chronic myeloproliferative diseases

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 HematocritElevated Hematocrit

Absolute polycythemia Relative polycythemiaPrimary Acquired HereditarySecondary

Hct > 50Hgb > 17 g/dL

Hct > 48Hgb > 15 g/dL

Hct > 60 Hct > 55

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• Gaisböck syndrome (stress polycythemia)

1. Which ONE of the following is NOT a cause of polycythemia?

A. Mutation of JAK 2‐B. chronic renal diseaseC. Congenital heart diseaseD. High-oxygen affinity hemoglobin

Myeloid Metaplasia• splenic infarction• hypersplenism• hypervolemia

Myeloid Metaplasia• splenic infarction• hypersplenism• hypervolemia

IncreasedNucleoproteinTurnover

HyperuricemiaIncreased UrinaryUric acid• Gout• Tophi• Renal stones• Nephropathy

IncreasedNucleoproteinTurnover

HyperuricemiaIncreased UrinaryUric acid• Gout• Tophi• Renal stones• Nephropathy

Hypermetabolism• Weight loss• Diaphoresis• Fatigue• Weakness• Fever

Hypermetabolism• Weight loss• Diaphoresis• Fatigue• Weakness• Fever

ErythemiaHypervolemia• Circulatory overloadErythemia• Thrombosis• Hemorrhage

ErythemiaHypervolemia• Circulatory overloadErythemia• Thrombosis• Hemorrhage

ThrombocythemiaThrombocytopathy• Thrombosis• Hemorrhage

ThrombocythemiaThrombocytopathy• Thrombosis• Hemorrhage

Basophil ProliferationIncreased HistamineTurnover and Release• Pruritus• Gastrointestinal symptoms

Basophil ProliferationIncreased HistamineTurnover and Release• Pruritus• Gastrointestinal symptoms

Acute leukemiaAcute leukemia

Myelofibrosis• Decreased hematopoietic tissueMyelofibrosis• Decreased hematopoietic tissue

OsteosclerosisOsteolysis• Decreased hematopoietic tissue• Pathologic fracture

OsteosclerosisOsteolysis• Decreased hematopoietic tissue• Pathologic fracture

Myelofibrosis• Decreased hematopoietic tissueMyelofibrosis• Decreased hematopoietic tissue

ErythrocyteErythrocyte

MegakaryocyteMegakaryocyte

GranulocyteGranulocyte

FibroblastFibroblast

OsteoblastOsteoclastOsteoblastOsteoclast

Clinical Features

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) -α

Which ONE of these statements is TRUE about pseudo (stress) polycythaemia?

A. It is caused by a raised red cell massB. It is associated with a large spleenC. It is treated with hydroxyureaD. It is most common in young male adults

Primary Myelofibrosis

agnogenic myeloid metaplasiamyelofibrosis 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 leuko erythroblastic 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 ThrombocythemiaIdiopathic thrombocythemiaPrimary Thrombocythemia

Primary Hemorrhagic Thrombocythemia

Major Causes of ThrombocytosisMajor Causes of Thrombocytosis

Reactive Thrombocytosis(Secondary)

Reactive Thrombocytosis(Secondary)

Familial ThrombocytosisFamilial Thrombocytosis Clonal ThrombocytosisClonal 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 JAK 2‐• 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 PMC. 50% in PV and 25% in ET and PMD. 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 LeukemiaChronic 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 (Fowler’s solution)• Prior to 1950s – Total-body or splenic

radiation therapy• 1950s – Busulfan• 1972 – Hydroxyurea• 1990s- Interferon α with or without cytosine

arabinoside

Imatinib mesylate

Allogeneic stem cell transplantation

Copyright ©2003 AlphaMed Press

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

Figure 1. An operational classification of hematologic malignancies