Hematology and Oncology

150591010

Hematology and OncologyAll New Content, Including 144 Multiple-Choice Questions

20 AMA PRA Category 1 Credits™

available until July 31, 2015.

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Medical Knowledge Self -Assessment Program®

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Table of Contents

Sickle Cell Syndromes. . . . . . . . . . . . . . . . . . . . . . . . 28Other Hemoglobinopathies . . . . . . . . . . . . . . . . . . . 31

Acquired Hemolytic Anemias. . . . . . . . . . . . . . . . . . . . . . 32Autoimmune Hemolytic Anemia . . . . . . . . . . . . . . . 32Warm Autoimmune Hemolytic Anemia . . . . . . . . . . 32Cold Agglutinin Disease . . . . . . . . . . . . . . . . . . . . . . 32Drug-induced Autoimmune Hemolytic Anemia . . . . 33Microangiopathic Hemolytic Anemia . . . . . . . . . . . . 33Paroxysmal Nocturnal Hemoglobinuria . . . . . . . . . . 34Other Causes of Hemolysis. . . . . . . . . . . . . . . . . . . . 35

Iron Overload Syndromes . . . . . . . . . . . . . . . . . . . . . . . . 35Hemochromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . 35Secondary Iron Overload . . . . . . . . . . . . . . . . . . . . . 36

TransfusionCellular Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Erythrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Platelets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Plasma Products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Fresh Frozen Plasma. . . . . . . . . . . . . . . . . . . . . . . . . 39Cryoprecipitate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Other Plasma-derived Transfusion Products . . . . . . . 39

Transfusion Complications. . . . . . . . . . . . . . . . . . . . . . . . 39Hemolytic Reactions. . . . . . . . . . . . . . . . . . . . . . . . . 39Nonhemolytic Reactions. . . . . . . . . . . . . . . . . . . . . . 40Allergic Reactions and Anaphylaxis . . . . . . . . . . . . . . 40Transfusion-associated Graft-Versus-Host Disease . . . 40Infectious Complications . . . . . . . . . . . . . . . . . . . . . 40

Therapeutic Apheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Bleeding DisordersOverview of Normal Hemostasis . . . . . . . . . . . . . . . . . . . 42Evaluation of Patients with Suspected Bleeding Disorders . . 42

History and Physical Examination. . . . . . . . . . . . . . . 42Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . 43

Congenital Bleeding Disorders. . . . . . . . . . . . . . . . . . . . . 43Hemophilia A and B. . . . . . . . . . . . . . . . . . . . . . . . . 43von Willebrand Disease. . . . . . . . . . . . . . . . . . . . . . . 45

Acquired Bleeding Disorders . . . . . . . . . . . . . . . . . . . . . . 46Acquired Hemophilia . . . . . . . . . . . . . . . . . . . . . . . . 46Coagulopathy of Liver Disease . . . . . . . . . . . . . . . . . 46Disseminated Intravascular Coagulation . . . . . . . . . . 46Vitamin K Deficiency . . . . . . . . . . . . . . . . . . . . . . . . 46

Hematopoietic Stem Cells and Their DisordersOverview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Bone Marrow Failure Syndromes. . . . . . . . . . . . . . . . . . . . 1

Aplastic Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Pure Red Cell Aplasia . . . . . . . . . . . . . . . . . . . . . . . . . 3Neutropenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

The Myelodysplastic Syndromes. . . . . . . . . . . . . . . . . . . . . 5Myeloproliferative Disorders . . . . . . . . . . . . . . . . . . . . . . . 6

Polycythemia Vera. . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Essential Thrombocythemia . . . . . . . . . . . . . . . . . . . . 8Chronic Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . 8Primary Myelofibrosis . . . . . . . . . . . . . . . . . . . . . . . . . 9Acute Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . . 10Acute Lymphoblastic Leukemia . . . . . . . . . . . . . . . . 11Hematopoietic Growth Factors. . . . . . . . . . . . . . . . . 12Hematopoietic Stem Cell Transplantation. . . . . . . . . 12

Multiple Myeloma and Related DisordersOverview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Clinical Manifestations and Findings . . . . . . . . . . . . . 13Diagnosis and Prognosis . . . . . . . . . . . . . . . . . . . . . . 14Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Monoclonal Gammopathy of UndeterminedSignificance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Immunoglobulin Light-Chain Amyloidosis . . . . . . . . . . . 16Waldenström Macroglobulinemia . . . . . . . . . . . . . . . . . . 17

Approach to AnemiaIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Anemia Due to Erythrocyte Underproduction orMaturation Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Iron Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Cobalamin (Vitamin B12) Deficiency. . . . . . . . . . . . . 21Folate Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Inflammatory Anemia. . . . . . . . . . . . . . . . . . . . . . . . 24Anemia of Kidney Disease. . . . . . . . . . . . . . . . . . . . . 24

Hemolytic Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Congenital Hemolytic Anemias . . . . . . . . . . . . . . . . . . . . 26Hereditary Spherocytosis . . . . . . . . . . . . . . . . . . . . . 26Glucose-6-Phosphate Dehydrogenase Deficiency . . . 26Thalassemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

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PlateletsNormal Platelet Physiology . . . . . . . . . . . . . . . . . . . . . . . 47Approach to the Patient with Thrombocytopenia. . . . . . . 47Immune (Idiopathic) Thrombocytopenic Purpura . . . . . . 49Heparin-induced Thrombocytopenia . . . . . . . . . . . . . . . . 50Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Other Thrombocytopenias Due to Underproduction. . . . 52Qualitative Platelet Disorders . . . . . . . . . . . . . . . . . . . . . . 52

Platelet Function Testing . . . . . . . . . . . . . . . . . . . . . 52Acquired Platelet Dysfunction. . . . . . . . . . . . . . . . . . 52

Thrombotic DisordersPathophysiology of Thrombosis and Thrombophilia . . . . 53Inherited Thrombophilic Conditions . . . . . . . . . . . . . . . . 53

Factor V Leiden . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Prothrombin G20210A Gene Mutation . . . . . . . . . . 53Antithrombin Deficiency . . . . . . . . . . . . . . . . . . . . . 53Protein C Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . 53Protein S Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . 53Dysfibrinogenemia . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Acquired Thrombophilic Conditions . . . . . . . . . . . . . . . . 54Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54Trauma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54Antiphospholipid Syndrome . . . . . . . . . . . . . . . . . . . 54Catastrophic Antiphospholipid Syndrome . . . . . . . . . 55Other Acquired Thrombophilic Disorders. . . . . . . . . 55

Management and Prevention . . . . . . . . . . . . . . . . . . . . . . 55Thrombophilia Testing . . . . . . . . . . . . . . . . . . . . . . . 55Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Use of Anticoagulants. . . . . . . . . . . . . . . . . . . . . . . . 56Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Hematologic Issues in PregnancyGestational Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Iron Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62Folate Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Thrombocytopenia in Pregnancy . . . . . . . . . . . . . . . . . . . 63

Gestational Thrombocytopenia . . . . . . . . . . . . . . . . . 63Immune Thrombocytopenic Purpura . . . . . . . . . . . . 63Microangiopathy of Pregnancy . . . . . . . . . . . . . . . . . 64

Thrombophilia and Venous Thromboembolism in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Epidemiology, Pathophysiology, and Risk Factors . . . 65Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Issues in OncologyStaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Surgical Resection. . . . . . . . . . . . . . . . . . . . . . . . . . . 67Adjuvant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Defining Treatment Goals . . . . . . . . . . . . . . . . . . . . 67Era of Personalized Cancer Treatment . . . . . . . . . . . 68

Breast CancerIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . . . . 69Chemoprevention and Other Risk Reduction Strategies . . 70Primary Breast Cancer Therapy . . . . . . . . . . . . . . . . . . . . 71

Ductal Carcinoma in Situ . . . . . . . . . . . . . . . . . . . . . 71Invasive Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . 71

Adjuvant Systemic Therapy for Early-Stage Breast Cancer . . 72Adjuvant Endocrine Therapy . . . . . . . . . . . . . . . . . . 72Adjuvant Chemotherapy . . . . . . . . . . . . . . . . . . . . . . 73

Locally Advanced and Inflammatory Breast Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73Breast Cancer Follow-up and Survivorship . . . . . . . . . . . . 74Metastatic Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 74

Ovarian and Cervical CancerOvarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . 75Screening and Risk Reduction Strategies . . . . . . . . . . 75Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76Management of Recurrent Ovarian Cancer . . . . . . . . 77Monitoring and Follow-Up . . . . . . . . . . . . . . . . . . . 77Supportive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . 78Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 78Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Gastrointestinal MalignanciesColorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80Postoperative Colorectal Cancer Surveillance . . . . . . 81

Anal Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Esophageal Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83Gastrointestinal Neuroendocrine Tumors. . . . . . . . . . . . . 83

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Lung CancerEpidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84Screening. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84Non–Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . 85

Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

Small Cell Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 87Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 87Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Head and Neck CancerRisk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88Diagnosis and Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . 88Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Genitourinary CancerProstate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . 89Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 90Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90Prostate Cancer Follow-up and PosttreatmentRecurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Testicular Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 93Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 94Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Renal Cell Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Diagnosis and Staging. . . . . . . . . . . . . . . . . . . . . . . . 96Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Lymphadenopathy and Lymphoid MalignanciesEpidemiology and Risk Factors of Malignant Lymphomas . . 97Diagnosis of Malignant Lymphomas . . . . . . . . . . . . . . . . 98Classification, Staging, and Prognosis of MalignantLymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98Overview and Treatment of Indolent Lymphomas. . . . . 100

Follicular Lymphoma . . . . . . . . . . . . . . . . . . . . . . . 100Mucosa-associated Lymphoid Tissue (MALT)Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101Chronic Lymphocytic Leukemia. . . . . . . . . . . . . . . 101Hairy Cell Leukemia. . . . . . . . . . . . . . . . . . . . . . . . 102

Overview and Treatment of Aggressive Lymphomas . . . 102Diffuse Large Cell Lymphoma . . . . . . . . . . . . . . . . 102

Mantle Cell Lymphoma . . . . . . . . . . . . . . . . . . . . . 103Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . 103Cutaneous T-cell Non-Hodgkin Lymphoma . . . . . 104

Cancer of Unknown Primary SiteIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104Favorable Prognostic Subgroups . . . . . . . . . . . . . . . . . . 105

Poorly Differentiated Carcinoma . . . . . . . . . . . . . . 105Isolated Regional Lymphadenopathy . . . . . . . . . . . 105Peritoneal Carcinomatosis in Women . . . . . . . . . . . 105

Management of Patients Not in Favorable PrognosisSubgroups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

MelanomaIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106Risk Factors and Prognosis. . . . . . . . . . . . . . . . . . . . . . . 106Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Primary Central Nervous System Tumors . . . . . . . 107

Oncologic Urgencies and EmergenciesStructural Urgencies and Emergencies . . . . . . . . . . . . . . 107

Superior Vena Cava Syndrome . . . . . . . . . . . . . . . . 107Brain Metastases Causing Increased Intracranial Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108Spinal Cord Compression . . . . . . . . . . . . . . . . . . . . 108Malignant Pleural and Pericardial Effusions. . . . . . . 108

Metabolic Urgencies and Emergencies . . . . . . . . . . . . . . 109Tumor Lysis Syndrome. . . . . . . . . . . . . . . . . . . . . . 109Hypercalcemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Effects of Cancer and Cancer Therapy . . . . . . . . . . . . . . 109Hematopoietic Disorders . . . . . . . . . . . . . . . . . . . . 109Disorders of Cardiac Function . . . . . . . . . . . . . . . . 110Disorders of Pulmonary Function . . . . . . . . . . . . . . 110Disorders of Genitourinary and Renal Function . . . 110Sexual Function . . . . . . . . . . . . . . . . . . . . . . . . . . . 110Secondary Malignancies . . . . . . . . . . . . . . . . . . . . . 110Other Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Self-Assessment Test . . . . . . . . . . . . . . . . . . . . . . . . 117

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Hematology and Oncology

microenvironment, stroma, and growth factors are essential tothe production of mature blood cells. Failure of the stem cellitself or any of its developmental regulators may lead to bonemarrow failure or abnormal maturation.

Bone Marrow Failure SyndromesAplastic AnemiaAplastic anemia refers to conditions in which the bone marrowfails to produce blood cells, resulting in a hypocellular bonemarrow and pancytopenia. The disease can be acquired orcongenital and may be classified as moderate, severe, or verysevere (Table 1). Most cases are idiopathic, but drugs, infec-tion, toxins, and radiation exposure must first be excluded as

Hematopoietic Stem Cellsand Their DisordersOverviewHematopoiesis refers to the orderly formation and differenti-ation of circulating blood cells. Hematopoietic stem cells arethe earliest cellular precursors, have the unique capacity forself-renewal and differentiation, and can develop into cells ofother lineages such as brain cells. Stem cells are recognized bytheir unique surface markers such as CD34. The developmentof mature blood cells follows an orderly progression fromcommitted progenitor cells (Figure 1) to the well-recognizedcellular elements of the peripheral blood. The bone marrow

1

F I G U R E 1 . Regulation of hematopoiesis. The process of hematopoiesis is regulated by lineage-specific cytokines. These cytokines stimulate the proliferationand/or differentiation of pluripotent stem cells to committed mature peripheral blood cells.

CFU GEMM = colony-forming unit–granulocyte, erythrocyte, megakaryocyte, monocyte; CFU GM = colony-forming unit–granulocyte, monocyte; BFU-E = burst-forming unit–erythrocyte; CFU MEG= colony-forming unit–megakaryocyte; CFU-G = colony-forming unit–granulocyte; CFU-M = colony-forming unit–monocyte; CFU-Baso = colony-forming unit–basophil; CFU-Eo = colony-formingunit–eosinophil; G-CSF = granulocyte colony-stimulating factor; M-CSF = macrophage colony-stimulating factor; CFU-E = colony-forming unit–erythrocyte.

2

potential causes. Aplastic anemia is inherited in approximately15% to 20% of patients.

The most common form of congenital aplastic anemia,Fanconi anemia, is an autosomal recessive, or X-linked, dis-order, often accompanied by skin defects, short stature,hypogonadism, microcephaly, and urogenital abnormalities.

In most patients with acquired aplastic anemia, immunedysfunction is thought to be central to the pathophysiology,and abnormal expression of suppressor T cells is often pre-sent. Patients with aplastic anemia may have the typical symp-toms of anemia, including fatigue, exertional dyspnea, orworsening angina. Alternative presentations include bleedingdue to thrombocytopenia or infection due to neutropenia.The complete blood count usually shows pancytopenia but,less commonly, may reveal more isolated anemia, neutrope-nia, or thrombocytopenia. The peripheral blood smear maydemonstrate morphologic changes suggestive of other disor-ders, such as myelodysplasia. The bone marrow aspirate andbiopsy is essential to the diagnosis and typically shows ahypocellular marrow with increased fat space and a decreasein hematopoietic elements (Figure 2).

Cytogenetic analysis should be performed to excludethe characteristic chromosome mutations seen in hypocellu-lar myelodysplastic syndrome and other bone marrow dis-orders. Additional laboratory studies to evaluate otherconditions associated with pancytopenia include serumcobalamin (vitamin B12) and folate measurement, liverchemistry tests, HIV testing, hepatitis serologies, paroxys-mal nocturnal hemoglobinuria (PNH) screening (seeHemolytic Anemia in Approach to Anemia), and, in patientsyounger than 50 years of age, chromosomal breakpointanalysis to exclude Fanconi anemia.

Small PNH clones identified by the absence of CD55and CD59, but without overt hemolysis, can be identified byflow cytometry in approximately 50% of patients with aplas-tic anemia, whereas patients with classic PNH may laterdevelop aplastic anemia. In patients with aplastic anemia whohave not undergone hematopoietic stem cell transplantation(HSCT), annual screening for a PNH clone is recommendedbecause an increase may predate a more classic hemolytic

Hematopoietic Stem Cells and Their Disorders

presentation or an evolving bone marrow failure syndrome.In the absence of hemolysis, treatment of asymptomatic PNHis generally not initiated.

Patients with severe aplastic anemia who are youngerthan 40 years with minimal comorbidities and a humanleukocyte antigen (HLA)–compatible sibling should beoffered allogeneic HSCT as initial therapy, which is associatedwith a cure rate ranging from 75% to 90% in some studies. Forpatients who are not HSCT candidates, who have less severedisease, or who have no matched donors, immunosuppressivetherapy consisting of antithymocyte globulin andcyclosporine has resulted in long-term survival in 60% to 85%of patients. Relapses occur in up to one third of patients, espe-cially as cyclosporine is tapered. The 10-year cumulative rateof myelodysplasia or acute myeloid leukemia is 5% to 10% insurviving patients.

Appropriate supportive care is essential for long-termsurvival. Prophylactic antibiotic, antiviral, and antifungalagents are appropriate to avoid life-threatening infections thatcan complicate treatment. Proper transfusion management isalso essential for minimizing bleeding risk. Leukodepletion oferythrocytes and platelets minimizes the risk for alloimmu-nization. Cytomegalovirus–negative products should betransfused until the patient’s cytomegalovirus status is deter-mined. Irradiation of blood products to prevent transfusion-acquired graft-versus-host disease (GVHD) can be consid-ered before transplantation; irradiation is generally performedafter transplantation. Prophylactic platelet transfusions may beappropriate in patients at high risk or in those with a plateletcount of less than 10,000/µL (10 × 109/L). The use ofgrowth factors such as granulocyte colony-stimulating factor(G-CSF) has been shown to be ineffective as primary therapyand is a controversial adjunctive treatment.

TABLE 1 . Classification of Aplastic Anemia

Classification Characteristics

Very severe aplastic anemia ANC <200/µL (0.2 × 109/L)

Severe aplastic anemia Two or more of the following:

ANC 200-500/µL (0.2-0.5 × 109/L)

Platelet count <20,000/µL (20× 109/L)

Absolute reticulocyte count<40,000/µL (40 × 109/L)

Moderate aplastic anemia ANC 500-1000/µL (0.5-1.0 × 109/L)

ANC = absolute neutrophil count.

F I G U R E 2 . Aplastic anemia. Hypocellular bone marrow with increased fatcontent in a patient with pancytopenia. Almost no identifiable hematopoiesiscan be seen.

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Hematology and Oncology Self-Assessment TestThis self-assessment test contains one-best-answer multiple-choice questions. Please read these directions carefullybefore answering the questions. Answers, critiques, and bibliographies immediately follow these multiple-choicequestions. The American College of Physicians is accredited by the Accreditation Council for Continuing MedicalEducation (ACCME) to provide continuing medical education for physicians.

The American College of Physicians designates MKSAP 16 Hematology and Oncology for a maximum of 20AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of theirparticipation in the activity.

Earn “Same-Day” CME Credits OnlineFor the first time, print subscribers can enter their answers online to earn CME credits in 24 hours or less. You cansubmit your answers using online answer sheets that are provided at mksap.acponline.org, where a record of yourMKSAP 16 credits will be available. To earn CME credits, you need to answer all of the questions in a test andearn a score of at least 50% correct (number of correct answers divided by the total number of questions). Takeany of the following approaches:

➢Use the printed answer sheet at the back of this book to record your answers. Go to mksap.acponline.org,access the appropriate online answer sheet, transcribe your answers, and submit your test for same-dayCME credits. There is no additional fee for this service.

➢ Go to mksap.acponline.org, access the appropriate online answer sheet, directly enter your answers, andsubmit your test for same-day CME credits. There is no additional fee for this service.

➢ Pay a $10 processing fee per answer sheet and submit the printed answer sheet at the back of this book bymail or fax, as instructed on the answer sheet. Make sure you calculate your score and fax the answer sheetto 215-351-2799 or mail the answer sheet to Member and Customer Service, American College of Physi-cians, 190 N. Independence Mall West, Philadelphia, PA 19106-1572, using the courtesy envelope pro-vided in your MKSAP 16 slipcase. You will need your 10-digit order number and 8-digit ACP ID number,which are printed on your packing slip. Please allow 4 to 6 weeks for your score report to be emailed backto you. Be sure to include your email address for a response.

If you do not have a 10-digit order number and 8-digit ACP ID number or if you need help creating a usernameand password to access the MKSAP 16 online answer sheets, go to mksap.acponline.org or email custserv@acponline.org.

CME credit is available from the publication date of July 31, 2012, until July 31, 2015. You may submit youranswer sheets at any time during this period.

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Hematology QuestionsItem 1A 62-year-old man undergoes a routine examination. Henotes increasing fatigue of 8 months’ duration but states hecan perform his usual daily activities. He has no fever, nightsweats, anorexia, or weight loss. The medical history is non-contributory, and he takes no medications.

On physical examination, vital signs are normal. Thespleen is palpable three finger breadths below the left mid-costal margin. There is no lymphadenopathy orhepatomegaly.

Laboratory studies indicate a hemoglobin level of 12.5g/dL (125 g/L), a leukocyte count of 14,400/µL (14.4 ×109/L), and a platelet count of 148,000/µL (148 ×109/L).

A peripheral blood smear is shown.

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Each of the numbered items is followed by lettered answers. Select the ONE lettered answer that is BEST in each case.

Laboratory studies:Hemoglobin 8.3 g/dL (83 g/L) (follow-

ing transfusion of 1 unit ofirradiated packed erythrocyteslast week)

Leukocyte count 500/µL (0.5 × 109/L) with23% neutrophils, 3% bandforms, and 71% lymphocytes

Platelet count 26,000/µL (26 × 109/L)Reticulocyte count 0.2%

Review of the bone marrow biopsy done 2 weeks agoconfirms the diagnosis of aplastic anemia, demonstrating anaplastic bone marrow with normal cytogenetics.

Which of the following is the most appropriate treat-ment?

(A) Allogeneic hematopoietic stem cell transplantation(B) Antithymocyte globulin, corticosteroids, and

cyclosporine(C) Autologous hematopoietic stem cell transplantation(D) Corticosteroids(E) Granulocyte colony-stimulating factor

Item 3A 32-year-old woman undergoes preoperative evaluationprior to a complex spinal surgery for repair of severe scolio-sis. Her expected blood loss is 2.5 liters. She had a severeanaphylactic reaction during a prior erythrocyte transfusionshe received for postpartum hemorrhage at age 25 years.

On physical examination, temperature is 36.8 °C(98.4 °F), blood pressure is 132/76 mm Hg, and pulse rateis 78/min.

Laboratory studies indicate a hemoglobin level of13.6 g/dL (136 g/L), a leukocyte count of 7800/µL (7.8× 109/L), and a platelet count of 186,000/µL (186 ×109/L). Previous laboratory studies indicate an IgG level of868 mg/dL (8.68 g/L), an IgA level <5 mg/dL (0.05g/L), and an IgM level of 64 mg/dL (0.64 g/L). No mon-oclonal spike is found on serum protein electrophoresis.

Which of the following is the most appropriate eryth -rocyte product for this patient?

(A) Cytomegalovirus negative(B) γ-Irradiated(C) Leukoreduced(D) Phenotypically matched(E) Washed

Item 4A 75-year-old man is evaluated in the hospital for commu-nity-acquired pneumonia. He is bedbound. He has heartfailure and hypertension for which he takes lisinopril andcarvedilol.

The bone marrow cannot be aspirated, but the bonemarrow biopsy reveals a hypercellular marrow with exten-sive fibrosis and abnormal-appearing megakaryocytes.Results of conventional cytogenetic testing are normal. TheJAK2 mutation assay is positive. Fluorescence in situhybridization of the bone marrow for the (9;22) transloca-tion is negative.

Which of the following is the most appropriate man-agement of this patient now?

(A) Allogeneic hematopoietic stem cell transplantation(B) Danazol(C) Hydroxyurea(D) Imatinib(E) Observation

Item 2A 24-year-old man undergoes follow-up evaluation fortreatment of aplastic anemia. Two of his siblings are HLA-identical matches.

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Hematology Answers

Item 1 Answer: EEducational Objective: Manage a patient withlow-risk primary myelofibrosis.

The most appropriate management of this patient nowis observation. This patient has primary myelofibrosis,which is a chronic myeloproliferative disorder character-ized by overproduction of megakaryocytes and bonemarrow stromal cell-mediated collagen deposition. Theperipheral blood smear shows marked leukoerythroblas-tic findings with tear drop–shaped erythrocytes andmegathrombocytes. The bone marrow aspirate is often“dry” (unsuccessful aspirate), and bone marrow biopsyshows marked fibrosis. This patient has low-risk primarymyelofibrosis (PMF) given the absence of high-risk fea-tures such as age older than 65 years; fever, night sweats,and a weight loss of 10% or more; a hemoglobin con-centration of less than 10 g/dL (100 g/L); a leukocytecount greater than 25,000/µL (25 × 109/L); and cir-culating blasts of 1% or more. As such, his median over-all survival is 135 months or approximately 11 years.Given his favorable prognosis, he requires only observa-tion for now.

Allogeneic hematopoietic stem cell transplantation ispotentially curative in patients with PMF but is associatedwith significant morbidity and mortality and would not be agood choice for a patient with low-risk disease, but it couldbe considered if the disease progresses. Transplantation is thepreferred treatment for younger patients with two or moreadverse prognostic features.

Danazol is used to treat PMF-related anemia and leadsto responses in 37% of patients with transfusion-dependentanemia or a hemoglobin level less than 10 g/dL (100 g/L).This treatment is not indicated in this patient considering hishemoglobin level of 12.5 g/dL (125 g/L).

Hydroxyurea would be a reasonable therapy if thepatient had constitutional symptoms such as fever, weightloss, night sweats, symptomatic splenomegaly, or prob-lematic thrombocytosis; however, this treatment is notrequired now.

Imatinib is appropriate therapy in patients withchronic myeloid leukemia, but it is not effective in treat-ing PMF.

K E Y P O I N T

• Close observation, with palliative care asneeded, is appropriate for patients with low-risk primary myelofibrosis.

BibliographyCervantes F, Dupriez B, Pereira A, et al. New prognostic scoring sys-tem for primary myelofibrosis based on a study of the InternationalWorking Group for Myelofibrosis Research and Treatment. Blood.2009;113(13):2895-2901. [PMID: 18988864]

Item 2 Answer: AEducational Objective: Treat aplastic anemia in ayoung patient.

The most appropriate treatment is allogeneic hematopoi-etic stem cell transplantation (HSCT). Aplastic anemia isclassified by the severity of the neutropenia. Moderateaplastic anemia is diagnosed when the absolute neutrophilcount (ANC) is 500 to 1000/µL (0.5-1.0 × 109/L).Severe aplastic anemia occurs when two or more of the following are present: ANC 200 to 500/µL (0.2-0.5 ×109/L), platelet count less than 20,000/µL (20 × 109/L),and reticulocyte count less than 0.2%. Very severe aplasticanemia is diagnosed when the ANC is less than 200/µL(0.2 × 109/L). ANC is calculated as leukocyte count × per-centage of polymorphonuclear cells + band forms. Thispatient has very severe aplastic anemia. Patients with severeaplastic anemia who have an HLA-identical sibling and areyounger than 40 years should be offered allogeneic HSCTas initial therapy. Because of the high mortality rate associ-ated with this procedure, HSCT is generally not recom-mended as initial therapy for patients older than 40 years orthose who are not medically fit to undergo transplantationor who have no HLA-identical sibling; these patients aretypically treated with antithymocyte globulin andcyclosporine as initial therapy. Because this patient is young,healthy, and has two siblings who are an HLA-identicalmatch, he should be offered allogeneic transplantation asinitial therapy.

In some clinical trials of patients who are not transplantcandidates, intravenous antithymocyte globulin pluscorticosteroids and cyclosporine can result in partial andcomplete responses in 60% to 80% of patients. Many ofthese patients become transfusion independent, althoughresponse is often delayed for 3 to 6 months, and relapsescan occur when the cyclosporine is tapered.

Autologous HSCT would not be an appropriate treat-ment choice because this patient has an essentially acellularbone marrow.

Prednisone as a single agent produces a very lowresponse rate in patients with aplastic anemia.

Growth factors such as granulocyte colony-stimulatingfactor should not be given as primary therapy for aplasticanemia, and the use of growth factors as concomitant ther-apy is controversial. These agents are expensive, and some

Answers and Critiques