CHRONIC MYELOPROLIFERATIVE DISORDERS

1. CHRONIC MYELOPROLIFERATIVE DISORDERS

2. CHRONIC MYELOPROLIFERATIVE DISORDERS(MPD) 1. Polycythemia vera 2. Chronic myeloid leukaemia 3. Essential thrombocythemia 4. Idiopathic myelofibrosis

3. CHRONIC MYELOPROLIFERATIVE DISORDERS(MPD) MPD are clonal diseases originating in pluripotential haematopoieticstem cell. The clonal expansion results in increased and abnormal haematopoiesis and produces a group of interrelated syndromes, classified according to the predominant phenotypic expression of the myeloproliferative clone.

4. ERYTHROCYTOSIS (Classification)(1) I. Absolute erythrocytosis (Polycythemia): A. Secondary erythrocytosis (abnormal increase of serum erythropoietin level) 1. Erythrocytosis secondary to decreased tissue oxygenation: a) chronic lung diseases b) cyanotic congenital heart diseases c) high-altitude erythrocytosis (Monge disease) d) hypoventilation syndromes (Sleep apnoe) e) hemoglobin-oxygen dissociation abnormalities - hemoglobinopathies associated with high oxygen affinity - carboxyhemoglobin in „smoker’s polycythemia”

5. ERYTHROCYTOSIS (Classification)(2) I.Absolute erythrocytosis (Polycythemia): A. Secondary erythrocytosis (abnormal increase of serum erythropoietin level) 2. Secondary to aberrant erythropoietin production or response: a) Erythropoietin-producting tumors: hepatoma, uterine leiomyoma, cerebellar hemangioblastoma, ovarian carcinoma, pheochromocytoma b) Renal diseases: renal cell carcinoma, kidney cysts and hydronephrosis, renal transplantation. c) Androgen abuse: adrenal cortical hypersecretion, exogenous androgens B. Primery erythrocytosis 1. Polycythemia vera 2. Familial erythrocytosis II. Relative erythrocytosis (pseudopolycythemia): 1. Hemoconcentration 2. Spurious polycythemia (Gaisboek syndrome)

6. POLYCYTHEMIA VERA(PV) Patogenesis PV is a clonal disorder involving the hematopoietic stem cells; it leads to an autonomous proliferation of the erythroid, myeloid, and megakaryocytic cell lines. Increased erythroid proliferation is usually more prominent than that of the other cell lines and occurs independently of erythropoietin levels (which are usually very low in PV) Epidemiology The incidence rate of PV is approximately 2 per 100.000 population. PV is slightly more prevalent in males with male/female ratio ranging from 1,2 to 2:1. Median age at diagnosis was 60 years in men and 62 years in women.

7. POLYCYTHEMIA VERAsymptoms 1. Erythrocytosis and hyperviscosity, leading to impaired oxygen delivery: • Poor CNS circulation: headaches, dizziness, vertigo, tinnitus and visual disturbances • Poor coronary circulation: angina pectoris • Peripheral circulation intermittent claudication 2. Venous thrombosis or thromboembolism 3. Hemorrhage: epistaxis, gingival bleeding, ecchymoses, gastrointestinal bleeding 4. Abdominal pain secondary to poptic ulcer 5. Early satiety due to splenomegaly 6. Pruritus is secondary to increased histamine release from the basophils and mast cells

8. POLYCYTHEMIA VERAphysical examination • Splenomegaly – is present in 75% of patients at the time of diagnosis. • Hepatomegaly - is present in approximately 30% of patients at the time of diagnosis. • Hypertension • On examination of the eye grounds, the vessels may be engorged, tortuous, and irregular in diameter; the veins may be dark purple.( fundus policythaemicus) • Facial plethora

9. DIAGNOSTIC CRITERIA FOR POLYCYTHEMIA VERA(Polycythemia Vera Study Group 75) CATEGORY A 1. Total red cell mass • male  36ml/kg • female  32 ml/kg 2. Arterial oxygen saturation  92% 3. Splenomegaly CATEGORY B 1. Thrombocytosis (platelet count > 400 G/l) 2. Leukocytosis (white cell count > 12 G/l, no fever or infection) 3. Increased leukocyte alkaline phosphatase (score> 100 ) 4. Serum vitamin B12> 900 pg/ml or vitamin B12 binding capacity >2200 pg/ml PV is diagnosed when A1+A2+A3 or A1+A2 and any two from category B

10. POLYCYTHEMIA VERA-therapy (1) I. Patients under the age of 50 with no history of thrombosis and without severe thrombocytosis (greater than 1000G/L)-phlebotomy alone - initially 450-500 ml phlebotomy every every other day until the hematocrit is less than 46% - older patients or these with underlying cardiovascular disase should undergo smaller phlebotomies 200-300mL twice weekly or 100-150mLevery day until Ht<46% - subsequently, Ht should be mainted between 42-46% - fluid replacement so that the patients remains isovolemic II. Patients over the age of 70, or with history of thrombosis and with severe thrombocytosis (greater than 1000G/L)-myelosuppresive agent - Hydroxyurea 15-30mg/kg III. Patients 50-70 years with no history of thrombosis and without severe thrombocytosis (greater than 1000G/L) individualize therapy I or II

11. POLYCYTHEMIA VERA-therapy (2) IV. Antiplatelets agents • Aspirin initially 150-300mg/d, maintence therapy 75-100 mg • Tiklid 2x1 • Dipyridamol • Anagrelide 2-2,5 mg/d V. Other modalities 1. Radioactive phosphorus (in older than 75 years) 2. Interferon alpha 3 million units 3 times weekly VI. Special Topics 1. Pruritus:antihistaminic agent, cyproheptadine-4mg three times per day 2. Hyperuricemia-allopurinol 300mg/day

12. POLYCYTHEMIA VERA-prognosis • Untreated patients– the median survival ranges from 1-3 years • Patients treated with phlebotomy or/and hydroxyurea - median survival is 13,9 years • Patients treated with 32P • - median survival is 11,8 years • The frequency of acute leukemia (%): • Patients treated with phlebotomy 1,5 % • Patients treated with 32P 9,6% The frequency of myelofibrosis (%): • Patients treated with phlebotomy 8,6 % • Patients treated with 32P 7,7%

13. Myelofibrosis=agnogenic myeloid metaplasia(primary myelofibrosis, osteomyelofibrosis, idiopathic myelofibrosis, myelofibrosis with myeloid metaplasia ) Myelofibrosis is a chronic myeloproliferative disease with clonal hematopoesis and secondary(non-clonal) hyperproliferation of fibroblasts (stimulated by PDGF, EGF, TGF- released from myeloid cells, mainly from neoplastic megakaryocytes) with increased collagen synthesis. It produces bone marrow fibrosis and to extramedullary hematopoesis in the spleen or in multiple organs.

14. MYELOFIBROSIS • The incidence of Myelofibrosis is about 0,5/100.000. The median age at diagnosis was approximately 65 years. • Common complaints: fatigue, weight loss, night sweats, bone pain, abdominal pain, fever • Physical findings: splenomegaly (often giant), hepatomegaly(in about 50% of patients), symptoms of anaemia and thrombocytopenia

15. MYELOFIBROSIS- laboratory findings (1) • Anemia - Hb<10g/dL in 60% of patients • Leukocytosis with counts generally below 50G/L(in about 50%), leukopenia (in about 25% at the time of diagnosis) • thrombocytosis in 50% at the time of diagnosis, with disease progression thrombocytopenia becomes common • eosinophilia and basophilia may be present • retikulocytosis • LAP score is usually elevaatedd • Increased level of lactate dehydrogenase • uric acid level is increased in most patients

16. MYELOFIBROSIS- laboratory findings(2) • Peripheral blood smear:anisocytosis and poikilocytosis with the presence of teardrop-shaped and nucleated red cells, immature neutrophils but myeloblasts not always • Aspiration of bone marrow is usually ansuccessful (dry tap). Smears from successful aspirates usually show neutrophilic and megakaryocytic hyperplasia • Trephine biopsy often shows a hypercellular marrow with increased reticulin fibers and variable collagen deposition . Increased numbers of megakaryocytes are frequently seen.

17. MYELOFIBROSIS- diagnosis (Polycythemia Vera Study Group criteria) • Myelofibrosis involving more than one-third of the sectional area of a bone marrow biopsy • a leukoerythroblaststic blood picture • splenomegaly • absence of the well-established diagnostic criteria for the MPD(i.e absence of increased red cell mass or the Ph chromosome),with systemic disorders excluded

18. MYELOFIBROSIS - therapy 1 1. Androgens(oxymetholone 2-4mg/kg) in anemia from decreased red cell production -overall response is about 40% 2. Cortykosteroids(prednisone 1mg/kg)in anemia with shortened red cell life-span-response in 25-50% of patients 3. Hydroksyurea (15- 20mg/kg) for the control of leukocytosis, thrombocytosis, or organomegaly 4. Allopurinol-to prevent hyperuricaemia 5. Vit. D3-analogues(1,25-dihydroxycholecalciferol-1ug/d (?) 6. Transfusions of packed red cells for anemia or platelets for thrombocytopenia with bleeding

19. MYELOFIBROSIS - therapy 2 6. Splenectomy should be considered for: portal hypertension, painful splenomegaly, refractory anemia and thrombocytopenia, or exccessive transfusion requirement. However,the procedere is hazardous (an operative mortality is up to 38%). 7. Splenic irradiation: when there is a contrindication to splenectomy 8. Allogeneic stem-cell transplantation: for young patients who have a poor prognosis and have a suitable donor identified. 9. Experimental therapies: Interferon-, antifibrotic and antiangiogenic drugs (anagrelide, suramin, pirfenidone, thalidomide,)

20. MYELOFIBROSIS- prognosis - a median survival of 3,5 to 5,5 years - the principal causes of death are infections, thrombohemorrhagic events, heart failure, and leukemic transformation - leukemic transformation occurs in approximately 20% of patients during first 10 years

21. ESSENTIAL THROMBOCYTHEMIA (ET) ET is a clonal myeloproliferative disorder characterized by bone marrow hyperplasia with excessive proliferation of megakaryocytes and sustained elevation of the platelet count.

22. ESSENTIAL THROMBOCYTHEMIAclinical picture 1. Thrombotic complications (intermittent or permanent occlusion of small blood vessels) • transient cerebral and ocular ischemic episodes that may progress to infarction • peripheral arterial occlusive disease associated with „erythromelalgia”(intermittent, painful errythema and cyanosis of the fingers and toes 2. Hemorrhagic complications - bleeding after surgery and spontaneus upper gastrointestinal bleeding (the hemorrhagic tendency is worsened if nonsteroidal anti-inflammatory agent are administered 3. Splenomegaly - 20-50% patients 4. Hepatomegaly - rarely

23. ESSENTIAL THROMBOCYTHEMIAlaboratory findings • Thrombocytosis (in most patients patients>1000 G/l) • Numerous thrombocyte aggregates in peripheral blood smear • Leukocytosis, usually less than 20G/l • Neutrophilia and a mild shift to the left(usually to metamyelocyte) • Slight eosinophilia and basophilia • Marked hyperplasia of the megakaryocytes in the bone marrow

24. ESSENTIAL THROMBOCYTHEMIA(UPDATED DIAGNOSTIC CRITERIA) 1. Platelets count> 600 G/l 2. Ht<40%, or normal RBC mass(males< 36mL/kg, females<32 mL/kg) 3. Stainable iron in marrow or normal serum ferritin or normal mean corpuscular volume (MCV) 4. No Philadelphia chromosome or bcrr/abl gene reagement 5. Collagen fibrosis of marrow A. Absent or B. < 1/3 biopsy area without both marked splenomegaly and leukoerythroblastic reaction 6. No cytogenetic or morphologic evidence for myelodysplastic syndrome (5q-) 7. No cause for reactive thrombocytosis

25. ESSENTIAL THROMBOCYTHEMIA-THERAPY 1. No treatment- asymptomatic( without thrombotic and bleeding complications), young (< 60 r.ż.) patients with platelet count<1000G/L 2. Cytoreductive therapy – patients with platelet count>1000 G/L, especially for these with previous thrombotic or bleeding problems - hydroxyurea at doses 15-30mg/kg,, to maintein platelet count between 400-600 G/l 3. Anti-aggregating therapy: Aspirin 75-150mg/d  dipyridamol for older patients and/or with a cardiovascular risk 4. Anagrelide (Agrylin)- drug that produces selective platelet cytoreduction, and it also inhibits platelet activation  doses from 0,5mg every 6 hours, to max. 10 mg/d ) 5. Interferon-: 3 million units/d s.c.