AML (Acute Myeloid/Myelogenous Leukemia)

Acute Myeloid Leukemia: 

Acute Myeloid Leukemia BY M.AHSAN QURBAN MALIK AWAN (RAWALIANS 35 th ) MEDICAL STUDENT, RAWALPINDI MEDICAL COLLEGE, RAWALPINDI,PAKISTAN

What is AML? : 

Acute myeloid leukemia (AML) is a type of cancer in which the bone marrow makes abnormal myeloblasts—precursor of red blood cells,platelets and granulocyte It is characterized by clonal proliferation of myeloid precursor cells with reduced capacity to differentiate into more mature cellular elements . What is AML?

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It results in accumulation of leukemic forms in bone marrow, peripheral blood, and other tissues. So it leads to reduction in RBCs, plt , PMNLs. "Acute" means that the leukemia can progress quickly, and if not treated, would probably be fatal in a few months.

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Normally, the bone marrow makes blood stem cells (immature cells) that develop into mature blood cells over time. The myeloid stem cell develops into one of three types of mature blood cells: Red blood cells that carry oxygen and other materials to all tissues of the body. White blood cells that fight infection Platelets that help prevent bleeding by causing blood clots to form.

BLOOD CELLS FORMATION:-: 

BLOOD CELLS FORMATION:-

Risk Factors: 

Smoking ………….. Cancer causing substances in tobacco smoke are absorbed by the lungs and spread through the bloodstream to many parts of the body. Certain chemical exposures……….. Long-term exposure to high levels of Benzene is a risk factor for AML. Benzene is a solvent used in the rubber industry, oil refineries, chemical plants, shoe manufacturing, and gasoline related industries, and is also present in cigarette smoke, and some glues, cleaning agents!!!!!!! Risk Factors

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Radiation Exposure:- High-dose radiation exposure (such as being a survivor of an atomic bomb blast or nuclear reactor accident ) increases the risk of developing AML . Having an identical twin with AML GENDER :- AML is more common in males than in females, but the reasons for this are not clear .

Presenting Signs/Symptoms: 

Presenting Signs/Symptoms Anemia weakness and easy fatigue Neutropenia infections Thrombocytopenia gingival bleeding, ecchymoses , epistaxis

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Extramedullary Disease Granulocytic sarcoma or chloroma . Most commonly related to cutaneous /gingival infiltration of leukemic cells but can also involve lymph nodes, small bowel, mediastinum , epidural sites, uterus, ovaries. Can manifest prior to onset of overt AML. Frequently misdiagnosed as lymphoma.

Diagnosis: 

Diagnosis Requires all of the following diagnostic components: Documentation of bone marrow infiltration Myeloid origin of the leukemic cells FAB/WHO classification of the leukemia Karyotypic analysis Histochemistry immunophenotyping

Pathophysiology: 

Pathophysiology Most AMLs are associated with acquired mutations in transcription factors that inhibit normal myeloid differentiation,leading to accumulation of cells at early stage of development T(15;17)translocation Fusion of retinoic acid receptor α (RARA) gene on chromosome 17 with PML gene on chromosome 15

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The chimeric genes produce abnormal PML/RARA fusion proteins that block myeloid differentiation at promyelocytic stage, probably by inhibiting the function of normal RARA receptors The pharmacological doses of retinoic acid, a Vitamin A analogue,overcome this block. So neoplastic promyelocytes terminally differentiate into neutrophils and die It results in rapid clearance of tumor cells and remission in high fraction of patients

Complementary Mutations: 

Complementary Mutations They promote enhanced proliferation and survival For example Gain-of-Function mutations in FLT3 FLT3 is a surface receptor with tyrosine kinase activity

FLT3: 

FLT3 A receptor tyrosine kinase expressed in 70 – 100% of AML cases. Activating mutations in FLT3 are seen in ~30% of AML cases. Tandem duplication of the juxtamembrane region. Point mutation within the activation loop of the kinase domain. Activation of FLT3 leads to deregulated proliferation of AML cells.

Morphology: 

Morphology Myeloid blasts or promyelocytes make up more than 20% of bone marrow Myeloblasts have delicate nuclear chromatin,3-5 nucleoli and fine azurophilic granules in the cytoplasm Distinctive red staining rod like structures(Auer Rods) may be present Auer rods are present only in neoplastic myeloblasts In other subtypes,monoblasts,erythroblasts or megakaryoblasts predominate

FAB Classifications: 

FAB Classifications M0: minimally differentiated M1: without maturation M2: with maturation. May have t(8;21) translocation. M3: promyelocytic. Good prognosis. Can be associated w/ t(15;17). M4: myelomonocytic; assoc. w/ t(16;16) or inv(16)(p13q22). M5: monoblastic M6: erythroleukemia M7: megakaryoblastic. Poor overall survival.

sification: 

sification

Histochemistry: 

Histochemistry Cases with granulocytic differentiation are typically positive for enzyme myeloperoxidase Auer rods are intensely peroxidase positive Monocytic differentiation is demonstrated by staining for lysosomal nonspecific esterases

Immunophenotype: 

Immunophenotype Most AMLs express a combination of CD13,CD14,CD15,CD64 OR CD117(CKIT) CD33 is expressed on pleuripotent stem cells but is retained on myeloid progenitor cells Monoclonal antibodies reactive with platelt -associated antigens are helpful in the diagnosis of M7 subtype

Treatment: 

Treatment Remission induction chemotherapy Remission consolidation

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Remission I nduction Chemotherapy Aims to reduce total body leukemia cell pop. from ~10(12) to below 10(9 ). Most common regimen is cytarabine IV x 7 days plus daunorubicin IV for first 3 days. This is the “7+3” regimen. 60-80% achieve complete remission.

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Remission Consolidation One or more courses of chemo or bone marrow transplant. Eradicates residual leukemia.

Prognosis: 

Prognosis “Good risk”: favorable karyotype, including t(8;21), t(15;17), inv(16)/t(16;16)/del(16q) or FAB subtype M3 “Poor risk”: adverse karyotype or resistant disease after first course of chemo (i.e. >15% blasts in post-tx bone marrow bx) 5-yr survival for good, standard, and poor risk patients 70, 48, and 15% respectively. Relapse rates are 33, 50, and 78% respectively.

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