MYELOPROLIFERATIVE DISORDERS in Uganda system

It’s a pdf slide teaching and basically explaining myeloproliferative disorders in a way that is simplified

1. MYELOPROLIFERATIVE DISORDERS ECIK CHRISTOPHER(SHO) 2/4/2025 1

2. Outline Introduction Polycythemia Primary polycythemia (PV) Essential thrombocythemia Primary myelofibrosis Conclusion References 2/4/2025 2

3. Introduction-functional physiology 2/4/2025 3

4. Introduction All blood cells are derived from pluripotent haematopoietic stem cells. Myeloproliferative disorders are clonal stem cell disorders. They are characterized by uncontrolled proliferation of one or more of the cell lines in the bone marrow, usually erythroid , myeloid and/or megakaryocyte lines. 2/4/2025 4

5. Myeloproliferative disorders(MPDs) Polycythemia vera(PV) Essential Thrombocythemia(ET) Primary myelofibrosis(PMF) chronic myeloid leukemia (CML) 2/4/2025 5

6. All have a mutation in the gene on chromosome 9 encoding the signal transduction molecule JAK-2 (JAK-2 V617F) except CML. More than 90% of PV cases, and 50% of those with ET and PMF. 2/4/2025 6

7. Introduction.. They have a capacity for extramedullary hematopoiesis due to circulating neoplastic cells in hematopoietic organs; spleen, Lymph nodes, liver. Grouped together, as there can be transition from one disease to another. There is overproduction of blood cell lines without significant dysplasia . Transformation to acute leukemia is uncommon in the absence of chemotherapy(non-leukemic) 2/4/2025 7

8. 2/4/2025 8

9. Polycythemia vera Polycythemia (or erythrocytosis) is defined as an increase in hemoglobin, packed cell volume (PCV) and red cell count . Relative erythrocytosis is where the red cell volume is normal but there is a decrease in the plasma volume. E.g in stress and dehydration. Can be classified as primary polycythemia (PV) or secondary polycythemia. Secondary polycythemia can be congenital or acquired . 2/4/2025 9

10. Causes of congenital secondary polycythemia Mutations in erythropoietin receptor. High-oxygen-affinity hemoglobins . Mutations in hypoxia-sensing pathways, e.g. Chuvash polycythemia mutation in von Hippel–Lindau gene. 2/4/2025 10

11. Causes of acquired secondary polycythemia Due to an appropriate (hypoxic) increase in erythropoietin • High altitude • Chronic lung disease • Cardiovascular disease (right-to-left shunt) • Sleep apnea • Morbid obesity • Heavy smoking Due to an inappropriate increase in erythropoietin • Renal disease: renal cell carcinoma, Wilms' tumor • Hepatocellular carcinoma • Adrenal tumors • Cerebellar hemangioblastoma • Massive uterine leiomyoma • Over-administration of erythropoietin • Treatment with androgen preparations. 2/4/2025 11

12. PRIMARY POLYCYTHEMIA (Polycythemia vera(PV) 2/4/2025 12

13. Polycythemia vera (PV) is a clonal stem cell disorder in which there is an excessive proliferation of erythroid, myeloid and/or megakaryocytic progenitor cells. PV is distinguished clinically from the other MPNs by the presence of an elevated red blood cell mass . However this is not enough to define PV because elevated red blood cell mass is also seen in hypoxia. 2/4/2025 13

14. Over 95% of patients with PV have acquired mutations of the gene Janus kinase 2 (JAK2). JAK2 is a cytoplasmic tyrosine kinase that transduces signals by growth factors such as erythropoietin. In PV, RBC production proceeds independently of erythropoietin levels. 2/4/2025 14

15. Epidemiology It is the most common of the myeloproliferative disorders; PV occurs in all populations, and all ages but occasionally in children. The median age at diagnosis is approximately 60 years . The incidence of PV was slightly higher in men than women (2.8 versus 1.3 cases/100,000 per year) and is highest for men aged 70 to 79 years (24 cases/100,000 persons per year) in a cohort study in minnesota. 2/4/2025 15

16. Clinical features Most patients with PV are discovered incidentally when an elevated hemoglobin or hematocrit is noted on a CBC. Isolated thrombocytosis, leukocytosis , or splenomegaly may be its initial presenting manifestation. 2/4/2025 16

17. Aquagenic pruritus. Uncontrolled erythrocytosis causes hyper -viscosity; neurologic symptoms; -vertigo, -tinnitus, -headache, -visual disturbances, and -(TIAs), -systolic hypertension. 2/4/2025 17

18. Disease-related symptoms; headache, dizziness, visual disturbances, early satiety) complications ( e.g , thrombosis, bleeding) 2/4/2025 18

19. venous or arterial thrombosis; may be the presenting manifestation of PV. cerebral, cardiac mesenteric vessels are most commonly involved . Hepatic venous thrombosis ( Budd-Chiari syndrome ) 2/4/2025 19

20. Digital ischemia, easy bruising. Acid-peptic disease, or gastrointestinal hemorrhage may occur due to vascular stasis or thrombocytosis. Erythromelalgia ( Erythema, burning, and pain in the extremities, is due to increased platelet stickiness. Hyperuricemia with secondary gout, uric acid stones , due to large turnover of hematopoietic cells. By Herbert L. Fred, MD and Hendrik A. van Dijk - http://cnx.org/content/m14932/latest/, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5038143 2/4/2025 20

21. Acquired von Willebrand disease may be present; likely due to increased binding of large von Willebrand factor multimers to the platelets and their removal from the plasma. Such patients may have increased bleeding, especially when treated with aspirin. 2/4/2025 21

22. Diagnosis With erythrocytosis + leukocytosis + thrombocytosis , or splenomegaly or any combination of these, the diagnosis is apparent. But elevated hemoglobin, hematocrit, or red cell count alone, the diagnostic evaluation is more complex because of the many diagnostic possibilities. CBC; microcytic erythrocytosis, elevated RDW due to associated iron deficiency. 2/4/2025 22

23. Peripheral smear ; excess of normochromic, normocytic red blood cells. Testing for JAK2 mutations Sometimes bone marrow examination; hypercellularity for age and trilineage growth with prominent erythroid, granulocytic, and megakaryocytic proliferation serum erythropoietin level normal or low normal. Use of WHO criteria 2/4/2025 23

24. WHO Criteria for polycythemia Vera MAJOR CRITERIA MINOR CRITERIA 1 Haemoglobin >16.5g/dl in men subnormal serum erythropoietin level Haemoglobin >16 g/dl in women 0r Hematocrit>49% in men Hematocrit >48% in women or Or Increased Red cell mass 2 Bone marrow biopsy showing hypercellurity for age with trilineage(panmyelosis) including prominent erythroid,granulocytic and megakaroctic proliferation with pleomorphic, mature megakaryocytes(differences in size) 3 Presence of JAK2 V617F or JAK2 exon 12 mutation Diagnosis of PV; 3 major criteria or 2 major and minor 2/4/2025 24

25. Management Management of PV is guided by the risk for thrombosis, as follows: Low risk  – Age ≤60 years  and  no history of thrombosis patients with low-risk PV, low-dose aspirin plus periodic phlebotomy to control hematocrit ( Hct ) rather than cytoreductive therapy High risk  – Age >60 years  or  history of thrombosis. Treatment of high-risk PV includes a cytoreductive agent plus low-dose aspirin . 2/4/2025 25

26. Treatment The mainstays of treatment for all patients with PV are; control of red blood cell (RBC) mass, symptom control, and prevention of PV-associated complications. 2/4/2025 26

27. Control red blood cell mass; Venesection/phlebotomy cytoreductive therapy-hydroxyurea(Dosing based on 15 to 20 mg/kg per day, using the patient's actual body weight. 500 mg twice daily by mouth is the typical starting dose. Hematocrit of <45% as target . 2/4/2025 27

28. 2. Low-dose aspirin Efficacy for alleviating microvascular symptoms, reducing deaths from CV and thromboembolic causes, and safety. Low-dose  aspirin  refers to doses of 40 to 100 mg per day. phase 3 ECLAP (European Collaboration on Low-Dose Aspirin in Polycythemia Vera) trial. achieved a reduction in the combined endpoint of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from CV causes. 2/4/2025 28

29. 3. Pegylated interferon( IFNa ) Pegylated IFN- α( PEG) 100 mcg is given subcutaneously once every two weeks, and the dose is increased by 50 mcg every two weeks to a maximum of 500 mcg until hematologic parameters are stabilized ( ie , Hct <45 percent, platelets <400,000/ microL , and leukocytes <10,000/. microL .  A phase 3 trial (MPD-RC 112) and  phase 3 PROUD/CONTINUATION-PV trials found that  hydroxyurea  and IFNa achieved similar outcomes in patients with PV. Primary end point was complete response at 12 months(platelet count <400 × 10 9 /L, hematocrit <45% without phlebotomy for patients with PV only, white blood cell count <10 × 10 9 /L, resolution of splenomegaly, and resolution of disease-related symptoms (microvascular disturbances, headache, and pruritus) 2/4/2025 29

30. 4. Ruxolitinib   A Janus associated kinase inhibitor ( JAKi ) Ruxolitinib is given orally at doses up to 20 mg twice daily, and dosing is adjusted for efficacy and tolerance. open-label trial (RESPONSE) ; Compared with BAT,  ruxolitinib  was more effective for reducing the number of patients who needed phlebotomy 2/4/2025 30

31. Treatment of complications: Hyperuricemia should be treated with allopurinol 300 mg po once/day Pruritus may be managed with antihistamines but is often difficult to control; myelosuppression often is most effective. Cholestyramine 4 g po tid , cyproheptadine 4 mg po tid to qid , cimetidine 300 mg po qid , or paroxetine 20 to 40 mg po once/day may be successful Erythromelalgia - relieved by Aspirin 2/4/2025 31

32. Prognosis Prognostic factors; Older age, control of hematocrit ( Hct ), leukocytosis, and Thrombosis 2/4/2025 32

33. Prognosis Median overall survival (OS) is at least 13 years in patients who receive treatment for PV. Thromboembolic events are the major cause of morbidity and mortality in PV. A major cause of death in PV is disease transformation to post-PV myelofibrosis (MF) and/or evolution to AML/myelodysplastic syndromes/neoplasms (MDS). Post-PV MF occurs in 12 to 21 percent of patients with PV. 2/4/2025 33

34. ESSENTIAL THROMBOCYTHEMIA 2/4/2025 34

35. Also called essential thrombocytosis and primary thrombocytosis. It is characterized by excessive, clonal platelet production with a tendency for thrombosis and haemorrhage. It is a clonal hematopoietic stem cell disorder associated with mutations in JAK2 (V617F), MPL, or CALR and manifested clinically by overproduction of platelets without a definable cause. 2/4/2025 35

36. Pathogenesis Platelet production is increased . Platelet survival is usually normal , although it may decrease due to splenic sequestration and in patients with erythromelalgia with digital ischemia. Thrombosis is the major cause of morbidity and mortality. Recent studies indicate that an elevated leukocyte count is a major independent risk factor for thromboses. Bleeding is more likely with extreme thrombocytosis ( ie , > 1.5 million platelets/ μL ) due to an acquired von Willebrand's factor deficiency . 2/4/2025 36

37. Clinical features Up to one-half of patients with ET are discovered incidentally when thrombocytosis is noted on a complete blood count obtained for some other reason. Common symptoms are; • Weakness • Hemorrhage • Gout • Ocular migraines • Paraesthesia's of the hands and feet vasomotor symptoms Headache Syncope Atypical chest pain Livedo reticularis Erythromelalgia (burning pain of the hands or feet associated with erythema and warmth) 2/4/2025 37

38. Thrombosis may cause symptoms in the affected site ( e.g , neurologic deficits with stroke or transient ischemic attack, leg pain, swelling or both with lower extremity thrombosis, chest pain and dyspnea with pulmonary embolism). Bleeding is usually mild and manifests as epistaxis, easy bruisability, or GI bleeding. Digital ischemia may occur. Splenomegaly (usually not extending > 3 cm below the left costal margin) occurs in < 50% of patients. Hepatomegaly may rarely occur. Recurrent spontaneous abortions . 2/4/2025 38

39. Diagnosis CBC and peripheral blood smear; ET is characterized by marked thrombocytosis in the peripheral blood. The platelets vary in size ( platelet anisocytosis ), ranging from very small to giant platelets. The leukocyte differential is usually normal. Basophils are absent or minimal. A leucoerythroblastic picture with teardrop-shaped red blood cells ( dacryocytes ), poikilocytosis, and circulating nucleated red cells suggests transformation to a post-ET myelofibrosis stage. 2/4/2025 39

40. Bone marrow aspiration and biopsy classically shows normocellularity or moderate hypercellularity for age. Trilineage growth with prominent large to giant megakaryocytes with abundant mature cytoplasm, and deeply lobulated and hyper lobulated nuclei. 2/4/2025 40

41. Genetic features The vast majority of patients with ET demonstrate mutually exclusive mutations in  JAK2 ,  MPL , or  CALR .  JAK2  mutation – 60 to 65 percent CALR  mutation – 20 to 25 percent MPL  mutation – 5 percent No  JAK2 ,  CALR , or  MPL  mutation ("triple negative") – 10 to 15 percent Differentiate patients with myeloproliferative neoplasm-associated thrombocytosis from those with reactive thrombocytosis . Does not allow differentiation among ET, polycythemia vera, and primary myelofibrosis. 2/4/2025 41

42. World Health Organization 5 th  edition diagnostic criteria Major criteria: Platelet count ≥450 x 10 9 /L (≥450,000/ microL ) Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyper-lobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers. Criteria for  BCR::ABL1 -positive chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, myelodysplastic syndrome, or other myeloid neoplasm not met Demonstration of a  JAK2 ,  CALR , or  MPL  mutation Minor criterion: Demonstration of another clonal marker ( ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2 , or  SRF3B1  mutation)  or  no identifiable cause of thrombocytosis ( eg , infection, inflammation, iron deficiency anemia) Requires all four of the following major criteria or the first three major criteria plus the minor criterion. 2/4/2025 42

43. Prognosis Life expectancy is near normal . Although symptoms are common, the course of the disease is often benign . Serious arterial and venous thrombotic complications are rare but can be life-threatening. Leukemic transformation occurs in < 2% of patients but may increase after exposure to cytotoxic therapy, especially alkylating agents. 2/4/2025 43

44. Treatment Low risk patients (<40 yrs , PLT <1500X109 and no bleeding or thrombosis) may not require treatment to reduce the platelet count. For those with a platelet count above 1500 × 10 9 /L, with symptoms, or with other risk factors for thrombosis such as diabetes or hypertension; treatment is required. 2/4/2025 44

45. TREATMENT Aspirin- For mild vasomotor symptoms ( e.g , headache, mild digital ischemia, erythromelalgia) and to decrease the risk of thrombosis in low-risk patients, aspirin 81 mg po once/day may be sufficient. Platelet-lowering drugs ( eg , hydroxyurea, anagrelide)- indications for such therapy are. Previous thrombosis or transient ischemic attack Age > 60 yr interferon-alfa has a role in younger patients, including pregnant women and women planning to conceive. Rarely plateletpheresis 2/4/2025 45

46. Causes of Secondary Thrombocythemia Chronic inflammatory disorders, e.g , RA, inflammatory bowel disease, TB, sarcoidosis, Wegener's Acute infection Hemorrhage Iron deficiency Hemolysis Cancer (particularly Hodgkin lymphoma, non-Hodgkin lymphoma) Splenectomy Myeloproliferative and hematologic disorders ( e.g , polycythemia vera, chronic myelocytic leukemia, sideroblastic anemia, myelodysplasia [5q- syndrome], idiopathic myelodysplasia) There are also congenital familial thrombocytoses such as those due to thrombopoietin and thrombopoietin receptor gene mutations. 2/4/2025 46

47. Platelet function is usually normal. Unlike ET, thrombocytosis does not increase the risk of thrombotic or haemorrhagic complications unless patients have severe arterial disease or prolonged immobility. With secondary thrombocytosis, the platelet count is usually < 1,000,000/ μL , and the cause may be obvious Treatment of the underlying disorder usually returns the platelet count to normal. 2/4/2025 47

48. PRIMARY MYELOFIBROSIS 2/4/2025 48

49. Aka Angiogenic Myeloid Metaplasia; Myelofibrosis with Myeloid Metaplasia ) Primary myelofibrosis (PMF) is a chronic, usually idiopathic disorder characterized by bone marrow fibrosis, splenomegaly, and anemia with immature and teardrop-shaped RBCs. JAK2 V617F is present in ∼55% of PMF patients, and mutations in the thrombopoietin receptor, MPL, occur in ∼4%. 2/4/2025 49

50. PMF is the least frequent among the chronic myeloproliferative diseases The peak incidence of PMF is between 50 and 70 yr. linked to exposure to thorium dioxide, petroleum manufacturing plants (especially toluene and benzene), and ionizing radiation .  A very high incidence in individuals exposed to atomic bombs at Hiroshima. 2/4/2025 50

51. Pathophysiology The marrow is initially hypercellular, with an excess of abnormal megakaryocytes that release growth factors, such as platelet-derived growth factor, to the marrow microenvironment, This results in a reactive proliferation of fibroblasts. As the disease progresses, the marrow becomes fibrosed. PMF is more common than secondary myelofibrosis and results from neoplastic transformation of a multipotent bone marrow stem cell. These PMF progeny cells stimulate bone marrow fibroblasts to secrete excessive collagen. 2/4/2025 51

52. In PMF, large numbers of nucleated RBCs (normoblasts) and granulocytes are released into the circulation ( leukoerythroblastosis Bone marrow failure eventually occurs, with consequent anemia and thrombocytopenia. Rapidly progressive, chemotherapy-incurable acute leukemia develops in about 10% of patients. 2/4/2025 52

53. Clinical features 15-30% are asymptomatic The most common presenting complaint in PMF is that of severe fatigue, occurring in 50 to 70 percent of patients. An enlarged spleen have been described in 25 to 50 percent of patients. Weight loss ,lassitude, and night sweats And 5 to 20 percent experience other signs of a hypermetabolic state such as low grade fever, bone pain, and night sweats. 2/4/2025 53

54. Diagnosis made during investigation of splenomegaly (occurring in at least 90 percent of patients), hepatomegaly (40 to 70 percent), or abnormal blood findings. Enlargement of the spleen and liver are due to the marked extramedullary hematopoiesis associated with PMF. 2/4/2025 54

55. Splenomegaly, often marked, is the hallmark of PMF. Symptoms due to splenic disease often figure prominently in PMF. dragging or heavy sensation in the left upper abdomen. Early satiety due to compression of the stomach. Severe left upper quadrant pain, with or without left shoulder pain(splenic infarction or inflammation of the tissues surrounding the spleen ). 2/4/2025 55

56. Hepatomegaly, Palpable hepatomegaly is present in 40 to 70 percent of patients Portal hypertension may develop as a result of increased splanchnic blood flow due to splenomegaly Complications include ascites, esophageal and gastric varices, gastrointestinal bleeding, and hepatic encephalopathy. Portal vein thrombosis is a recognized complication of PMF 2/4/2025 56

57. Extramedullary hematopoiesis; Foci of extramedullary hematopoiesis may occur in almost any organ. splenomegaly, hepatomegaly, lymphadenopathy; pleural, pericardial, or abdominal effusions. Bone and joint involvement   osteosclerosis is characterized by a diffuse or patchy increase in bone density Periostitis can lead to debilitating bony pain. Secondary gout due to chronic overproduction of uric acid. 2/4/2025 57

58. Diagnosis CBC and peripheral blood smear Anemia with hemoglobin less than 10 g/dL is seen in approximately 50 percent of patients with PMF, and 20 percent present with a hemoglobin less than 8 g/dl. The peripheral smear is quite characteristic, showing anisocytosis (i.e., RBCs of varying size), poikilocytosis ( ie , RBCs of varying shape), teardrop-shaped RBCs (dacrocytes), nucleated RBCs, and variable degrees of polychromasia. 2/4/2025 58

59. Bone marrow examination Bone marrow biopsy is necessary to demonstrate fibrosis  Bone marrow sinusoids are expanded and there is intravascular hematopoiesis.  Atypical megakaryocytic hyperplasia and thickening and distortion of the bony trabeculae (osteosclerosis) 2/4/2025 59

60. WHO diagnostic criteria overt primary myelofibrosis Major criteria: Megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3. WHO criteria for polycythemia vera (PV), essential thrombocythemia (ET), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or other myeloid neoplasm not met. Demonstration of a  JAK2 ,  CALR , or  MPL  mutation  or  another clonal marker ( ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2 , or  SR3B1  mutation)  or  no identifiable cause of reactive fibrosis ( eg , infection, autoimmune disorder, chronic inflammatory disorder, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or chronic toxic myelopathy). Minor criteria  (confirmed in two consecutive measurements): Anemia not attributable to a comorbid condition Leukocytosis ≥11 x 10 9 /L (>11,000/ microL ) Palpable splenomegaly LDH above the upper limit of normal Leukoerythroblastosis Diagnosis of overt PMF requires all three of the following major criteria and at least one minor criterion 2/4/2025 60

61. Clues to diagnosis Anemia is typically present and usually increases over time. Blood cell morphology is variable. RBCs are poikilocytic . teardrop-shaped RBCs ( dacryocytes ) are characteristic morphologic features. Reticulocytosis and polychromatophilia may be present; Nucleated RBCs and neutrophil precursors are typically present in peripheral blood. 2/4/2025 61

62. Clues to diagnosis CONT; WBC counts are usually increased but are highly variable; A low WBC count tends to indicate a poor prognosis . Neutrophils are usually immature , and myeloblasts may be present, even in the absence of acute leukaemia. Platelet counts initially may be high, normal, or decreased ; however, thrombocytopenia tends to supervene as the disorder progresses. If diagnosis is difficult, CD34+ cell count on peripheral blood can be done Bone marrow aspiration is usually dry. 2/4/2025 62

63. Treatment The goals of management of myelofibrosis are to relieve symptoms, prevent complications, and prolong survival. Prognosis is generally poor. Treatment of MF is guided by prognosis. Prognostic classification as high risk PMF or low risk PMF. patients with higher-risk MF, allogeneic HCT rather than symptom-directed therapy is preferred. Folic acid should be given to prevent deficiency. 2/4/2025 63

64. Treatment 1. Symptomatic therapy Treatment is directed at symptoms and complications. Androgens, splenectomy, chemotherapy, and splenic embolization and radiation therapy have been used for palliation.   Danazol  is a synthetic androgen that improves anemia in one-third of patients with PMF. For patients with low erythropoietin levels relative to the degree of anemia , erythropoietin may increase Hct sufficiently; otherwise, RBC transfusion may be necessary. 2/4/2025 64

65. For patients with symptomatic splenomegaly and no associated anemia , hydroxyurea   rather than a JAKi is preffered , based on efficacy and little toxicity. Inhibitors of the JAK pathway, Ruxolitinib (JAK inhibitor) is a recently approved drug for treating symptomatic PMF that also reduces splenomegaly and abnormal peripheral hematologic abnormalities. The initial dose of   ruxolitinib   is guided by the baseline platelet count: 20 mg twice daily for a platelet count >200,000/ microL 15 mg twice daily for a platelet count between 100,000 and 200,000/ microL 5 mg twice daily for a platelet count between 50,000 and <100,000/ microL 2/4/2025 65

66. Ruxolitinib demonstrated superiority over BAT in a phase 3 controlled myelofibrosis study. The COMFORT II trial. Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment II (COMFORT-II), a randomized, phase 3 trial N Engl J Med 2012; 366:787-798 DOI: 10.1056/NEJMoa1110556 2/4/2025 66

67. Pacritinib  was more effective than best available therapy (BAT) for relieving symptoms in patients with MF with thrombocytopenia in the phase 3 PERSIST-2 trial. Study in patients with advanced myelofibrosis who were intolerant of or had become resistant to Ruxolitinib. Pacritinib is given 200 mg twice daily by mouth, with or without food. 2/4/2025 67

68. 2. Bone marrow transplant is the only cure Allogeneic stem cell transplantation ; For younger patients with advanced disease, allogeneic stem cell transplantation should be considered. Non-myeloablative allogeneic stem cell transplantation has been successfully used even in older patients; but is usually limited to patients < 65 yr. 2/4/2025 68

69. Prognosis The median survival is 5 yr from onset, Unfavorable prognostic markers include Hb < 10 g/ dL , history of transfusions, leukocytosis and leukopenia , and platelet count < 100,000/ μL . Patients in the least favorable risk group usually survive < 1 yr. No treatment reverses or controls the underlying process except for allogeneic stem cell transplant. 2/4/2025 69

70. CONCLUSION PMF carries the worst prognosis among the MPNs, although survival is still measured in years PV and ET can show gradual progression to secondary myelofibrosis over decades. 2/4/2025 70

71. References Barbui , T., Vannucchi , A. M., De Stefano, V., Masciulli , A., Carobbio , A., Ferrari, A., Ghirardi , A., Rossi, E., Ciceri , F., Bonifacio, M., Iurlo , A., Palandri , F., Benevolo , G., Pane, F., Ricco, A., Carli, G., Caramella , M., Rapezzi , D., Musolino , C., Siragusa, S., … Rambaldi , A. (2021). Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre , randomised phase 2 trial.  The Lancet. Haematology ,  8 (3), e175–e184. https://doi.org/10.1016/S2352-3026(20)30373-2 Vannucchi , A. M., Kiladjian , J. J., Griesshammer , M., Masszi , T., Durrant , S., Passamonti , F., Harrison, C. N., Pane, F., Zachee , P., Mesa, R., He, S., Jones, M. M., Garrett, W., Li, J., Pirron , U., Habr , D., & Verstovsek , S. (2015). Ruxolitinib versus standard therapy for the treatment of polycythemia vera.  The New England journal of medicine ,  372 (5), 426–435. https://doi.org/10.1056/NEJMoa1409002 Mascarenhas , J., Kosiorek , H. E., Prchal, J. T., Rambaldi , A., Berenzon , D., Yacoub, A., Harrison, C. N., McMullin, M. F., Vannucchi , A. M., Ewing, J., O'Connell, C. L., Kiladjian , J. J., Mead, A. J., Winton, E. F., Leibowitz, D. S., De Stefano, V., Arcasoy , M. O., Kessler, C. M., Catchatourian , R., Rondelli , D., … Hoffman, R. (2022). A randomized phase 3 trial of interferon- α vs hydroxyurea in polycythemia vera and essential thrombocythemia.  Blood ,  139 (19), 2931–2941. https://doi.org/10.1182/blood.2021012743 Kröger , N., Giorgino , T., Scott, B. L., Ditschkowski , M., Alchalby , H., Cervantes, F., Vannucchi , A., Cazzola , M., Morra , E., Zabelina , T., Maffioli , M., Pereira, A., Beelen , D., Deeg , H. J., & Passamonti , F. (2015). Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis.  Blood ,  125 (21), 3347–3364. https://doi.org/10.1182/blood-2014-10-608315 2/4/2025 71

72. Ref.. Overview of the myeloproliferative neoplasms; https://www.uptodate.com/contents/overview-of-the-myeloproliferative-neoplasms?source=mostViewed_widget Davidsons principles and practice of medicine, 24 th edition ,chapter 25,myloproliferative disorders page 979. Harrisons principles of internal medicine 21 st edition, Chapter 103,Polycythemia Vera and Other Myeloproliferative Neoplasms by Jerry L. Spivak. Mascarenhas J, Hoffman R,  Talpaz M, et al. Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial.  JAMA Oncol.  2018;4(5):652–659. doi:10.1001/jamaoncol.2017.5818 2/4/2025 72