Acute myeloid leukemia Malignant clonal disorder of immature hematopoietic cells characterized by abberant hematopoietic cellular proliferation and maturation. Leukamic blasts may express capabilities for maturation to a variable degree, which lead to morphological heterogeneity

Acute leukemias Adults: - acute limphoblastic leukemia (ALL) 20% - acute myeloid leukemia (AML) 80%

Cytological criteria for the diagnosis of acute myeloid leukaemia: French-American-British (FAB) classification FAB subtype MicroscopyCytochemistry/ Immunology M0 Blasts >30% of bone marrow nucleated cells <3% of blasts positive for Sudan Black B or POX Myeloperoxidase-positivity by ultrastructural cytochemistry Myeloid immunological markers (e.g. CD13, CD33, myeloperoxidase) M1 Blasts >90% of bone marrow nonerythroid cells > 3% of blasts positive for Sudan Black B or POX Maturing granulocytic cells (i.e. promyelocytes to PMN cells) < 10% non erythroid cells (Pro)monocytes < 10% non-erythroid cells

Cytological criteria for the diagnosis of acute myeloid leukaemia: French-American-British (FAB) classification FAB subtype MicroscopyCytochemistry/ Immunology M2 with maturation Blasts 30-89% of bone marrow nonerythroid cells Maturing granulocytic cells (i.e. promyelocytes to PMN cells) > 10% non erythroid cells Monocytic cells (i.e. monoblasts to monocytes) < 20% of nonerythroid cells and not meeting other criteria for M4 M3 Promyelocytes ( most hypergranular) >30% of bone marrow nucleated cells M3 variant Promyelocytes (hypogranular or microgranular) >30% of bone marrow nucleated cells

Cytological criteria for the diagnosis of acute myeloid leukaemia: French-American-British (FAB) classification FAB subtype Microscopy Cytochemistry / Immunology M4 Acute myelomono cytic leukaemia Blasts 30-89% of bone marrow nucleated cells Granulocytic cells (i.e. myeloblasts to PMN cells) > 20% non erythroid cells Monocytic cells (i.e. monoblasts to monocytes) < 20% of nonerythroid cells andperipheral blood monocytes > 5x10 9 /l (or) Monocytic cells > 20% of nonerythroid cells and confirmed by cytochemistry or elevated urinary lysozyme Marrow resembling M2, but blood monocytes > 5x10 9 /l and confirmed by cytochemistry or elevated urinary lysozyme Positive for SBB, POX, chloroesterase (granulocyte lineage) + -naphtyl esterase (monocyte lineage)

Cytological criteria for the diagnosis of acute myeloid leukaemia: French-American-British (FAB) classification FAB subtypeMicroscopy Cytochemistry / Immunology M5A Acute monoblastic leukaemia Blasts 30% of bone marrow nonerythroid cells Bone marrow monocytic component > 80% of nonerythroid cells Monoblasts > 80% of bone marrow monocytic component M5B Acute monoblastic monocytic leukaemia Blasts 30% of bone marrow nonerythroid cells Bone marrow monocytic component > 80% of nonerythroid cells Monoblasts < 80% of bone marrow monocytic component

Cytological criteria for the diagnosis of acute myeloid leukaemia: French-American-British (FAB) classification FAB subtypeMicroscopy Cytochemistry/ Immunology M6 Acute erythro- leukaemia Erythroblasts > 50% of bone marrow nucleated cells Blast >30% of bone marrow non nonerythroid cells Glycophorine A positivity M7 Acute megakayoblastic leukaemia Blasts 30% of bone marrow nucleated cells Blasts demonstrated to be megakaryoblasts by immunological markers, ultrastructural morphology or cytochemistry

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

Infiltration of bone marrow by leukemic cells supression of normal hematopoietic progenitor cells growth granulocytopenia, thrombocytopenia and anemia -infection of skin, mucous membranes, gums, respiratory, GI and GU tracts -bleeding in skin, mucous membranes, gums, GI and GU tracts -fatigue, weakness 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) -gum hypertrophy (AML-M4 and M5) -bone and join pain and tenderness -neurological symptoms: headache, nausea, vomiting, blurred vision, cranial nerve dysfunction (AML-M4 and M5) -DIC (AML-M3) Acute myeloid leukemia Clinical features

Acute myeloid leukemia Approximate frequency of organ infiltration OrganPercent on initial examPercent at autopsy Lymph nodes Liver Spleen Bone and joint Lungs Heart CUN GI

Acute myeloid leukemia The diagnosis of AML is primarily based on morphological (< 30% of basts and suppression of other lineages) and cytochemical criteria Immunophentyping, cytogenetic analysis and molecular examination are employed to add specific information for a more precise diagnosis (e.g. to identify undifferentiated leukemias as being myeloid)

Acute myeloid leukemia Remission induction treatment The mainstay drugs have been daunorubicin and cytosine arabinoside* given as a 3+7 day schedule -number of cycled 1-2 REMISSION 60-80% *in the treatment of AML-M3 all-trans retinoic acid is also used REMISSION 80%

Acute myeloid leukemia The aims of the induction treatment obtain the complete remission (RC)* and restoration of polyclonal hemopoiesis * defined as reduction of the blast cells in the marrow < 5% (inapparent) and normalzation of the picture of the peripheral blood However, monoclonal hemopoiesis is still present!

Acute myeloid leukemia Principle of the treatment 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

Acute myeloid leukemia Post-remission chemotherapy The aims of the intensification treatment: - elimination of residual disease -prolongation of the time of remission

Acute myeloid leukemia risk groups Good risk disease -t(8;12), t(15;17) inv 16 Standard risk disease Poor risk disease - abnormalities of chromosome 5, complex changes, monosomy 7 and 3q-