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White Blood Cell Disease

National Taiwan University Hospital Department of Internal Medicine Division of Hematology 陳建源. White Blood Cell Disease. Non-malignant Disorder of Leukocyte . 1.Variations of leukocytes in disease 2.Neutropenia 3.Qualitative disorder of leukocytes

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White Blood Cell Disease

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  1. National Taiwan University Hospital Department of Internal Medicine Division of Hematology 陳建源 White Blood Cell Disease

  2. Non-malignant Disorder of Leukocyte • 1.Variations of leukocytes in disease • 2.Neutropenia • 3.Qualitative disorder of leukocytes • 4.Abnormal monocyte-macrophage system • 5.Langerhans cell histocytosis X • 6.Infectious Mononucleosis • 7.Hematology aspects of HIV and AIDS • 8.Disorder of spleen Wintrobe’s Clinical Hematology 10th ed

  3. Variations of leukocytes in disease Wintrobe’s Clinical Hematology 10th ed

  4. Neutropenia-acquired • The most common cause of acquired neutropenia is infection. HBV, EBV, and HIV. • The second most common is medication exposure: beta-lactam antibiotics, anti-thyroid drug, anti-tuberculosis, ticlopidine, baktar, carbamazepine, captopril, digitals, indomethacin Wintrobe’s Clinical Hematology 10th ed

  5. Neutropenia-congenital • Kostmann syndrome Severe congenital neutropenia • Cyclic neutropenia • Ela2 gene • HAX1 is a ubiquitously expressed mitochondrial protein with weak homology to bcl-2 • Wiskott-Aldrich syndrome protein (WASp) • Gfi-1 zinc-finger protein, transcriptional repressor Nancy Berliner Blood 2008

  6. Qualitative disorder of leukocytes • Pelger Huet Anomaly: AD, bilobed PMN • Alder-Reilly Anomaly: AR, Large azurophil granules • May-Hegglin Anomaly: AD, inclusion in granulocytes, giant platelets with thrombocytopenia • Chediak-Higashi Anomaly: AR, lysosome-like inclusion body, children with pale hair Wintrobe’s Clinical Hematology 10th ed

  7. Abnormal monocyte-macrophage system • Fabry disease: X-linked, glycosphingolipid anemia, decreased serum iron concentration, platelet aggregation. Lipid-laden foamy macrophage in BM • Gaucher disease: AR, Glycocerebroside • Niemann-Pick disease: sphingomyelin and cholesterol accumulation Wintrobe’s Clinical Hematology 10th ed

  8. Langerhans cell histocytosis X • Hand-Schuller-Christian Disease • Clinical Triad: defect in membranous bone, exophthalmos and polyuria • Pathology: granulomatosis, histocytes, mature eosinophil, and lymphocytes • Birbeck granules Wintrobe’s Clinical Hematology 10th ed

  9. Infectious Mononucleosis • Sorethroat and dysphagia (80-85%) • Lymphadenopathy • Hepatosplenomegaly • Fever, malaise • Lymphocytosis • Abnormal liver function • Hyperbilirubinemia Wintrobe’s Clinical Hematology 10th ed

  10. Infectious Mononucleosis • Polyclonal T cell, CD8 subset • Hematological complications Immune hemolytic anemia Immune thrombocytopenia Granulocytopenia Marrow aplasia Virus-associated hemophagocytic syndrome Acquired immune Deficiency • Non-Hematological complication Splenic rupture, Neurological complication, Cardiac complication, Respiratory complications, Liver failure, Pancreatitis, Renal Failure

  11. Hematology aspects of HIV and AIDS: anemia Increased Loss Hemolysis Thrombotic thrombocytopenic purpura Glucose-6-phosphate dehydrogenase deficiency trimethoprim-sulfamethoxazole, dapsone, primaquine, Autoimmune hemolytic anemia Idiopathic Drugs (ceftriaxone, indinavir, “Ecstasy”) Infection (cytomegalovirus [CMV]) Gastrointestinal bleeding Kaposi’s sarcoma Non-Hodgkin’s lymphoma Infection (CMV, Candida) Hypersplenism Infection Lymphoma Hemophagocytosis Cirrhosis (hepatitis B virus, hepatitis C virus) • Decreased Production • Drugs • Zidovudine, Trimethoprim-sulfamethoxazole • Amphotericin B, Ganciclovir, Dapsone, Delavirdine • Deficiencies • Erythropoietin, Iron, Folate, Vitamin B12 • Infection • HIV, Parvovirus B19, Mycobacterium avium complex (MAC), Mycobacterium tuberculosis, Histoplasma capsulatum • Neoplasia • Non-Hodgkin’s lymphoma, Multiple myeloma, • Castleman’s disease, Hodgkin’s disease • Miscellaneous • Anemia of chronic disease • Preexisting condition (sickle cell disease, thalassemia, Hematology Am Soc Hematol Educ Program. 2003:294-313

  12. Hematology aspects of HIV and AIDS: thrombocytopenia Hematology Am Soc Hematol Educ Program. 2003:294-313

  13. Hematology aspects of HIV and AIDS: neutropenia • Deficiencies • Folate • Vitamin B12 • Infection • Human immunodeficiency virus (HIV) • Mycobacterium avium complex (MAC) • Mycobacterium tuberculosis • Histoplasma capsulatum • Neoplasia • Non-Hodgkin’s lymphoma • Multiple myeloma • Increased Loss • Autoimmune neutropenia • Hypersplenism • Infection • Hemophagocytosis • Cirrhosis • Decreased Production • Drugs Ganciclovir Zidovudine Trimethoprim-sulfamethoxazole Pentamidine Rifabutin Antineoplastic chemotherapy Dapsone Amphotericin B Ritonavir Delavirdine Nelfinavir Hematology Am Soc Hematol Educ Program. 2003:294-313

  14. Disorder of spleen Wintrobe’s Clinical Hematology 10th ed

  15. Malignant hematopoietic disorder

  16. Stemcell MDS MPD Tumor suppressor gene? Mutation of transcriptional factor/ cofactor Ex: PML/RARa, AML1, CEBPA, CBFB, NPM, MLL Mutation of proliferation, survival gene Ex: FLT3, PTPN11, RAS, Kit, JAK2, PDGF gene Acute leukemia Mutation of transcriptional factor and proliferation gene

  17. Interactionsof Class I and Class II gene mutations (NTUH 1995-2003) NTUH 1995-2003 * Some patients had more than one mutations. ** Excluding patients with the Class II gene mutation shown above.

  18. Interactions between Class I and II Gene Mutations : Negativeassociation : Positiveassociation NTUH 1995-2003

  19. Minimal residual disease

  20. Flow cytometry for MRD detection Leukemia-associated Aberrant Immunophenotypes (LAIP) Classification • Cross-lineage expression of lymphoid antigens CD33+CD2+CD34+ CD34+CD13+CD19+ • Over-expression HLA-DR++CD33++CD34++ CD64++CD4++CD45++ • Lack of expression of antigen HLA-DR-CD33+CD34+ • Asynchronous expression of antigens CD15+CD33+CD34+ CD65+CD33+CD34+ • + indicates expression; ++, over-expression; -, no expression. Kern W et al. Cancer 2008 112(1):4-16

  21. Myeloproliferative disorder • ET, PV, MF, • MPD, unclassified • JAK2 mutation • mpl W515L(5% MF, 1%ET) • PTPN11:JMML • PDGFR: CMML, HES

  22. The frequency of JAK2 V617 mutation in hematopoietic disorders Human Pathology 2008(39):795–810

  23. PV: 2001 WHO criteria and the proposed 2007 WHO criteria Proposed 2007 WHO criteria Diagnosis requires: Both major criteria and one minor criteria, or the first major criterion and 2 minor criteria Major criteria: 1. Hemoglobin >18.5 g/dL in men, Hemoglobin >16.5 g/dL in women, or Other evidence of increased red cell volume 2. Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation Minor criteria: 1. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation 2. Serum EPO level below the reference range . 3. EEC growth 2001 WHO criteria Diagnosis requires: Both 1 and 2 of the A criteria, plus 1 additional A criteria, or 2 B criteria A-criteria: 1.Increased red cell mass 1. >25% above mean normal predicted value, or >18.5 g/dL in men. >16.5 g/dL in women, or >99th percentile of method-specific reference range for age, sex, altitude of residence 2. No cause of secondary erythrocytosis, including: Absence of familial erythrocytosis, No elevation of EPO caused by: i.Hypoxia arterial PO2 ≤92%, ii. High oxygen affinity hemoglobin, iii. Truncated EPO receptor ,iv. Inappropriate EPO production by tumor 3. Splenomegaly 4. Clonal genetic abnormality other than Philadelphia chromosome or BCR-ABL fusion gene in marrow cells 5. EEC formation B-criteria: 1. Thrombocytosis >400 × 109/L 2. Leukocytosis >12 × 109/L 3. Bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation 4. Low serum EPO levels Smith CA. Human Pathology 2008:795-810

  24. Chronic myeloid leukemia • Philadelphia chromosome(+) • t(9;22) • BCR-ABL • Tyrosine kinase • Glivec • Dasatinib • Niclotinib

  25. Mechanism of BCR/ABL resistance • Mechanisms of Imatinib Resistance • Decreased intracellular drug levels Plasma binding by -1 acid glycoprotein Drug efflux from P-glycoprotein (MDR-1) overexpression • Increased expression of BCR-ABL kinase from genomic amplification • Clonal evolution (non-BCR-ABL–dependent mechanism) • Mutations in ABL kinase of BCR-ABL affecting drug interaction or kinase activity Arch Pathol Lab Med. 2006 May;130(5):669-79.

  26. Myelodysplastic syndrome • Nuclear Budding • Nuclear fragmentation • Micro-megakaryocyte • Nuclear-cytoplasm differentiation disassociation • apoptosis

  27. Myelodysplastic syndrome • Clinical manifestation: cytopenia, ineffective hematopoiesis, leukemic transformation • Cytogenetic: -5, -7, +8 , 20q, complex • Classification: FAB, WHO, IPSS • Treatment: Supportive, Allogeneic HSCT, ATG, CsAChemotherapy(Low dose Ara-C or Standard dose) , Danazole, Demethylating agent , lenalidomide Blood. 2008 May 15;111(10):4841-51.

  28. Myelodysplastic syndrome • Ringed sideroblasts and associated with marked thrombocytosis (RARS-T), JAK2 V617F mutation • 5-Azacytidine was approved for the treatment of MDS in 2004 • Azacytidine prolonged survival, delayed progression to AML, and improved quality of life. Complete response (CR) rate 7%, 16%PRs and 37% hematologic improvement also seen. • Decitabine was also evaluated in a phase 3 trial, and a 35% overall response rate was seen (9% CR, 8% PR, 18% hematologic improvement). Blood. 2008 May 15;111(10):4841-51.

  29. Acute Myeloid Leukemia Hematology Am Soc Hematol Educ Program. 2006:169-77

  30. Genetic alterations affecting clinical outcome of cytogenetically normal acute myeloid leukemia (AML) patients Kit mutation in patients with t(8;21) most studies revealed unfavorable outcome, in patients with inv(16) no significance related to outcomes Hematology Am Soc Hematol Educ Program. 2006:169-77

  31. Acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL): incidence & biological differences Hematology Am Soc Hematol Educ Program. 2006:128-32

  32. Acute lymphoblastic leukemia

  33. Chronic lymphoblastic leukemia • Prognostic factor: Traditional staging according to Rai or Binet IgHV mutation status, lymphocyte doubling time morphology, Immunophenotype characteristics, CD23 expression, Beta-2-microglobulin, Cytogenetics, ZAP-70, Pattern of bone marrow involvement, • Cytogenetic: 13q14 in about 50% of cases (by FISH) followed by del 11q22–q23 (20%), trisomy 12 (15%), del 6q21 (10%) and del 17p13 (5–10%). BJH 2007 139(5):630-634 Blood 2005 105(5):1839-1840

  34. Surface marker of B-Cell Lymphomas

  35. EBV associated lymphoproliferative disorder Blood. 2006 Feb 1;107(3):862-9.

  36. EBV associated lymphoproliferative disorder

  37. Lymphoma Follicular Rituximab Plus Chemotherapy in First-Line Therapy of Advanced Stage Follicular Lymphoma J Clin Oncol. 2005 Sep 10;23(26):6394-9

  38. Mantle Cell Lymphoma Surface Marker MCL • Small-medium sized cells, indented nuclei; occasional small-cell variant • Expresses B cell antigens (CD20); CD5 • Over-express cyclin D1 (immunohistochemistry) • Genetic hallmark: t(11;14) (q13;q32) translocation • Molecular: BCL1 translocation, mutated IGH ~20-30% CD5 ++ Surface Ig ++ CD19 ++ CD20 +++ CD10 - CD23 - Cyclin D1 +++ Cytogenetics t(11:14)

  39. NCCN Mantle Cell Lymphoma Guidelines 2006 1st Line Rituximab + HyperCVAD Rituximab + CHOP Rituximab + EPOCH ASCT Allogeneic transplant in the context of a clinical trial Bortezomib Cladribine FCMR FC PCR Thalidomide + Rituximab 1st Line Consolidation Second-line Therapy • HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) • CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) • EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) • FCMR (fludarabine, cyclophosphamide, mitoxantrone, rituximab) • FC (fludarabine, cyclophosphamide) ± rituximab • PCR (pentostatin, cyclophosphamide, rituximab) • Thalidomide + rituximab

  40. Lymphoma MALToma J Clin Oncol. 2005 Sep 10;23(26):6370-8

  41. Lymphoma Follicular Prediction of patients with follicular lymphoma outcome based on the FLIPI *Factors adversely affecting survival in the FLIPI include age greater than 60 years; Ann Arbor stage III–IV; number of nodal sites greater than 4; serum LDH level greater than the upper limit of normal; and hemoglobin level less than 12 g/dL. Hematology 2007:216-225

  42. NK Lymphoma

  43. Lymphoma ALCL • Pleomorphic large lymphocytes, Young adult • CD30+ (CD 30 also expressed in CTCL, lymphomatoid papulosis, regressing atypical histocytosis, HD and some embryonal cell, pancreatic carcinoma) • t(2;5)(p23;q35) NPM/ALK • Nodal • Extranodal: skin

  44. Plasma cell dyscrasia Plasma cell labeling index (PCLI)

  45. Thank you for your attention

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