Myeloproliferative Neoplasms (MPNs)

Chronic Myeloproliferative Disorders

Definition
clonal hematologic diseases that arise from a transformation in a hematopoietic stem cell main clinical features are
overproduction of one or more of the formed elements of the blood without significant dysplasia Predilection to extramedullary hematopoiesis Myelofibrosis Transformation at varying rates to acute leukemia

PVSG Classification
Chronic myeloid leukemia Idiopathic myelofibrosis/agnogenic myeloid metaplasia Polycythemia vera Essential or idiopathic thrombocythemia

WHO (2008)classification of MPN

Chronic myelogenous leukemia [Ph chromosome, t(9;22)(q34;q11), BCR/ABL-positive] Chronic neutrophilic leukemia Polycythemia vera Primary myelofibrosis Essential thrombocythemia Chronic eosinophilic leukemia not otherwise specified Mastocytosis Myeloproliferative neoplasms, unclassifiable

Non-leukemic MPNs
Polycythemia vera (PV) Essential thrombocytosis (ET) Primary myelofibrosis

Common clinical features of non-leukemic MPNs (non-MPNs)

Predominantly affecting middle-aged and older groups Insidous, sometimes asymptomatic onset Panhyperplasia of bone marrow (granulocytic with or without monocytic elements Extramedullary hematopoiesis (myeloid metaplasia) manifested primarily in the spleen and less frequently in the liver Bone marrow fibroblastic proliferation and reticulin/collagen formation

 Transition often occurring between these disorders; overlapping manifestations Increased propensity for terminating in acute leukemia Bone marrow may demonstrate large number of megakaryocytes, sometimes atypical in appearance Evidence of platelet dysfunction Cytogenetic abnormalities

Cardinal Features non-MPNs

Role of JAK2

Role of JAK2

Role of JAK2

Polycythemia Rubra Vera

Polycythemia
Polycythemia an increase in circulating red blood cells above normal. other term erythrocytosis

Classification of Polycythemia
Elevated Hematocrit
Hct > 48 Hct > 50 Hgb > 17 g/dL Hgb > 15 g/dL Hct > 60 Hct > 55 Absolute polycythemia Primary Acquired Hereditary Secondary Relative polycythemia

Classification of Polycythemia
Absolute (true) polycythemia (RCM)
Primary polycythemia
Acquired
Polycythemia vera

Hereditary
Primary familial congenital polycythemia Erythropoietin receptor mutation Unknown gene mutation

Secondary polycythemia

Secondary polycythemia
Acquired (Physiologically appropriate increase in EPO)
Hypoxemia
chronic lung disease sleep apnea right-to-left cardiac shunts high altitude smoking

Carboxyhemoglobinemia
smoking carbon monoxide poisoning

Secondary polycythemia
Acquired
Autonomous erythropoietin production
hepatocellular carcinoma renal cell carcinoma cerebellar hemangioblastoma pheochromocytoma parathyroid carcinoma meningioma polycystic kidney disease

Secondary polycythemia
Acquired
Exogenous erythropoietin administration (Epo doping) Complex or uncertain etiology
postrenal transplant (probable abnormal angiotensin II signaling) androgen/anabolic steroids

Secondary polycythemia
Hereditary
High-oxygen affinity hemoglobins Congenital methemoglobinemia 2,3-biphosphoglycerate deficiency

Relative (spurious) polycythemia (normal red cell mas)

Dehydration Diuretics Smoking Gaisbck syndrome (stress polycythemia)

1. Which ONE of the following is NOT a cause of polycythemia? A. Mutation of JAK2 B. chronic renal disease C. Congenital heart disease D. High-oxygen affinity hemoglobin

Clinical Features
Myeloid Metaplasia splenic infarction hypersplenism hypervolemia Increased Nucleoprotein Turnover Hyperuricemia Increased Urinary Uric acid Gout Tophi Renal stones Nephropathy Hypermetabolism Weight loss Diaphoresis Fatigue Weakness Fever Erythrocyte

Erythemia Hypervolemia Circulatory overload Erythemia Thrombosis Hemorrhage

Megakaryocyte

Thrombocythemia Thrombocytopathy Thrombosis Hemorrhage Basophil Proliferation Increased Histamine Turnover and Release Pruritus Gastrointestinal symptoms Acute leukemia

Granulocyte

Fibroblast

Myelofibrosis Myelofibrosis Decreased hematopoietic tissue Decreased hematopoietic tissue

Osteosclerosis Osteolysis Decreased hematopoietic tissue Pathologic fracture

Osteoblast Osteoclast

Diagnostic Approach

PVSG criteria for diagnosis of PV

Category A (Major Criteria)
elevated red cell mass normal arterial oxygen saturation splenomegaly

Category B (Minor Criteria)

leukocytosis thrombocytosis elevated leukocyte alkaline phosphatase (score) increase serum vitamin B12 or vitamin B12-binding protein

PSVG Polycythemia vera study group: To establis a diagnosis of PV either all 3 major or elevated red mass and normal arterial oxygen saturation plus two minor criteria

General Principles of Therapy

Reduce the risk of thrombosis by normalizing hematocrit to 45% in males and 42% females Use of aspirin Chemotherapy
hydroxyurea anagrelide interferon (IFN) -

Which ONE of these statements is TRUE about pseudo (stress) polycythaemia? A. It is caused by a raised red cell mass B. It is associated with a large spleen C. It is treated with hydroxyurea D. It is most common in young male adults

Primary Myelofibrosis
agnogenic myeloid metaplasia myelofibrosis with myeloid metaplasia

Definition
a chronic hematologic neoplasm characterized by
splenomegaly leukoerythroblastosis teardrop poikilocytosis marrow fibrosis neoangiogenesis extramedullary hematopoiesis

Clinical features
An insidious onset in older people is usual with symptoms of anemia. Symptoms resulting from massive splenomegaly (e.g. abdominal discomfort, pain or indigestion) are frequent; splenomegaly is the main physical finding

Clinical features
Hypermetabolic symptoms such as loss of weight, anorexia, fever and night sweats are common. Bleeding problems, bone pain or gout occur in a minority of patients. Transformation to acute leukemia in 10 20 % of cases

Laboratory features
Anemia is usual but a normal or increased hemoglobin level may be found in some patients.

Laboratory features
The white cell and platelet counts are frequently high at the time of presentation. Later in the disease leucopenia and thrombocytopenia are common. A leucoerythroblastic blood film is found. The red cells show characteristic 'tear-drop' poikilocytes

Laboratory features
Bone marrow is usually unobtainable by aspiration. Trephine biopsy shows a fibrotic hypercellular marrow.
Increased meg-akaryocytes are frequently seen. In 10% of cases there is increased bone formation with increased bone density on X-ray.

Laboratory features
JAK2 kinase is mutated in approximately 50% of cases. High serum urate and LDH levels reflect the increased but largely ineffective turnover of hemopoietic cells.

Which ONE of the following is NOT a typical feature of primary myelofibrosis? A It causes a leukoerythroblastic blood film B It may be associated with a raised platelet count C Normal serum lactate dehydrogenase level D It may cause massive splenomegaly

Treatment
usually palliative and aimed at reducing the effects of anemia and splenomegaly
Blood transfusions and regular folic acid therapy are used in severely anemic patients. Hydroxyurea may help to reduce splenomegaly and hypermetabolic symptoms. Trials of thalidomide, lenalidomide, azacytidine and histone deacetylase inhibitors are in progress. JAK inhibitors (clinical trial)

Prognosis
The median survival is less than 5 years and causes of death include heart failure, infection and leukemic transformation.

Differential Diagnosis of Myelofibrosis

Chronic IMF/agnogenic myeloid metaplasia Other chronic myeloproliferative disorders Infiltrative disorders/secondary causes of myelofibrosis
metastatic carcinoma granulomatous disorders (e.g. Tb, sarcoidosis, histoplasmosis

Hematologic malignancies
acute leukemia hairy cell leukemia myelodysplastic syndrome non Hodgkin lymphoma

Essential Thrombocytosis (ET)

Essential Thrombocythemia Idiopathic thrombocythemia Primary Thrombocythemia Primary Hemorrhagic Thrombocythemia

Major Causes of Thrombocytosis

Reactive Thrombocytosis (Secondary)

Familial Thrombocytosis

Clonal Thrombocytosis

Regulation of Platelet Production

PVSG diagnostic criteria for ET

Platelet count > 600 X 109/L Megakaryocytic hyperplasia Absence of identifiable causes of reactive thrombocytosis Absence of Philadelphia chromosome Hemoglobin no higher than 13 g/dL or normal red cell mass Absence of significant marrow fibrosis Presence of stainable marrow iron or failure of iron trial Splenomegaly

Peripheral blood smear and bone marrow findings in essential thrombocytosis

Causes of Secondary (Reactive) Thrombocytosis

Transient processes
Acute blood loss Recovery (rebound) from thrombocytopenia Acute infection or infammation Response to exercise

Sustained processes
Iron deficiency Hemolytic anemia Asplenia Cancer Chronic inflammatory or infectious diseases Drug reactions

 Which ONE of the following does NOT cause a raised platelet count? A Hemorrhage B Chronic myeloid leukaemia C Mutation of JAK2 D Aplastic anemia

5. What is the approximate frequency of the Val617Phe mutation in JAK2 in myeloproliferative neoplasms? A. 99% in polycythaemia vera (PV) and 50% in essential thrombocythaemia (ET) and primary myelofibrosis (PM) B. Approximately 50% in PV, ET and PM C. 50% in PV and 25% in ET and PM D. 90% in PV, rare in ET and PM

Mastocytosis
Mastocytosis is a clonal neoplastic proliferation of mast cells that accumulate in one or more organ systems.

Mastocytosis
Mast cells (tissue basophils) are derived from hemopoietic stem cells. Mature cells survive for months or years in vascular tissues and most organs. Systemic mastocytosis is a clonal myeloproliferative disorder involving usually the bone marrow, heart, spleen, lymph nodes and skin.

Mastocytosis
The somatic KIT mutation Asp816Val is detected in the majority of patients and may be partly responsible for autonomous growth and enhanced survival of the neoplastic mast cells. In many patients this mutation is also detected in other hmopoietic cells.

Mastocytosis
Symptoms are related to histamine and prostaglandin release and include flushing, pruritus, abdominal pain and bronchospasm.

Mastocytosis
Serum tryptase is increased and can be used to monitor treatment. Interferon, chlorodeoxyadenos-ine and tyrosine kinase inhibitors can be helpful.

Mastocytosis
In many patients the disease runs a chronic indolent course. In others an aggressive course may be associated with acute myeloid leukemia, mast cell leukemia or other hemopoietic proliferative or dysplastic condition

Chronic Myelogenous Leukemia

Chronic Myeloid Leukemia Chronic Granulocytic Leukemia

Epidemiology
Accounts for 15% of adult leukemias Incidence of 1-2 cases per 100 000 population Male-to-female ratio of 1.3 to 1 Incidence increases with age Median age at presentation is 45 to 55 years

Definition
Chronic myeloid leukemia (CML) is a pluripotent stem cell disease characterized by:
anemia extreme blood granulocytosis and granulocytic immaturity basophilia thrombocytosis splenogemaly reciprocal translocation between chromosomes 9 and 22 Inevitable transition from a chronic to an accelerated phase and on to blast crisis

Philadelphia Chromosome

 The clinical course may be characterized by three separate phases

Chronic phase, which is generally controllable with chemotherapeutic agents and lasts 2 to 5 years Accelerated phase, which lasts approximately 6 to 18 months; Blastic (acute) leukemia phase, which lasts 3 to 4 months and is generally unresponsive to treatment

Risk factors
DNA topoisomerase II inhibitors exposure to very high doses of ionizing radiation

Pathophysiology
Molecular Basis of CML

The Ph Chromosome

ABL gene

BCR gene

BCR-ABL gene

Structure of BCR-ABL Fusion Protein

Molecular Consequence of t(9;22)

Mechanism of BCR-ABL mediated malignant transformation

Mechanisms implicated in the pathogenesis of CML

Characteristics of Patients with Chronic Myeloid Leukemia at Presentation

Clinical findings
Fatigue, anorexia, weight loss Splenomegaly Hepatomegaly

Peripheral-blood findings
Elevated WBC > 25,000/mm3 Elevated platelet count in 30 to 50% of cases Basophilia Reduced leukocyte alkaline phosphatase activity All stages of granulocyte differentiation visible on peripheral smear

Faderl, S. et. al. Ann Intern Med 1999;131:207-219

Peripheral blood and bone marrow in CML

Characteristics of Patients with Chronic Myeloid Leukemia at Presentation

Bone marrow findings

Hypercellularity, reduced fat content Increased ration of myeloid to erythroid cells Increased number of megakaryocytes Blasts and promyelocytes constitute less than 10 percent of all cells

Therapy for CML

Milestone in the Treatment of CML

1856 Arsenicals (Fowlers solution) Prior to 1950s Total-body or splenic radiation therapy 1950s Busulfan 1972 Hydroxyurea 1990s- Interferon with or without cytosine arabinoside

Imatinib mesylate

Allogeneic stem cell transplantation

Figure 1. An operational classification of hematologic malignancies

Tefferi, A. Oncologist 2003;8:225-231

Copyright 2003 AlphaMed Press