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1、第六篇 血液系统疾病 第九章白血病(Leukemia)周剑峰周剑峰学时数：学时数：3 3学时学时讲授目的和要求1.掌握急、慢性白血病的临床表现，实验室检查及诊断标准，治疗原则2.熟悉急性白血病FAB分型，联合化疗的原则，完全缓解的概念讲授主要内容概述病因和发病机制临床表现实验室检查诊断标准鉴别诊断治疗Erythrocytes: transport oxygenErythrocytes: transport oxygenNeutrophilBasophilEosinophilMonocytes/MacrophageDefense against infectionDefense against
2、infectionPlatelets: Mediate blood clottingPlatelets: Mediate blood clottingT-lymphocytes: antigen presenting T-lymphocytes: antigen presenting B-lymphocytesB-lymphocytes Plasma cell: Plasma cell:Source of antibodiesSource of antibodiesPluripotential Pluripotential stem cellsstem cellsMyeloid stem ce
3、llsMyeloid stem cellsLymphoid stem cellsLymphoid stem cellsUnipotentialUnipotential progenitor cells progenitor cellsImmature Immature hematopoietichematopoietic cells cellsmature mature hematopoietichematopoietic cells cellsHematopoiesis composes of the options of commitment to different Hematopoie
4、sis composes of the options of commitment to different lineages and the progressive stages of maturation at which partial or lineages and the progressive stages of maturation at which partial or complete arrest can occur, results in the wide array of malignant complete arrest can occur, results in t
5、he wide array of malignant disease-Leukemiadisease-LeukemiaStem cell Progenitor cellImmature cellMature cell Accumulation of mutations of DNA within a pluripotential stem cell or very early progenitor cell gives rise to leukemic stem cellsNormal stem cellLeukemic stem cellEtiology&Pathogenesis Envir
6、onmental factors Acquired diseasesLesions to the DNAClonal expansionA lot of environmental factors has been reported to cause A lot of environmental factors has been reported to cause leukemia. However, only four of them are firmly established leukemia. However, only four of them are firmly establis
7、hed causal agents. They are:causal agents. They are:Irradiation exposureIrradiation exposure Chronic benzene exposure Chronic benzene exposure Chemotherapeutic agents Chemotherapeutic agents Leukemia virus infection Leukemia virus infection Environmental factorscause leukemiaInherited syndromes such
8、 as ataxia-Inherited syndromes such as ataxia-telangiectasiatelangiectasia, down , down syndrome predispose to subsequent development of syndrome predispose to subsequent development of leukemia. Usually, these kinds of syndromes share the leukemia. Usually, these kinds of syndromes share the common
9、 features that they all have heretic defects in their common features that they all have heretic defects in their genome gave by their parentsgenome gave by their parentsInherited syndromes predispose to leukemiaAcquired disease predispose to leukemiaLeukemia may also develop from the progression of
10、 other clonal disorders of hematopoietic stem cells. Ploycythemia vera, idiopathic myelofibrosis, etc Leukemia ClassificationThere are at least dozens of varieties of leukemia. There are at least dozens of varieties of leukemia. They are classified by how quickly it progresses. They are classified b
11、y how quickly it progresses. Acute leukemia is fast-growing and can overrun the Acute leukemia is fast-growing and can overrun the body within a few weeks or months. By Contrast, body within a few weeks or months. By Contrast, chronic leukemia is slow-growing and progressively chronic leukemia is sl
12、ow-growing and progressively worsen over yearsworsen over yearsAcute versus chronic leukemiaAcute: the blood cells of acute leukemia remain in an immature state, so they reproduce and accumulate very rapidly. Therefore, they need treatment immediately, otherwise the disease may be fatal within few m
13、onthsChronic: in Chronic leukemia, the blood cells eventually mature, or partially mature. But they are not “normal”. They remain in the blood much longer than normal blood cells and they can not act functional cells wellMyelogenous versus lymphocytic leukemiaIf the leukemic cells arise from myeloid
14、 pluripotential stem cells:myeloid leukemia If the leukemic cells arise from lymphocytic pluripotential stem cells:lymphocytic leukemia Clinical manifestations Leukemic hematopoiesis Normal hematopoiesismarrow failureInfiltrationMarrow failureAnemia (loss of erythocytes): fatigues, pallor weakness,
15、reduced exercise toleranceFever and infection (Poor infection fighters)Abnormal bleeding (loss of platelets)InfiltrationsOral tissue: swollen painful, and bleeding gumsSplenomegaly and hepatomegalyLymph node enlargementBone or joint painCNS-headaches, seizures, weakness, blurred vision and vomiting
16、Blood test findings Anemia is a constant feature.Nucleated red cells or immature red blood cell may be present. Thrombocytopenia is nearly always present at the time of diagnosis.The total leukocyte counts can be high, normal or low. Immature hematopoietic cells are almost present in the bloodMarrow
17、 findingsNormal bone marrow AML marrow Cytogenetic findingsDiagnosis & Classification Other newly developed Other newly developed methodsmethodsMorphology : the bone marrow cells are evaluated according to their size,shape, and content of granules and then they are classified with respected to matur
18、ityCytochemistry staining: identification of the chemical components of cells is conducted to distinguish different types of leukemia. Cytochemistry often use special colored dyes Acute leukemiaAMLALLM0: undifferentiated AMLM0: undifferentiated AMLM1: Myeloblastic leukemia (without maturation)M1: My
19、eloblastic leukemia (without maturation)M2: Myeloblastic leukemia (with maturation)M2: Myeloblastic leukemia (with maturation)M3: promyelocytic leukemia M3: promyelocytic leukemia M4: Myelomonocytic leukemiaM4: Myelomonocytic leukemiaM5: Monocytic leukemiaM5: Monocytic leukemiaM6: ErythroleukemiaM6:
20、 ErythroleukemiaM7: Megkaryoblastic leukemiaM7: Megkaryoblastic leukemiaL1: Mature appearing lymphoblasts L1: Mature appearing lymphoblasts L2: Immature and variously shaped lymphoblastsL2: Immature and variously shaped lymphoblastsL3: Lymphoblasts are large and uniform L3: Lymphoblasts are large an
21、d uniform P142 (CD tables)A lot of CD provides clues for the diagnosisFlow CytometryFlow CytometryImmunohistochemistry Immunohistochemistry ImmnuophenotypingImmnuophenotyping panel used in St. Jude Childrens panel used in St. Jude Childrens research hospital U.S.A. research hospital U.S.A. CD13 CD33
22、 CD19 CytoCD79a CD7 CytoCD3 AML - - - -B-ALL - - - -T-ALL - - - -By using this method of analysis, one can make a firm diagnosis in 99% of cases免疫表型分型方案T 细胞B 细胞（4%）B 细胞前体 CD7（敏感），cCD3 （特异） CD19 (敏感), cCD79a (特异)成熟T 细胞 （18%）前 T 细胞（6%）前 B-细胞 （9%）早期前-B 细胞 （52%）前-前- B 细胞 （11%）sIg, sIgInsert table 90% of
23、 the cases with leukemia have non-randomized translocationP118 types of translocationsCML AML-M2AML-M3AML-M4AMLAML-M4E0 Other new developed methodsDifferential DiagnosisPseudoleukemia Myelodysplastic syndrome Nonleukemic pancytopenia Treatment1.Supportive cares and preparation of the patients2.Antil
24、eukemic therapy3.Therapy of the central nervous system4.Stem cell transplantationAnemia Hemorrhage Infection Hematological supportTransfusion of Platelets Transfusion of packed red cells Transfusions of granulocytes Transfusions of IgG Infection controlSpecial precautions: protective isolation Elimi
25、nation of contaminated foods Oral and digestive system care Broad spectrum antibiotics GM-CSF administration Antileukemic therapyChemotherapy to kill leukemia cells using strong anti-cancer drugs Treatment phasesInduction therapy: the aim is to bring about remission , that is leukemic cells are no l
26、onger found in the bone marrow and the recovery of normal hematopoiesisPost-remission therapy: to eliminate any leukemia cells potential hiding in the body Special subtypes Acute promyelocytic Leukemia (APL): because of the small particles (procoagulants) inside the APL cell, DIC are commonly seen i
27、n this type of AMLNormal APLGenes essential for differentiation are shut down Genes essential for differentiation are shut down by the fusion proteins PML-by the fusion proteins PML-RARalphaRARalphaDifferentiation agents (all-trans retinoic acid, arsenic trioxide)Hyperleukecytosis: cause a batch of
28、complications and should be treated using leukapheresis ( exchanging transfusion) or preinduction treatment prior to intensive chemotherapy Acute leukemia over 60 years of age is less responsive to chemotherapyStandard two-drugs therapy can be used. CR 30%Intolerant to standard therapy. Low-dose of
29、Ara-C can be used for 14-28 days Therapy of the CNS leukemiaThe CNS is a frequent sanctuary site for leukemic cells because most of the chemotherapy drugs are not able to reach the CNS. Some types of acute leukemia have tendency to be with CNS leukemia such as AML (M4, M5), ALLIntrathecal chemothera
30、pyCranial irradiation Stem cell transplantationsThe main purpose of BMT and PBSCT in cancer treatment is to make it possible for patients to receive very high doses of chemotherapy and/or radiation therapy. In addition, re-established normal hematopoiesis and immune system by the healthy stem cells
31、fight against leukemia effectively. So it change the vision in the medical history that leukemia is incurable malignancies Three types of transplantation performedAllogeneic transplantation (HLA-matched individual donors)Syngeneic transplantation: identical twinsAutologous transplantation: patients
32、receive their own stem cellsClinical results of stem cell transplantationAML ALL CMLFive-years disease free survival rate Five-years disease free survival rate TransplantationChemotherapy Chronic myelogenous leukemia (CML)Future directions复习思考题1.慢性粒细胞白血病与类白血病反应的鉴别要点？2.白血病完全缓解的标准？为何要进行巩固、 强化化疗？3.骨髓增生异常综合征的分型、临床表现、与急性 白血病的关系？
