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Acute myeloid leukemia

Acute myeloid leukemia. Malignant clonal disorder of immature myeloid progenitor cells characterized by clonal proliferation of abnormal blast cells and impaired production of normal blood cells

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Acute myeloid leukemia

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  1. Acute myeloid leukemia • Malignant clonal disorder of immature myeloid progenitor cells characterized by clonal proliferation of abnormal blast cells and impaired production of normal blood cells • Leukamic blasts may express capabilities for maturation to a variable degree, which lead to morphological heterogeneity

  2. Acute leukemias • Adults: • acute myeloid leukemia (AML) 80% - acute lymphoblastic leukemia (ALL) 20%

  3. Acute myeloid leukemia • Theincidence 4/100 000 population per year • Median age 60 years with an incidence 10/100000 population per year in individuals 60 years and older

  4. Acute myeloid leukemia Clinical features • Suddent onset of the disease and very fast progression • If not treated  death after a few months • Most of the common systemic manifestations, such a fatigue, weakness, fever and weight loss are non-specific

  5. Acute myeloid leukemia Clinical features

  6. Acute myeloid leukemia Clinical features • The prevalence and degree of organ infiltration vary somewhat with the different types of leukemia • abdominal fullness (enlargement of the liver and spleen) • bone and join pain and tenderness • gum hypertrophy (AML-M4 and M5) • neurological symptoms: headache, nausea, vomiting, blurred vision, cranial nerve dysfunction (AML-M4 and M5) • DIC (AML-M3)

  7. Acute myeloid leukemiaApproximate frequency of organ infiltration

  8. Acute myeloid leukemia- diagnosis • The diagnosis of AML primarily based on morphological and cytochemical criteria • >20% of blasts and suppression of other lineages • Immunophenotyping, cytogenetic analysis and molecular examination employed to add specific information for a more precise diagnosis

  9. Cytological criteria for the diagnosis of acute myeloid leukaemia: French-American-British (FAB) classification • Eight morphologic subtypes (M0-M7) are distinguished according to FAB classification system based on the morphologic features of the blasts and histochemical staining

  10. Antigen M0 M1 M2 M3 M4 M5 M6 M7 ALL HLA - DR ++ ++ + - ++ ++ + - + CD11b + + + - +++ +++ - - - ++ ++ + +/ - CD13 +++ +++ +++ +++ +++ CD14 - + + - +++ +++ - - - CD15 - - +++ + + + - - - CD33 +++ +++ +++ +++ +++ +++ ++ + +/ - CD41, CD61 - - - - - - - +++ - Glycophorin A - - - - - - +++ - - TdT ++ + + - - - - - +++ CD117 +++ +++ ++ + ++ ++ + - CD2 + + - ++ ++ - - - +++ CD7 + + - - - - - ++ ++ CD19 + ++ - - - - - ++++ CD34 +++ ++ ++ - + - - + ++ Immunophenotype of AML subtypes

  11. AML M1 ³90% Blasts, Granulocytic component <10%. Monocytic component <10% SBB/MPO ³3% AML M2 >30% Blasts Granulocytic component >10% , monocytic component < 20%MPO ³3%, CAE >10% , NSE < 20% AML M3 Hypergranular PromyelocytesMultiple Auer rodsStrong positivity for MPO/SBB and CAE. NSE +/- AML M3v Deeply notched nuclei. Fine dust granules. (Multiple) Auer rods +/-Cytochemical features like the hypergranular variant AML M4 > 30% Blasts. Monocytic component > 20%, granulocytic component >20%MPO ³3%, CAE > 20%, NSE > 20%.A distinctive subtype, M4Eos- a variable increase of abnormal eosinophils with basophilic granules. AML M5a >30% Blasts. Granulocytic component < 20%. Monocytic component ³80%. Monoblasts ³80% of monocytic component. MPO may be < 3%, NSE > 80% inhibited by fluoride AML M5b ³30% Blasts. Granulocytic component < 20%. Monocytic component ³80%. Monoblasts < 80% of monocytic component. MPO may be <3%, NSE >80% inhibited by fluoride AML M6 ³30% Blasts (nonerythroid population)³50% Erythroid precursors (total marrow cells) MPO³3% in blasts. PAS, Acid phosphatase and NSE may be positive in erithroblasts

  12. Acute myeloid leukemiacytogeneticrisk groups • Favorable risk disease • t(8;21), t(15;17), inv 16 • Intermadiate risk disease • Unfavorable risk disease • abnormalities of chromosome 5, complex changes, monosomy 7 and 3q-

  13. WHO classification of acute myeloid leukemia (2008) • Acute myeloid leukemia with recurrent cytogenetic abnormalities • t (8:21) • t (15:17) • inv (16) • 11q23 abnormalities • Acute myeloid leukemia with myelodysplasia-related changes • Therapy-related acute myeloid leukemia • Alkylating agent related • Topoisomerase type II inhibitor related • Other type • Acute myeloid leukemia not otherwise categorised

  14. Genetic alterations affecting clinical outcome of cytogenetically normal AML pts • Unfavorable • FLT3-ITD (internal tandem duplication) • Significantly shorter DFS (Disease Free Survival) and OS (overall survival) FLT3- fms-related tyrosine kinase 3; an important role in the proliferation of hematopietic progenitor cells • Favorable • NPM1 mutations • Pts with NPM1 mutations who do not harbor FLT3-ITD. have significantly better CR rate, DFS, OS • CEBP mutations • Better OS • NPM1- nucleophosmin • CEBPA- CCAAT/enhancer binding protin alfa

  15. Treatment of AML-strategy • Induction chemotherapy • The aim: obtaining complete remission • reduction of the blast cells in the marrow < 5% (inapparent) with normal picture of the peripheral blood • Postremission therapy • The aim: elimination of residual disease

  16. Induction chemotherapy • Gold standard „3+7” • The anthracyclin drug for 3 days • Cytarabine for 7 days • Complete remission- 60-70% • Modification of standard chemotherapy • High doses of Ara-C • Purine analoges (fludarabina, 2-CDA) • 6-TG • etoposide

  17. Postremission therapy • Intensification of remission • High-dose cytarabine based regimens with anthracycline drug • Allogeneic HSCT • Autologous HSCT • Maintance chemotherapy • Low-dose Ara-C, 6-TG, anthracycline drug

  18. Acute myeloid leukemia • CNS prophylaxis/treatment • if clinical symptoms suggest meningeal leukemia • AML-M4 or 5 • patients < 18 years old combination of drugs administered intrathecally (Ara-C plus Fenicort, MTX plus Fenicort) or CNS radiotherapy

  19. Chemotherapy autoHSCT alloHSCT 30%-40% 40%-50% 40%-55% The results of postremission therapy in patients in CR1 • 3-5 years Disease Free Survival

  20. ACUTE LEUKAEMIA REGISTRY : 1ST & 2N TRANSPLANT JANUARY 1994 - JANUARY 2008 (n=51023) AUTOLOGOUS TRANSPLANT CHILDREN : AML (n=839) ADULTS : AML (n=8298) 57+/-2 CR1 (670) 62+/-3 CR1 (240) CR1 CR1 (6575) 42+/-1 36+/-4 CR2 (149) 32+/-2 CR2 (1246) CR2 8+/-2 ADV (477) ADV (20) ADVANCED 38+/-1 CR1 (1705)

  21. ACUTE LEUKAEMIA REGISTRY : 1ST & 2N TRANSPLANT JANUARY 1994 - JANUARY 2008 (n=51023) HLA IDENTICAL TRANSPLANT CHILDREN : AML (n=1146) ADULTS : AML (n=10191) CR1 61+/-2 CR1 (789) 55+/-1 CR1 (6499) 45+/-4 CR2 CR2 (208) 41+/-2 CR2 (1444) 18+/-4 ADV (149) 15+/-1 ADV (2248) ADVANCED 64+/-2 CR1 (756) 45+/-1 CR1 (2739)

  22. Treatment of acute promyelocytic leukaemiat(15:17)/ PML/RAR-alfa gene • All-trans retinoic acid (ATRA) based induction and intensification regimen in combination with anthracycline-based chemotherapy • ATRA targets RAR-alfa moiety of the fusion transcript and induces differentiation of leukemic clone • CR 85%, approximately 70% of pts can be cured

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