第六篇 血液系统疾病

1. 第六篇 血液系统疾病 白血病 (Leukemia) 周剑峰 学时数：3学时

2. 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

3. 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

4. Erythrocytes: transport oxygen Neutrophil Basophil Eosinophil Monocytes/Macrophage Defense against infection Platelets: Mediate blood clotting T-lymphocytes: antigen presenting B-lymphocytes Plasma cell: Source of antibodies

5. Pluripotential stem cells Lymphoid stem cells Myeloid stem cells Unipotential progenitor cells Immature hematopoietic cells mature hematopoietic cells

6. Hematopoiesis composes of the options of commitment to different lineages and the progressive stages of maturation at which partial or complete arrest can occur, results in the wide array of malignant disease-Leukemia Progenitor cell Immature cell Stem cell Mature cell

7. Accumulation of mutations of DNA within a pluripotential stem cell or very early progenitor cell gives rise to leukemic stem cells Leukemic stem cell Normal stem cell

10. Etiology&Pathogenesis Environmental factors Acquired diseases Clonal expansion Lesions to the DNA

11. Environmental factors cause leukemia A lot of environmental factors has been reported to cause leukemia. However, only four of them are firmly established causal agents. They are: Irradiation exposure Chronic benzene exposure Chemotherapeutic agents Leukemia virus infection

13. Inherited syndromes predispose to leukemia Inherited syndromes such as ataxia-telangiectasia, down syndrome predispose to subsequent development of leukemia. Usually, these kinds of syndromes share the common features that they all have heretic defects in their genome gave by their parents

14. Acquired disease predispose to leukemia Leukemia may also develop from the progression of other clonal disorders of hematopoietic stem cells. Ploycythemia vera, idiopathic myelofibrosis, etc

15. Leukemia Classification There are at least dozens of varieties of leukemia. They are classified by how quickly it progresses. Acute leukemia is fast-growing and can overrun the body within a few weeks or months. By Contrast, chronic leukemia is slow-growing and progressively worsen over years

16. Acute versus chronic leukemia Acute: 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 months Chronic: 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 well

17. Myelogenous versus lymphocytic leukemia If the leukemic cells arise from myeloid pluripotential stem cells: myeloid leukemia If the leukemic cells arise from lymphocytic pluripotential stem cells: lymphocytic leukemia

18. Clinical manifestations Normal hematopoiesis Leukemic hematopoiesis Infiltration marrow failure

19. Marrow failure Anemia (loss of erythocytes): fatigues, pallor weakness, reduced exercise tolerance Fever and infection (Poor infection fighters) Abnormal bleeding (loss of platelets)

20. Infiltrations Oral tissue: swollen painful, and bleeding gums Splenomegaly and hepatomegaly Lymph node enlargement Bone or joint pain CNS-headaches, seizures, weakness, blurred vision and vomiting

22. 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 blood

23. Marrow findings AML marrow Normal bone marrow

24. Cytogenetic findings

25. Diagnosis & Classification Other newly developed methods

26. Morphology : the bone marrow cells are evaluated according to their size,shape, and content of granules and then they are classified with respected to maturity Cytochemistry staining: identification of the chemical components of cells is conducted to distinguish different types of leukemia. Cytochemistry often use special colored dyes

27. M0: undifferentiated AML M1: Myeloblastic leukemia (without maturation) M2: Myeloblastic leukemia (with maturation) M3: promyelocytic leukemia M4: Myelomonocytic leukemia M5: Monocytic leukemia M6: Erythroleukemia M7: Megkaryoblastic leukemia L1: Mature appearing lymphoblasts L2: Immature and variously shaped lymphoblasts L3: Lymphoblasts are large and uniform AML Acute leukemia ALL

29. P142 (CD tables) A lot of CD provides clues for the diagnosis

30. Flow Cytometry Immunohistochemistry

31. Immnuophenotyping panel used in St. Jude Children’s research hospital U.S.A. CD13 CD33 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

32. 免疫表型分型方案 CD19 (敏感), cCD79a (特异) CD7（敏感），cCD3 （特异） B 细胞（4%） sIg, sIg T 细胞 B 细胞前体 成熟T 细胞 （18%） 前 B-细胞 （9%） 前 T 细胞（6%） 早期前-B 细胞 （52%） 前-前- B 细胞 （11%）

34. Insert table 90% of the cases with leukemia have non-randomized translocation

35. CML AML-M2 AML-M4E0 P118 types of translocations AML AML-M3 AML-M4

39. Other new developed methods

40. Differential Diagnosis Pseudoleukemia Myelodysplastic syndrome Nonleukemic pancytopenia

41. Treatment • Supportive cares and preparation of the patients • Antileukemic therapy • Therapy of the central nervous system • Stem cell transplantation

42. Anemia Hemorrhage Infection

43. Hematological support Transfusion of Platelets Transfusion of packed red cells Transfusions of granulocytes Transfusions of IgG

44. Infection control Special precautions: protective isolation Elimination of contaminated foods Oral and digestive system care Broad spectrum antibiotics GM-CSF administration

45. Antileukemic therapy Chemotherapy to kill leukemia cells using strong anti-cancer drugs

46. Treatment phases Induction therapy: the aim is to bring about remission , that is leukemic cells are no longer found in the bone marrow and the recovery of normal hematopoiesis Post-remission therapy: to eliminate any leukemia cells potential hiding in the body

47. Special subtypes Acute promyelocytic Leukemia (APL): because of the small particles (procoagulants) inside the APL cell, DIC are commonly seen in this type of AML

48. Genes essential for differentiation are shut down by the fusion proteins PML-RARalpha APL Normal

49. Differentiation agents (all-trans retinoic acid, arsenic trioxide)

50. Hyperleukecytosis: cause a batch of complications and should be treated using leukapheresis ( exchanging transfusion) or preinduction treatment prior to intensive chemotherapy