2.Myeloproliferative disorders.pdf

Myeloproliferative disorders Clonal neoplastic disorder of pluripotent haematopoietic stem cell characterized by excessive proliferation of one or more of the myeloid cell lineages – Granulocytic – Erythroid – Megakaryocytic Relatively normal maturation  Stem Ce...

Myeloproliferative disorders Clonal neoplastic disorder of pluripotent haematopoietic stem cell characterized by excessive proliferation of one or more of the myeloid cell lineages – Granulocytic – Erythroid – Megakaryocytic Relatively normal maturation  Stem Cell Basis of Hematopoiesis Stem cells Progenitors Blood Normal Myeloproliferative disease  Myeloproliferative disorders WHO Classification of CMPD Ch Myeloid leukemia Ch Neutrophillic leukemia Ch Eosinophillic leukemia / Hyper Eo Synd Polycythemia Vera Essential Thrombocythemia Myelofibrosis CMPD unclassifiable Myeloproliferative disorders MPD PRV CML AML ET MF CMML MDS RA RARS RAEB I RAEB II  Myeloproliferative disorders Ch Myeloid leukemia (BCR-ABL positive) Polycythemia Vera Essential Thrombocythemia Myelofibrosis – Specific clinicopathologic criteria for diagnosis and distinct diseases, have common features – Increased number of one or more myeloid cells – Hepatosplenomegaly – Hyper-catabolism – Clonal marrow hyperplasia without dysplasia – Predisposition to evolve  Bone marrow stem cell Clonal abnormality Granulocyte Red cell Megakaryocytes Reactive precursors precursors fibrosis Chronic myeloid Polycythaemia Essential Myelofibrosis leukemia rubra vera thrombocytosis (PRV) (ET) 10% 10% 70% AML 30%  Epidemiology of CML is a type of leukemia characterized by the uncontrolled proliferation of myeloid cells in the bone marrow It is associated with a specific genetic abnormality known as the Philadelphia chromosome, which results from a translocation between chromosomes 9 and 22 Incidence: – CML accounts for approximately 15-20% of adult leukemias – It is more commonly diagnosed in adults, with a median age at diagnosis ranging from 50 to 60 years. However, CML can occur at any age.  Epidemiology of CML Incidence 1-1.5/100,000 population Male predominance Philadelphia Chromosome: The Philadelphia chromosome, the hallmark genetic abnormality in CML, is found in the majority of cases It results from the fusion (reciprocal translocation) of the BCR (Breakpoint Cluster Region) gene on chromosome 22 with the ABL (Abelson) gene on chromosome 9 No evidence of other genetic factors Chemical have not been associated with CML The Philadelphia Chromosome: t(9;22) Translocation 9 9+ Philadelphia 22 chromosome Ph bcr bcr-abl abl Fusion protein with tyrosine kinase activity  The translocation leads to the formation of a fusion gene called BCR-ABL. The BCR (Breakpoint Cluster Region) gene from chromosome 22 fuses with the ABL (Abelson) gene on chromosome 9 This fusion gene encodes a fusion protein with constitutive tyrosine kinase activity Tyrosine kinase activity is a key driver in the development of CML. It leads to uncontrolled cell division and inhibits apoptosis (programmed cell death), contributing to the expansion of leukemia cells in the bone marrow  Clinical Course: Phases of CML Advanced phases Chronic phase Accelerated phase Blastic phase (blast crisis) Median 4–6 years Median duration Median survival stabilization up to 1 year 3–6 months Terminal phase  Presentation Chronic Phase: – Fatigue: Persistent tiredness and weakness are common – Abdominal Discomfort: Feeling fullness or discomfort in the abdomen, often due to an enlarged spleen – Weight Loss: Unexplained weight loss can occur Accelerated Phase: – As the disease progresses, symptoms may become more severe, and additional symptoms may develop, including: – Increased Fatigue: Fatigue may worsen – Fever and Night Sweats: Spiking fevers and night sweats may occur – Bone Pain: Pain or discomfort in bones, joints, or the Blast Crisis: is a more aggressive phase of CML and is characterized by the rapid accumulation of immature white blood cells (blasts). Symptoms may include: – Severe Fatigue: Extreme tiredness. – Shortness of Breath: Difficulty breathing may occur – Pale Skin: Due to anemia – Bruising and Bleeding: Increased susceptibility to bruising and bleeding – Frequent Infections: Weakened immune system may lead to recurrent infections – Enlarged Lymph Nodes: Swelling of lymph nodes – Spleen and Liver Enlargement: Further enlargement of the spleen and liver  Diagnosis of CML Complete Blood Count (CBC):often an increase in the number of white blood cells, particularly granulocytes Peripheral Blood Smear Bone Marrow Aspiration and Biopsy: essential for confirming the diagnosis of CML Cytogenetic Analysis: – Cytogenetic analysis involves studying the chromosomes in cells, and it is crucial for identifying the Philadelphia chromosome, a hallmark of CML  Fluorescence In Situ Hybridization (FISH): – used to confirm the presence of the Philadelphia chromosome and detect the BCR-ABL fusion gene. It is often employed as a complementary test to cytogenetic analysis Quantitative Polymerase Chain Reaction (qPCR): – qPCR is used to quantify the amount of BCR-ABL transcripts in the blood. Monitoring the level of BCR- ABL transcripts is crucial for assessing the response to treatment and disease progression Immunophenotyping: – Flow cytometry and immunohistochemistry can be used to analyze the surface markers of cells in the bone marrow, aiding in the characterization of abnormal cell populations Blood picture Bone marrow biopsy Treatment of Chronic Myeloid leukemia Arsenic Lissauer, 1865 Radiotherapy Pusey, 1902 Busulfan Galton, 1953 Hydroxyurea Fishbein et al, 1964 Autografting Buckner et al, 1974 Allogeneic BMT Doney et al, 1978 Interferon Talpaz et al, 1983 Donor Leukocytes Kolb et al, 1990 Imatinib Druker et al, 1998 Imatinib/Combination therapy O’Brien et al, 200……  Issues related to BMT 70% long term cure rate Donor Availability Age of patient Length/stage of disease Treatment related mortality Long term sequalae – infertility, cGVHD  CML Diagnosis Young with a Start Imatinib at well-matched donor 400mg/day Poor response or Initial response Good response Cosider for Allograft Followed by maintained Loss of response Add or substitute Other agents Continue Imatinib Allo SCT Allo-SCT indefinitely Auto  Polycythemia vera is a rare, chronic myeloproliferative neoplasm characterized by the excessive production of red blood cells (erythrocytosis) in the bone marrow This condition results in an increased thickness of the blood, which can lead to complications such as blood clots and an increased risk of cardiovascular events  Polycythemia True / Absolute – Primary Polycythemia; abnormal proliferation of bone marrow cells – Secondary Polycythemia; increase in red blood cell production due to factors external to the bone marrow Epo dependent – Hypoxia dependent – Hypoxia independent Apparent / Relative – Reduction in plasma volume  Causes of secondary polycythemia ERYTHROPOIETIN (EPO)-MEDIATED – Hypoxia-Driven Chronic lung disease Right-to-left cardiopulmonary vascular shunts High-altitude habitat Chronic carbon monoxide exposure (e.g., smoking) Hypoventilation syndromes including sleep apnea Renal artery stenosis or an equivalent renal pathology – Hypoxia-Independent (Pathologic EPO Production) Malignant tumors – Hepatocellular carcinoma – Renal cell cancer – Cerebellar hemangioblastoma Nonmalignant conditions – Uterine leiomyomas – Renal cysts – Postrenal transplantation – Adrenal tumors EPO RECEPTOR–MEDIATED – Activating mutation of the erythropoietin receptor DRUG-ASSOCIATED – EPO Doping – Treatment with Androgen Preparations  POLYCYTHEMIA VERA Chronic, clonal myeloproliferative disorder characterized by an absolute increase in number of RBCs A rare disorder, with a relatively low prevalence in the general population Incidence; 2-3 / 100,000 Median age at presentation: 55-60 M/F: 0.8:1.2  JAK2 Mutation Is a key genetic abnormality associated with PV The JAK2 mutation leads to the constitutive activation of the JAK-STAT signalling pathway. This results in uncontrolled cell proliferation, leading to the overproduction of red blood cells, white blood cells, and platelets deficiency in mice at embryonic stage is lethal due to the absence of definitive erythropoiesis a single nucleotide JAK2 somatic mutation (JAK2V617F mutation) in the majority of PV patients  Clinical features Plethora; Elevated hematocrit & Hb levels, Persistent leukocytosis Persistent thrombocytosis Microcytosis secondary to iron deficiency Splenomegaly Generalized pruritus (after bathing) Unusual thrombosis (e.g., Budd-Chiari syndrome) Erythromelalgia (acral dysesthesia and erythema)  Complications Hypertension Gout Leukaemic transformation Myelofibrosis  Diagnostic Criteria A1 Raised red cell mass Hemoglobin level greater than 16.5 g/dL in men or 16.0 g/dL in women, or Hematocrit level greater than 49% in men or 48% in women, or Red cell mass greater than 25% above mean normal predicted value A2 Normal O2 sats and EPO A3 Palpable spleen A4 No BCR-ABL fusion B1 Thrombocytosis >400 x 109/L B2 Neutrophilia >10 x 109/L B3 Radiological splenomegaly B4 Endogenous erythroid colonies A1+A2+either another A or two B establishes PV  Treatment The mainstay of therapy in PV remains phlebotomy to keep the hematocrit below 45 percent in men and 42 percent in women Additional hydroxyurea in high-risk pts for thrombosis (age over 70, prior thrombosis, platelet count >1,500,000/microL, presence of cardiovascular risk factors) Aspirin (75-100 mg/d) IFNa (3mu three times per week) in patients with refractory pruritus, pregnancy Anagrelide (0.5 mg qds/d) is used mainly to manage thrombocytosis in patients refractory to other treatments Allopurinol - used in the treatment of gout  Essential Thrombocythaemia (ET) Clonal MPD Persistent elevation of Plt >600 x109/L Poorly understood Lack of positive diagnostic criteria 2.5 cases/100000 M:F 2:1 Median age at diagnosis: 60, however 20% cases 600 x 109/L for at least 2 months Megakaryocytic hyperplasia on bone marrow aspiration and biopsy No cause for reactive thrombocytosis Absence of the Philadelphia chromosome Normal red blood cell (RBC) mass or a HCT