cell oncogenes is altered by DNA point mutations and DNA modification or by chromosomal rearrangement, so that hematopoietic stem cells Chromosomal breaks or rearrangements, producing abnormal functional proteins, such as ras, myc, and c-fms. Many patients with t-MDS/AML have imbalanced chromosome changes that can partially or completely lose the chromosome. It turns out that there may be some loss in the lost area. a certain tumor suppressor gene, which is often involved in t-MDS/AML caused by topoisomerase II inhibitor The chromosome 21 transcription factor CBF2 (AMlL-1), which is most susceptible to translocation, and affects chromosomes 8, 12 and 3, and the MLL (myeloid-lymphoid leukemia) gene regulates the Drosophila trithorax gene, which is homologous to humans. The gene, MLL gene plays an important role in controlling the differentiation of early hematopoietic stem cells. It has been confirmed that there are more than 20 kinds of chromosome translocations involving 11q23, such as VP16-induced t(9;11) translocation with MLL gene, resulting in new Fusion genes directly cause significant loss of growth and leukemia.

2. Genetic susceptibility Through studies of hereditary diseases that are predisposed to high-grade leukemia, these patients are sensitive to the mutagenic effects of ultraviolet light and chemical carcinogens (such as alkylating agents) due to defects in their DNA repair functions, such as Fanconi. Anemia, Bloom syndrome and Kostmann granulocytosis, the probable cause of leukemia in these diseases is the presence of a heterozygous gene associated with genetic susceptibility to leukemia, such as patients with Li-Fraumeni syndrome with p53 tumor suppressor gene embryos Mutant heterozygotes, the incidence of leukemia in these patients increased.

Secondary leukemia prevention

Intensive chemotherapy and radiotherapy prolong the survival of ALL, lymphoma, myeloma, testicular cancer, ovarian cancer, adjuvant chemotherapy is often used in the recent diagnosis of breast cancer patients with only axillary lymph node metastasis and other chemotherapy-sensitive tumor patients Pre- and post-operative treatment, in these patients, the application of hematopoietic stem cell support therapy after high-dose chemotherapy or radiotherapy is increasing, and the survival time after treatment is prolonged. Therefore, the incidence of secondary leukemia may increase accordingly. Although these treatments significantly improve the survival rate and quality of life of cancer patients, the risk of developing secondary leukemia should be estimated as part of the overall treatment plan. The treatment of leukemia should be fully considered when treating In a certain disease, if the effect is equivalent, the drug that causes leukemia should replace the alkylating agent; when the risk of recurrence of the primary disease is low, the choice of adjuvant chemotherapy should be cautious, try not to use alkylating agents, how many A disease in which childhood genetic mutations are prone to develop into secondary leukemia, such as Down syndrome, congenital immunity Epidemic deficiency syndrome, Fanconi anemia and neurofibroblastoma, alkylating agents, nitrosourea alkylating agents, podophyllotoxins can not be used, anti-metabolites should be used, alkylating agents in polycythemia The use should be cautious, it is best to use hydroxyurea, when treating HD, ABVD is better than MOPP, cyclophosphamide has less leukemia than other alkylating agents.

All alkylating agents and podophyllotoxins should be used with extreme caution in the treatment of non-malignant diseases.

Secondary leukemia complications Complications septic shock cerebral hemorrhage multiple lung infection

1. Infection, fever is mainly seen in pulmonary infection, sepsis, and toxic shock.

2. Bleeding skin mucosal bleeding, cerebral hemorrhage.

Symptoms of secondary leukemia Common symptoms High fever, dyspnea, hypothermia, prone to bruising

The onset is slow, there is a clear history of primary disease and the history of chemical drug use and/or radiotherapy, age and gender are the same as the primary disease, and most patients show different degrees of bone marrow failure at the time of diagnosis.

1. The general characteristics of about 70% secondary to the use of alkylating agents or radiotherapy, the patient has pre-leukemia performance, the typical pre-leukemia phase lasts about 11.2 months, the patient has fatigue, fatigue and other anemia-related symptoms, may be associated with the skin Bleeding, ecchymosis, nosebleed and other bleeding symptoms, may have fever but no obvious signs of infection; podophyllotoxin (VP16 or VM26) or other topoisomerase II inhibitors caused by secondary leukemia, often no leukemia Performance in the early stage.

2. Bone marrow failure Patients from the early stage of leukemia into the acute leukemia, often present with typical bone marrow failure, clinical manifestations of the disease is significantly worse and rapid progress, poor treatment, if not actively treated, patients can die short-term, due to severe bone marrow failure Symptoms such as anemia, hemorrhage and fever infection, fatigue, dizziness, palpitation, difficulty breathing; skin bruises, ecchymosis, bleeding gums, oral blood vesicles, nosebleeds, hematuria, blood in the stool are rare, severe cases can be caused by intracranial hemorrhage Death; common infections, may have low fever or high fever, some patients may have clear local infections, and some patients have no obvious infection sites, severe infections, septic shock, sepsis, sepsis, etc. Of the common causes of death in secondary leukemia, only 5% of patients have liver, spleen, and enlarged lymph nodes.

Secondary leukemia examination

Blood picture

(1) Pre-leukemia:

The prominent manifestations of this period are three-line ineffective hematopoiesis, complete blood cell reduction, and most patients show reduced erythropoiesis, decreased hemoglobin (Hb) and red blood cell (RBC) counts, increased MCV, decreased reticulocyte count, and elliptical giant in peripheral blood. Red blood cells and nucleated red blood cells, which is the earliest hematological change of secondary leukemia. The increase of MCV is associated with the occurrence of high risk of secondary leukemia in Hodgkin's disease (HD). The MCV increased group is 3 years earlier than the secondary leukemia in the control group. 4 years, 75% of patients have mild neutropenia, there may be cytoplasmic granule reduction and pseudo Pelger-Het abnormalities, may have mononucleosis, basophilia, 60% of patients have thrombocytopenia, visible No granular platelets, huge platelets.

(2) Acute leukemia:

Hemoglobin, red blood cells, reticulocytes decreased, white blood cell count can be increased, normal or decreased, neutropenia can be seen, granulocytes can be seen in peripheral blood, immature granulocytes or primitive monocytes, immature monocytes, thrombocytopenia Platelet crisis.

2. Bone marrow

1. Pre-leukemia:

One of the characteristics of bone marrow morphology in this period is the abnormal proliferation of the three lines of cells, which is more obvious with erythroid hyperplasia. Secondly, it is difficult to diagnose t-MDS with FAB typing. If the FAB classification is used to standardize t-MDS Type, patients diagnosed with RAEB were significantly higher than primary MDS, 1/3 to 1/2 of patients with marked or extremely active bone marrow hyperplasia, 1/3 of patients with hyperplasia, a small number of patients with normal bone marrow hyperplasia; erythroid Abnormal proliferation includes megaloblastic megaloblastic changes, and the number of ring-shaped iron granules is increased. Even the ring-shaped iron granules are dominant, the number of primitive red blood cells is increased, nuclear sprouting, nuclear fragmentation and binuclear red blood cells are present, and cytoplasmic staining is uneven. Phenotypic or smear red blood cells, ho-week corpuscles are easy to see; granulocyte lineage shows increased cytoplasmic granules, too little or no, little or no nuclear lobes, Pelger-Het-like abnormalities, immature granulocyte ratio Increase; megakaryocyte cells can be seen in small megakaryocytes, megakaryocyte particles are reduced, the number of naive megakaryocytes can be increased, and different degrees of myelofibrosis can occur in this period.

2. Acute leukemia:

The degree of myeloproliferation is the same as that of t-MDS. The three lines of cells show obvious pathological hematopoiesis. The primordial cells increase by 30%, Auer bodies are rare, and the granulocytes increase, which is M1, M2, often caused by alkylating agents; Mononuclear cells, M4, M5, often caused by topoisomerase II inhibitors, the former incidence rate is higher than the latter, t-AML is often difficult to use FAB typing standard typing, often two or two More than one morphological change, t-ALL, t-CML, t-APL bone marrow changes with primary leukemia.

3. Cell chemistry

(1) Neutrophil alkaline phosphatase (NAP) NAP positive rate decreased, and the score decreased.

(2) Peroxidase (POX) The positive rate of this enzyme is reduced in patients with t-AML, which is 10% in secondary leukemia and 100% in primary leukemia.

(3) Patients with chloracetic acid AS-D naphthol esterase 20% t-AML were positive for this enzyme, and the positive rate was lower than that of primary AML, and the latter was 47%.

4. Chromosome examination

By chromosomal G-band staining and sister chromosome exchange, it can be detected that 76% to 90% of patients with secondary leukemia have clonal chromosomal abnormalities in primary cells, while primary AML is only 48% to 66%, primary MDS. 38% to 60%, the composite chromosomal abnormality of secondary leukemia is 75%, higher than primary AML (45%) and MDS (25%), and 49% of patients with secondary leukemia have abnormal karyotype (AA) ), 36% of patients are normal karyotype and abnormal karyotype chimera (AN), 15% of patients are normal karyotype (NN), in the abnormal chromosome number, often subdiploid chromosome, hyperdiploid It is rare, and the primary AML is mostly diploid or hyperdiploid. The secondary leukemia after the alkylating agent is used has multiple complex chromosomal abnormalities, the most common being -5/5q-, -7/7q-, followed by Secondary leukemias arising from topoisomerase II inhibitors are most likely to affect 11q23 or 2lq22, causing chromosomal translocations. The cytogenetic abnormalities of secondary leukemia are shown in Table 2.

5. Molecular biology examination

The chromosomal translocation is the formation of specific fusion genes, involving nuclear binding factors (CBF), HOX family members, ETS family members and other transcriptional regulators, resulting in the appearance of new transcription factors or transcription factor receptors, leading to abnormal differentiation. Proliferation and apoptosis, t-MDS/AML chromosomal translocations are shown in Table 3.

6. In vitro culture of primordial cells

The original cell culture of patients with secondary leukemia showed that CFU-GM colony formation decreased or not, and the number of clusters increased. Similar to patients with primary leukemia, it is considered that the decrease of myeloid colony formation rate in pre-leukemia has diagnostic and prognostic significance. However, the value of clinical treatment is limited.

Secondary leukemia can occur bleeding, infection, hepatosplenomegaly, etc., should be X-ray, CT, B-ultrasound, electrocardiogram, blood biochemistry, blood culture, sputum culture and other tests.

Diagnosis and diagnosis of secondary leukemia

According to the primary disease, medication history, radiological history, occupational exposure history, clinical manifestations, blood and bone marrow characteristics, diagnosis is generally not difficult.

Differential diagnosis

1. Primary acute leukemia has an acute onset, usually no obvious early leukemia, anemia, infection, bleeding and tissue infiltration, chromosomal abnormalities are rare, initial chemotherapy is sensitive, and the remission rate is high.

2. Primary MDS Primary MDS usually has no primary disease and medication history and radiotherapy history. Secondary MDS tri-line hyperplasia is abnormal, and RAEB is more common, and the treatment effect is poor.

3. The megaloblastic anemia is sometimes confused with secondary MDS, but the primordial cells in the bone marrow of the former do not increase, the PAS staining of the young red blood cells is negative, and there is no secondary leukemia.

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