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Acute Myelogenous Leukaemia






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    Acute Myelogenous Leukaemia Acute Myelogenous Leukaemia Presentation Transcript

    • Acute Myelogenous Leukemia Prof. Dr.S.TITO’s Unit M4 Dr.Rakesh Pinninti
      • Definition
      • Epidemiology
      • Etiology & Pathogenesis ; predisposing diseases .
      • Molecular Pathogenesis
      • Classification
      • Cytogenetic
      • Clinical Features & Special Clinical situations
      • Lab findings
      • Therapy
    • Definition
      • Acute myelogenous leukemia (AML) is a clonal, malignant disease of hematopoietic tissues that is characterized by
      • accumulation of abnormal (leukemic) blast cells, principally in the marrow, and
      • impaired production of normal blood cells.
      • AML is the result of a sequence of somatic mutations in a multipotential primitive hematopoietic cell or, in some cases, a more differentiated progenitor cell.
    • Epidemiology
      • The incidence rate of AML is
      • approx 1.5 / 100,000 in infants --- < 1 yr approx 0.4 / 100,000 children ---- 5 to 9 yrs, approx 1.0 / 100,000 ----------until age 25 yrs, increases exponentially until the rate reaches approx 25 per 100,000 persons in octogenarians
      • The exception to this exponential age-related increase in incidence is acute promyelocytic leukemia (APL), which does not change greatly in incidence with age .
      • AML accounts for 15 to 20 percent of the acute leukemias in children and 80 percent of the acute leukemias in adults. It is slightly more common in males.
    • Etiology and Pathogenesis
      • Environmental factors
      •   Radiation
      •      Benzene Cytotoxic drugs
      •    Tobacco smoke
      • Acquired diseases  
      • a) Clonal myeloid diseases   
      • 1.  Chronic myelogenous leukemia
      • 2.  Primary myelofibrosis
      • 3. Essential thrombocythemia
      • 4.  Polycythemia vera   
      • 5.  Clonal cytopenias
      • 6. Paroxysmal nocturnal hemoglobinuria
      •   Other hematopoietic disorders    
      •   Aplastic anemia   Eosinophilic fasciitis    Myeloma
      • Inherited or Congenital Conditions
      •   sibling with AML       Amegakaryocytic thrombocytopenia, congenital        Ataxia-pancytopenia       Bloom syndrome       Congenital agranulocytosis ( Kostmann syndrome)       Chronic thrombocytopenia with chromosome 21q 22.12 microdel        Diamond-Blackfan syndrome       Down syndrome       Dubowitz syndrome       Dyskeratosis congenita
      •   Familial (pure, nonsyndromic) AML       Familial platelet disorder        Fanconi anemia       Naxos syndrome        Neurofibromatosis       Noonan syndrome       Poland syndrome       Rothmund-Thomson syndrome       Seckel syndrome       Shwachman syndrome       Werner syndrome (progeria)       Wolf-Hirschhorn syndrome, WT syndrome  
    • Classification
      • WHO classification is based on immunophenotype , clinical features, cytogenetic & molecular abnormalities, in addition to morphology.
      • A major difference btw WHO & FAB systems is the blast cut-off for the diagnosis of AML as opposed to MDS; it is 20% in WHO & 30% in FAB.
      • The WHO classification is the 1 st luekemia classification to incorporate genetic information. For example, AML FAB M3 is designated as Acute promyelocytic leukemia (APL), based on the presence of either the t(15,17)(q22;12) cytogenetic rearrangement or the PML/RARa product of translocation.
    • Clinical Features
      • Signs and Symptoms
      • GENERAL
      • Nearly half have had symptoms for <3months, before the leukemia is diagnosed.
      • ½ mention fatigue as first symptom
      • Fever with/without an identifiable infection is the initial symptom in 10% of patients.
      • Signs of abnormal hemostasis noted first in 5%
      • Major infections, such as pneumonia, pyelonephritis, and meningitis, are uncommon presenting features of the disease, partly because absolute neutrophil counts less than 500/L (0.5 x 10 9 /L) are uncommon until chemotherapy starts.
    • Specific Organ System Involvement
      • Extramedullary involvement is most common in monocytic or myelomonocytic leukemia
      • A) Skin involvement
      • B) The gastrointestinal tract
      • C) The respiratory tract
      • D) Cardiac involvement
      • E) The urogenital system
      • F) Osteoarticular
      • H) Central or peripheral nervous system
      • nonspecific lesions, leukemia cutis, or granulocytic (myeloid) sarcoma .
      • Nonspecific lesions include macules, papules, vesicles, pyoderma gangrenosum, vasculitis, neutrophilic dermatitis (Sweet syndrome), cutis vertices gyrata, and erythema multiforme or nodosum.
      • Gingival or periodontal infiltration and dental abscesses
      • Ileotyphlitis (enterocolitis )
      • Fever, abdominal pain, bloody diarrhea, or ileus
      • intestinal perforation, an inflammatory mass, and associated infection with enteric gram-negative bacilli or clostridial species often are associated with a fatal outcome.
      • Proctitis, especially common in the monocytic variant of AML, can be a presenting sign or a vexing problem during periods of severe granulocytopenia and diarrhea.
      • Central or peripheral nervous system involvement by infiltration of leukemic cells is very uncommon , although meningeal involvement is an important consideration in the treatment of the monocytic type of AML .
      • An association of CNS involvement and diabetes insipidus in AML with monosomy 7 and inv 16 has been reported.
    • Special Clinical situations
      • Hyperleukocytosis
      • Hypoplastic Leukemia
      • Oligoblastic (Subacute, Smoldering) Leukemia
      • Ph-Chromosome–Positive AML
      • Marrow Necrosis
      • Neonatal Myeloproliferation and Leukemia
      • Myeloid (Granulocytic) Sarcoma
      • Hyperleukocytosis
      • Leukocyte count is an independent prognostic factor in the outcome of AML treatment.
      • Approx 5 percent of patients with AML develop signs or symptoms attributable to a markedly elevated blood blast cell count, usually greater than 100 x 10 9 /L
      • The circulations of the CNS, lungs, and penis are most sensitive to the effects of leukostasis.
      • Dizziness, stupor, dyspnea, and priapism may occur.
      • Diabetes insipidus is another association.
      • A high early mortality in patients with AML correlates with hyperleukocytosis greater than 100 x 10 9 /L .
      • Chemotherapy in hyperleukocytic patients may lead to a pulmonary leukostatic syndrome, presumably from the effects of rigid, effete blast cells, or the discharge of large amounts of cell contents and resultant cell aggregation or other effects. 274–
    • Myeloid (Granulocytic) Sarcoma
      • A) Myeloid sarcoma (also known as granulocytic sarcoma, chloroma, myeloblastoma, monocytoma) is a tumor composed of myeloblasts, monoblasts, or megakaryocyes.
      • B) The tumors originally were called chloromas because of the green color imparted by the high concentration of the enzyme myeloperoxidase present in myelogenous leukemic cells.
      • C) Biopsy specimens are positive for chloracetate esterase, lysozyme, myeloperoxidase, and cluster of differentiation (CD) markers of myeloid cells.
      • D) Patients having AML with t(8;21) have a propensity to develop extramedullary leukemia, and such patients with myeloid sarcomas have a poorer outcome after treatment. 192,194
    • Laboratory Features
      • Blood Cell Findings
      • A) Anemia is a constant feature.
      • The reticulocyte count usually is between 0.5 and 2.0 percent.
      • Occasional poikilocytosis , Nucleated red cells or stippled erythrocytes may be present.
      • B) Thrombocytopenia is nearly always present at the time of diagnosis. Platelet count <1lakh are found in 75% and about 25% have <25,000/ micL
      • C) The total leukocyte count is less than 5000/L (5 x 10 9 /L) in approximately half of patients at the time of diagnosis
      • The absolute neutrophil count is less than 1000/L (1 x 10 9 /L) in more than half of cases at diagnosis .
      • The median presenting leukocyte count is 15,000/micl
      • <5% have no detectable leukemic cells in the blood.
      • In 20% TC may be > 100,000/micl
      • Cytochemical abnormalities of blood neutrophils include low or absent myeloperoxidase or low alkaline phosphatase activity.
      • D) Myeloblasts almost always are present in the blood but may be infrequent in severely leukopenic patients.Examination of a white cell concentrate (buffy coat) may permit their identification.
      • E) Auer rods are elliptical cytoplasmic inclusions approximately 1.5 m long and 0.5 m wide that derive from azurophilic granules. The inclusions are present in the blast cells of approximately 15 percent of cases, examined with polychrome stains .
      • An exception is APL, in which a high proportion of cells have Auer rods and some have multiple (bundles) of rods .
      • Marrow Morphology
      • The marrow always contains leukemic blast cells. From 3 to 95 percent of marrow cells are blasts at the time of diagnosis or relapse.
      • The World Health Organization (WHO) has invoked an arbitrary breakpoint of 20 % of marrow nucleated cells being blast cells to distinguish polyblastic AML (≥20% blasts) from oligoblastic myelogenous leukemia (<20% blasts).
      • The WHO choice of ≥20 percent blasts is an arbitrary, inconsistent, and confusing standard.
      • Myeloblasts are distinguished from lymphoblasts by any of three pathognomonic features:
      • a) reactivity with specific histochemical stains;
      • b) Auer rods in the cells;
      • c) reactivity with a panel of monoclonal antibodies against epitopes present on myeloblasts (e.g., CD13, CD33, CD117).
      • Leukemic myeloblasts give positive histochemical reactions for peroxidase, Sudan black B, or naphthyl AS-D-chloroacetate esterase stains.
      • Auer rods can be found in the marrow blast cells in approximately one-sixth of cases.
      • Blast cells may express granulocytic (CD15, CD65) or monocytic (CD11b, CD11c, CD14, CD64) surface antigens.
      • In a proportion of otherwise typical cases of AML, the cells may contain terminal deoxynucleotidyl transferase (TdT).
      • Normal erythropoiesis, megakaryocytopoiesis, and granulopoiesis are decreased or absent in the marrow aspirate.
      • Dysmorphic changes in hematopoietic cells may occur in 30 to 50 percent of patients with de novo AML.
      • Marrow reticulin fibrosis is common but usually is slight to moderate except in cases of megakaryoblastic leukemia , in which intense fibrosis is the rule.
      • AML cytogenetic variants may result in marrow basophilia (usually t(6;9)) or marrow eosinophilia (usually inv16 or t(16;16)).
    • Immunologic Phenotypes of AML Phenotype Usually Positive Myeloblastic CD11b, CD13, CD15, CD33, CD117, HLA-DR Myelomonocytic CD11b, CD13, CD14, CD15, CD32, CD3, HLA-DR Erythroid Glycophorin, spectrin, ABH antigens, carbonic anhydrase I, HLA-DR Promyelocytic CD13, CD33 Monocytic CD11b, 11c, CD13, CD14, CD33, CD65, HLA-DR Megakaryoblastic CD34, CD41, CD42, CD61, anti-von Willebrand factor Basophilic CD11b, CD13, CD33, CD123, CD203c Mast cell CD13, CD33, CD117
    • Plasma Chemical Findings
      • Severe hyponatremia associated with SIADH secretion has occurred at presentation.
      • Severe hypernatremia as a consequence of diabetes insipidus can be an initial event.
      • Hypokalemia is a more frequent finding at presentation and is related to kaliuresis.
      • Hypercalcemia can occur.
      • Severe lactic acidosis prior to treatment has been reported.
      • Hypophosphatemia as a result of phosphate uptake by leukemic cells can occur.
      • Uric acid and lactic dehydrogenase levels levels are higher in myelomonocytic and monocytic AML than in other AML phenotypes
      • Acute promyelocytic and acute monocytic leukemia are associated with hypofibrinogenemia and other indicators of activation of coagulation or fibrinolysis
      • The levels of the shed form of L-selectin and anticardiolipin antibodies , levels of soluble VEGF receptor-1 (VEGFR-1) and VEGFR-2 are frquently elevated
      • The ratio of soluble VEGFR-1 to VEGF correlates with greater leukemic blast cell burden and with less favorable outcome.
    • Poor prognostic markers Older age Unfavorable karyotypes Multidrug resistance phenotype Prior clonal hemopathy Higher white cell count: Count >30,000/ µ L (30 x 10 9 /L) or a blast cell count >15,000/ µ L Very low platelet count (<30,000/ µ L [<30 x 10 9 /L]) High serum lactic dehydrogenase, Low serum albumin or prealbumin   Low expression of retinoblastoma gene Another medical disorder: extreme obesity, diabetes mellitus, chronic renal disease     Need for intubation or ventilator support during induction therapy High BCL-2, MCL-1 expression, mutated KIT with t(8;21), MLL tandem duplications and 11p23/MLL abnormalities
    • Cytogenetics
    • Therapy
    • References
      • Williams Hematology - 8th Edition
      • Harrison’s Principles of Internal Medicine 17 th edition
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      Thank you