The Non – Leukemic Myeloproliferative Disorders Dr. Ahmed Hassaneen

Non-leukemic Chronic Myeloproliferative Disorders The term myeloproliferative disorders (MPD) describes a group of conditions arising from marrow stem cells and characterized by clonal proliferation of one or more haemopoietic components in the bone marrow and, in many cases, the liver and spleen. The three major non - leukemic MPD included in this classification are: Polycythemia vera (PV) Essential thrombocythemia (ET) Primary myelofibrosis (PMF)

Non-leukemic Chronic Myeloproliferative Disorders They are closely related to each other and transitional forms can occur with evolution from one entity into another during the course of the disease . These diseases are associated with acquired mutations of the genes that encode the tyrosine kinase proteins: Janus‐associated kinase 2 (JAK2) , MPL (the receptor for thrombopoietin), or calreticulin (CALR) Acquired mutation of the cytoplasmic tyrosine kinase Janus - associated kinase 2 (JAK2) occurs in the marrow and blood of almost all patients with PV and in about 60% of those with ET and PMF, showing the common etiology of these three diseases

Polycythemia Vera Polycythemia (Erythrocytosis) is defined as an increase in the haemoglobin concentration above the upper limit of normal for the patient’s age and sex. Classification of polycythaemia Absolute polycythaemia , in which the red cell mass (volume) is raised to greater than 125% of that expected for body mass and gender Relative or pseudopolycythaemia in which the red cell volume is normal but the plasma volume is reduced.

Polycythemia Vera If the hematocrite is > 0.60 , this will confirm that red cell mass is increased without the need for isotope studies. Hb > 18.5 g/dL or hematocrite > 0.52 in men , and Hb > 16.5 g/dL or hematocrite > 0.48 in women, indicate that erythrocytosis is likely but isotope studies may be required. Once established, absolute polycythaemia can be subdivided into : 1-Primary polycythaemia (in which the erythroid progenitor cell shows an enhanced response to cytokines) 2-Secondary polycythaemia (driven by factors outside the erythroid compartment)

Polycythemia Vera The disease results from somatic mutation of a single haemopoietic stem cell which gives its progeny a proliferative advantage. The JAK2 V6 17F mutation is present in haemopoietic cells in over 95% of patients and JAK2 exon 12 mutation is seen in the remainder. Although the increase in red cells is the diagnostic finding, in many patients there is also an increase of granulocytes and platelets.

Polycythemia Vera Clinical features This is a disease of older subjects with an equal sex incidence. Clinical features are the result of hyperviscosity, hypervolaemia or hypermetabolism: Headache. Dyspnoea. Blurred vision. Night sweats. Pruritus , characteristically after a hot bath, can be a severe problem. Plethoric appearance and conjunctival suffusion .

Polycythemia Vera Clinical features (Con.) 7. Splenomegaly in 75% of patients. 8. Haemorrhage (e.g. gastrointestinal, uterine, cerebral) or thrombosis either arterial (e.g. cardiac, cerebral) or venous (e.g. deep or superficial leg veins, portal or hepatic veins) are frequent. 9. Hypertension in one - third of patients. 10. Gout as a result of increased uric acid production (Hypermetabolism)

Splenomegay and Hepatomegaly in patient with Polycythemia Vera

Polycythemia Vera Laboratory findings The haemoglobin, haematocrite and red cell count are increased. The total red cell volume is increased. Neutrophil leucocytosis is seen in over 50 % of patients. Increased platelet count is present in about 50 % of patients. The JAK2 mutation is present in the bone marrow and peripheral blood granulocytes in over 95% of patients. The bone marrow is hypercellular with trilineage growth best assessed by a trephine biopsy . Serum erythropoietin is low.

Polycythemia Vera Laboratory findings (Cont.) 8. Blood urate (uric acid) is often increased. 9. Serum lactate dehydrogenase (LDH) is normal. 10. Circulating erythroid progenitors (erythroid colony - forming unit ; CFU-E and erythroid burst -forming unit ; BFU E) are increased compared to normal and grow in vitro independently of added erythropoietin (endogenous erythroid colonies).

Bone Marrow Pathology_ Barbra Bain_3rd edition

Iliac crest trephine biopsies Polycythaemia vera: fat spaces are almost completely replaced by hyperplastic haemopoietic tissue. All haemopoietic cell lines are increased specially megakaryocytes.

Polycythemia Vera Treatment Treatment is aimed at maintaining a normal blood count. The haematocrit should be maintained at about 0.45 and the platelet count below 400,000 /ul. 1- Venesection Venesection to reduce the haematocrit to less than 0.45 is particularly useful when a rapid reduction of red cell volume is required (e.g. at the start of therapy). indicated in younger patients and those with mild disease. The resulting iron deficiency may limit erythropoiesis.

Polycythemia Vera Treatment (Cont.) 2- Cytotoxic myelosuppression e.g. Hydroxyurea Indicated if there is poor tolerance of venesection, symptomatic splenomegaly, thrombocytosis, weight loss or night sweats. 3- Interferon α-Interferon suppresses excess proliferation in the marrow. 4- Aspirin Low - dose aspirin reduces thrombotic complications without an increased risk of major hemorrhage.

Polycythemia Vera Course and prognosis Typically, the prognosis is good with a median survival of 10 to 16 years. Transition from PV to MF occurs in approximately 30% of patients. Transition from PV to acute myeloid leukemia occurs in approximately 5%

Essential Thrombocythemia A persisting platelet count of > 450,000 /ul is the central diagnostic feature but other causes of a raised platelet count (particularly iron deficiency, inflammatory or malignant disorder and myelodysplasia) need to be fully excluded before the diagnosis can be made. There is a sustained increase in platelet count, because of megakaryocyte proliferation and overproduction of platelets. The haematocrite is normal and the Philadelphia chromosome or BCR - ABL1 rearrangement are absent. The bone marrow does not show fibrosis.

50 % to 60% of patients show the JAK2 (V617F) mutation and these cases tend to resemble more closely PV with higher haemoglobin and white cell counts than JAK2‐negative cases. The JAK2 mutation also affects platelet function leading to a pro‐thrombotic state. Mutations in the CALR gene are seen in around 75% of JAK2‐negative ET patients (= about 30 % of total). Mutations in the MPL gene are seen in 4 % of cases.

Essential Thrombocythemia

The suggested diagnostic criteria for essential thrombocythaemia are: A1 : Sustained platelet count above 450,000 /ul. A2 : Presence of an acquired mutation (e.g. in JAK2 or CALR). A3 : No other myeloid malignancy, PV, primary myelofibrosis, chronic myeloid leukemia (CML) or myelodysplastic syndrome. A4 : No reactive cause for thrombocytosis and normal iron stores. A5 : Bone marrow trephine histology showing increased megakaryocytes with prominent large hyperlobulated forms; reticulin fibers are generally not increased. ► Diagnosis requires A1–A3 or A1 + A3–A5

Essential Thrombocythemia Clinical and laboratory findings The dominant clinical features are thrombosis (venous or arterial ) and haemorrhage , however , Most cases are symptomless Erythromelalgia is a characteristic symptom : burning sensation felt in the hands or feet and rapidly relieved by aspirin. Palpable splenomegaly present in up to 40% of patients whereas in others there may be splenic atrophy because of infarction. Abnormal large platelets and megakaryocyte fragments may be seen on the blood film . The bone marrow is similar to that in PV but an excess of abnormal megakaryocytes is typical. Platelet function tests are consistently abnormal : Characteristically there is failure of aggregation with adrenaline.

Peripheral blood film in essential thrombocythemia showing increased numbers of platelets and a nucleated megakaryocytic fragment.

Essential Thrombocythemia Treatment and Prognosis The principle is to reduce the risk of thrombosis or hemorrhage which are the major clinical problems. The patients most at risk of thrombosis are those over 60 years old or with previous thrombotic episodes. Low dose aspirin (75 mg/day) is recommended in all cases. Hydroxyurea is the most widely used treatment. Often the disease is stationary for 10 – 20 years. The disease may transform after years to MF. It may also transform into acute myeloid leukemia ( Less than 5% of cases).

Primary Myelofibrosis A clonal stem cell disease. The fibrosis of the bone marrow is secondary to hyperplasia of abnormal megakaryocytes → secretion of platelet - derived growth factor (PDGF) and other cytokines by megakaryocytes and platelets → stimulation of fibroblasts → fibrosis of bone marrow. Haemopoiesis occurs in the spleen and liver (known as myeloid metaplasia) to compensate for B.M fibrosis. Mutations in JAK2, CALR and MPL occur in 55%, 25% and 10 % of patients respectively.

Primary Myelofibrosis Clinical features Usually affecting old age. About one – third of patients have a previous history of PV or ET. Symptoms and signs of anemia. Massive splenomegaly which can cause abdominal discomfort, pain or indigestion). Hypermetabolic symptoms such as loss of weight, anorexia, fever and night sweats. Primary myelofibrosis and CML are responsible for most cases of massive splenic enlargement ( > 20 cm) in the UK and North America Transformation to AML occurs in 10–20% of patients.

WHO Classification of Tumours, Revised 4th Edition, Volume 2

Primary Myelofibrosis Laboratory findings Anemia is usual but a normal or increased haemoglobin level may be found in some patients. 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 ’ appearance. Bone marrow aspiration usually can not be obtained (Dry tap) due to marked fibrosis. Bone marrow trephine biopsy shows a fibrotic hypercellular marrow with increased megakaryocytes . High serum urate and LDH levels reflect the increased but largely ineffective turnover of haemopoietic cells.

Bone Marrow Pathology_ Barbra Bain_3rd edition

Peripheral blood film in primary myelofibrosis Peripheral blood film in primary myelofibrosis. Leucoerythroblastic change with ‘tear-drop’ cells and an erythroblast (nucleated red cell).

Iliac crest trephine biopsies Primary myelofibrosis: Normal marrow architecture is lost and haemopoietic cells are surrounded by increased fibrous tissue and intercellular substance.

Bone Marrow Pathology_ Barbra Bain_3rd edition

Bone Marrow Pathology_ Barbra Bain_3rd edition

Primary Myelofibrosis Treatment This is 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. Splenectomy is considered for patients with severe symptomatic splenomegaly , thrombocytopenia, excessive transfusion requirements or hypermetabolic symptoms

Primary Myelofibrosis Course The median survival is less than 5 years and causes of death include heart failure, infection and leukemic transformation (Transformation into AML occurs in about 10 % of cases) A hemoglobin level of < 10 g/dl , a white cell count of less than 4 or greater than 30 × 10 9 /L and the presence of abnormal chromosomes are associated with a worse prognosis.

WHO Classification of Tumours, Revised 4th Edition, Volume 2

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