Myeloproliferative Neoplasms.pdf

Myeloproliferative neoplasms (MPNs) ILOs At the end of this session, the student will be able to: ▪ Define Myeloproliferative neoplasms (MPN). ▪ Identify the underlying pathogenetic mechanism of MPN. ▪ Enumerate WHO classification of MPN. ▪ Differentiate between var...

Myeloproliferative neoplasms (MPNs) ILOs At the end of this session, the student will be able to: ▪ Define Myeloproliferative neoplasms (MPN). ▪ Identify the underlying pathogenetic mechanism of MPN. ▪ Enumerate WHO classification of MPN. ▪ Differentiate between varies causes of MPN according to the laboratory features ▪ Mention the different causes of Polycythemia and reactive thrombocytosis. ▪ Mention the WHO diagnostic criteria of essential thrombocythemia and Primary myelofibrosis. ▪ Describe the clinical picture and diagnostic approach to essential thrombocythemia and Primary myelofibrosis. ▪ Outline the treatment options for ET and PMF. ▪ Discuss the course and prognosis of ET and PMF. General Considerations Myeloproliferative disorders are due to acquired clonal abnormalities of the hematopoietic stem cell. Since the stem cell gives rise to myeloid, erythroid, and platelet cells, qualitative and quantitative changes are seen in all of these cell lines. Classically, the myeloproliferative disorders produce characteristic syndromes with well-defined clinical and laboratory features. However, these disorders are grouped together because they may evolve from one into another and because hybrid disorders are commonly seen. All of the myeloproliferative disorders may progress to AML. Constitutive tyrosine kinase activation appears to be a common patho-genetic mechanism. The Philadelphia chromosome seen in chronic myeloid leukemia (CML) was the first recurrent cytogenetic abnormality to be described in a human malignancy. Since that time, there has been tremendous progress in elucidating the genetic nature of these disorders, with identification of mutations in JAK2, MPL, CALR, CSF3R, and other genes. The JAk2 gene What is the normal function of the JAK2 gene? The JAK2 gene provides instructions for making a protein that promotes the growth and division (proliferation) of cells. This protein is part of a signaling pathway called the JAK/STAT pathway, which transmits chemical signals from outside the cell to the cell's nucleus. The JAK2 protein is especially important for controlling the production of blood cells from hematopoietic stem cells. Incidence of JAK-2 mutations World Health Organization classification of myeloproliferative disorders  Laboratory features of myeloproliferative neoplasms. Focus on: Polycythemia vera (PV) Essential thrombocythemia (ET) Primary myelofibrosis (PMF) Polycythemia (erythrocytosis) Defined as: an increase in hemoglobin concentration above the upper limit of normal for the patient's age & sex. Causes of Polycythemia (I) Absolute (Increase in the red cell mass) (1) Primary (Polycythemia vera= PV). (2) Secondary … caused by the following: Appropriate increase in erythropoietin Inappropriate increase in erythropoietin Appropriate increase in erythropoietin 1- Pulmonary disease and alveolar hypoventilation. 2- Congenital cyanotic heart disease. 3- Increased affinity hemoglobin (familial polycythemia). 4- Heavy cigarette smoking. Inappropriate erythropoietin increase 1- Renal diseases: hydronephrosis, Renal artery stenosis, renal cysts, renal carcinoma. 2-Uterine fibromyoma. 3-Hepatocellular carcinoma.  4-Cerebellar hemangioblastoma. (II) Relative or stress or pseudo polycythemia (normal red cell mass and reduced plasma volume) (1) Dehydration: Water deprivation, vomiting (2) Plasma Loss: Burns, enteropathy (severe diarrhea). Essential Thrombocythemia ET is the most common MPN. The median age at diagnosis is about 60 years, although the diagnosis is increasingly made in younger adults. Women > men by 1.5–2-fold, particularly among those diagnosed in the third to fifth decade of life. 2016 WHO Criteria for Essential thrombocythemia (ET) Major criteria: Platelet count ≥ 450 X 10⁹/L Bone marrow biopsy → proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left-shift of neutrophil granulopioesis or erythropoiesis and very rarely minor increase in reticulin fibers. Not meeting WHO criteria of BCR-ABL-1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms. Presence of JAK-2, CALR or MPL mutation. Minor criteria: Presence of a clonal marker or absence of evidence of reactive thrombocytosis For diagnosis of ET: All 4 major criteria OR The first 3 major criteria+ one of the minor criteria Causes of reactive thrombocytosis Iron deficiency Blood loss (acute or chronic) Hyposplenism/splenectomy Surgery  Chronic inflammation Vasculitis Inflammatory bowel disease Connective tissue disorders Chronic infections Malignancies Rebound thrombocytosis Following treatment of ITP Recovery from chemotherapy Drugs-----Vincristine Clinical features 1-Vasomotor “Vascular” headaches, visual disturbances, dizziness, burning dysesthesia of the palms and soles, acrocyanosis, paresthesias, cutaneous ulcers, cognitive or psychiatric deficits, seizures 2-Thrombotic Arterial: cerebral (TIA, CVA), coronary, ophthalmic, distal/extremities Venous: deep extremities, pelvic, mesenteric, hepatic, portal 3-Hemorrhagic Gastrointestinal, mucosal, epistaxis, urogenital, deep hematoma, hemarthrosis 4-Obstetric First trimester, spontaneous abortion, fetal growth retardation, premature delivery, placental abruption. 5-Splenomegaly: in 50% of patients Laboratory Investigations (1) Blood film: Abnormal large platelets and megakaryocyte fragments. (2) Bone marrow trephine biopsy: hypercellular bone marrow with excess abnormal megakaryocytes. (3) Cytogenetics and molecular analysis:  BCR –ABL fusion gene analysis → mandatory to exclude CML. JAK2 mutation analysis: +ve in 60% of cases.. (4) Abnormal platelet function tests → failure of aggregation with adrenaline. Treatment The aim of treatment: To control platelet count and to reduce the risk of thrombosis: (1) Hydroxyurea: to control platelet count 11 X 109/L. Palpable splenomegaly LDH increased above upper limit of normal Leukoerythroblastosis For diagnosis of PMF: All 3 major criteria + minor criteria. Clinical Features (1) The onset is insidious in older people with symptoms of anemia (2) Symptoms resulting from massive splenomegaly (abdominal discomfort, pain, or indigestion) (3) Hypermetabolic features such as loss of weight, anorexia, fever, and night sweats. (4) Bleeding manifestations, bone pain or gout may occur (5) Splenomegaly is the main physical finding. Laboratory Investigations (1) Anemia is usual but normal or increased Hb level may be found in some patients. (2) The WBC and platelet counts are frequently high at presentation. Later in the course of the disease, leukopenia and thrombocytopenia are common. (3) A leukoerythroblastic blood picture is found. The red cells show characteristic “tear – drop” appearance. (4) Bone marrow is unobtainable (dry tap) by aspiration, trephine biopsy shows fibrotic hypercellular marrow and increased number of megakaryocytes are frequent. In 10% of the cases, there is increased bone formation with increased bone density on X- ray (Myelosclerosis) (5) Low serum and red cells folate. (6) Raised serum B12 and vitamin B12 – binding capacity. (7) NAP score is normal. (8) High serum uric acid and LDH levels reflect the increased turnover of hematopoietic cells. (9) JAK2 mutation analysis: +ve in 60% of cases.  The red cells show characteristic “tear fibrotic hypercellular marrow with – drop” appearance. increased number of megakaryocytes Treatment This is palliative and aims at reducing the effects of anemia and splenomegaly Blood Transfusion and folic acid tablets are used for treatment of anemia. Hydroxyurea may help to reduce splenomegaly and hypermetabolic symptoms. Splenectomy for severe symptomatic splenomegaly → mechanical discomfort, thrombocytopenia, portal hypertension, excessive transfusion requirements or hypermetabolic symptoms. Splenic irradiation is an alternative but provides relief for 3-6 months. Allopurinol is used to prevent gout and urate nephropathy from hyperuricemia. Allogeneic stem cell transplantation may be curative in young patients. JAK2 inhibitors (Ruxolitinib) Course & prognosis The median survival is around 3.5 years. Causes of death include:- (1) Heart Failure. (2) Infection. (3) Leukemic transformation. Transformation to acute myeloid leukemia occurs in 10 – 20% of patients.