Chapter 12 Chronic Myeloproliferative Disorders Introduction Myeloproliferative disorders are a group of disorders that are considered clonal malignancies of the hematopoietic stem cell Chronic myelogenous leukemia CML Myelofibrosis with myeloid metaplasia MMM Polycythemia vera PV Essential thromocythemia ET Introduction World Health Organization WHO developed classification system for myeloid and lymphoid neoplasms based on Morphology Genetic information Immunophenotypic information Biologic and clinical features Chronic Myeloproliferative Disorders CMPDs CMPDs are primarily diseases of adults meaning they take time to develop Usually present with normocytic normochromic anemia with all three cell lines involved Chronic Myeloproliferative Disorders Other common features shared by these disorders include Splenomegaly Hepatomegaly Increased leukocytosis Thrombocytosis Erythrocytosis Often show marrow fibrosis Replacement of normal bone marrow elements with connective tissue Bone marrow shows varying degrees of abnormal proliferation of myeloid erythroid and megakaryocytic elements Chronic Myelogenous Leukemia CML Pathophysiology Marked neutrophil leukocytosis Hallmark of initial phase Whole spectrum of neutrophilic cell development can be seen Extremely high white blood count Philadelphia chromosome Translocation between chromosome 9 and chromosome 22 t9 22 BCR ABL translocation Increased tyrosine kinase activity May suppress apoptosis May cause excess cell production Chronic Myelogenous Leukemia CML Clinical features and symptoms Fatigue Weight loss Low grade fever Normocytic normochromic anemia Night sweats Splenomegaly Two phases Chronic Acute Similar to acute leukemia Peripheral blood and bone marrow Severe leukocytosis Entire spectrum of myeloid cell development Eosinophils and basophils are increased Thrombocytosis present in chronic phase Blasts increased in acute phase Bone marrow shows hyperplasia and may be fibrotic M E ratio can be as high as 25 1 Chronic Myelogenous Leukemia CML Treatment Hydroxyurea alpha interferon or busulfan therapy used for chronic phase cell cycle inhibitor Leukaphoresis cell separator to lower WBC count New approach includes inhibition of abnormal molecules by causing apoptosis and inhibits proliferation Interferes with cell division to decrease white count No therapy for acute phase Allogenic bone marrow transplant Chronic Myelogenous Leukemia CML Prognosis Chronic phase is responsive to treatment Poor prognosis based on factors Patient s age Phase of CML Amount of blasts in the peripheral blood and bone marrow Size of the spleen at diagnosis Marrow fibrosis Patient s general health Chronic Neutrophilic Leukemia Rare chronic myeloproliferative disease characterized by an increased neutrophil count Philadelphia chromosome is absent Bone marrow is hypercellular with an increase in granulocytic proliferation Chronic Eosinophilic Leukemia Chronic myeloproliferative disease characterized by increased proliferation of eosinophils in bone marrow circulation and peripheral tissue Eosinophil count greater than 1 500 l No other signs for eosinophil increase Also called hypereosinophilic syndorme HES Polycythemia Vera Disease overview Usually ages 60 70 Bone marrow is hypercellullar with hyperplasia Clonal disorder characterized by overproduction of mature red blood cells white blood cells and platelets Increase in hemoglobin hematocrit and red cell mass Increase in blood viscosity Patients predisposed to arterial and venous thrombosis 90 have the JAK mutation Polycythemia Vera Symptoms Hypertension Hyperviscosity Increased hematocrit Headache Blurred vision Fatigue Plethora Red complexion due to expanded blood volume Ulceration or gangrene Myocardial infarction Stroke Deep vein thrombosis Transient ischemic attacks Easy bruising Epistaxis Hyperuricemia Gout Stomach ulcers Hepatomegaly Spenomegaly Polycythemia Vera Peripheral blood and bone marrow findings Increase in all three cell lines Normoblastic erythroid proliferation Increase of red blood cells Reticulocyte count normal or slightly increased Neutrophilia with shift to the left Basophilia RDW increased Leukocyte alkaline phosphatase LAP score is usually elevated Platelet counts increased Polycythemia Vera Peripheral blood and bone marrow findings cont Platelets may have abnormal shape or function Bone marrow is hypercellular and shows increased reticulin or fibrosis Iron stores or bone marrow depleted Immature WBCs and RBCs found in peripheral blood Microcytes Elliptocytes Dacrocytes tear drop cells Polycythemia Vera Diagnosis Must be distinguished from secondary and relative erthyrocytosis Increase in red cell mass without evidence of changes in other cell lines Most significant symptoms Increased red cell mass Splenomegaly with increase in leukocytes and platelets Bone marrow aspirate and biopsy assist in diagnosis Serum erythropoietin often found to be low compared to secondary erythrocytosis Polycythemia Vera Treatment Therapy recommended based on Age Sex Clinical manifestations Hematologic findings Therapeutic phlebotomy Prognosis Median survival time is 10 years Major cause of death of untreated patients is hemorrhage or thrombosis Myelofibrosis With Myeloid Metaplasia Disease overview Chronic myeloproliferative disorder characterized by bone marrow fibrosis proliferation of megakaryocytic and granulocytic cells and extramedullary hematopoiesis Absence of the Philadelphia chromosome Synonyms Agnogenic myeloid metaplasia Chronic idiopathic myelofibrosis Idiopathic myelofibrosis Primary myelofibrosis Leukoerythroblastic anemia Myelosclerosis with myeloid metaplasia Myelofibrosis With Myeloid Metaplasia Pathophysiology Etiology is unknown It is believed that fibrosis of bone marrow is caused by cytokines release Initial phase Prefibrotic stage Hypercellular bone marrow with minimal reticulin Second phase is the fibrotic stage Bone marrow having marked reticulin or collagen fibrosis Normal hematopoiesis blocked as bone marrow becomes more fibrotic Myelofibrosis With Myeloid Metaplasia Clinical features and symptoms Splenomegaly Anemia Marrow fibrosis Pancytopenia thrombocytopenic and neutropenic causes patient to have bleeding tendencies and infection Night sweats Low grade fever Weight loss Anorexia Osteosclerosis Can cause severe joint pain Myelofibrosis With Myeloid Metaplasia Peripheral blood and bone marrow findings Initially WBC and platelet count increased but decrease as disease