Acute Myeloid Leukemia

Acute Leukemia David Lee, MD, FRCPC Overview • • • • • Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Chronic Chronic Myeloid Leukemia (CML) Acute Lymphoblastic Leukemia (ALL) Chronic Lymphocytic Leukemia (CLL) ALL naïve B-lymphocytes Plasma cells T-lymphocytes Lymphoid progenitor AML Hematopoietic stem cell Myeloid progenitor Neutrophils Eosinophils Basophils Monocytes Platelets Red cells Myeloid maturation myeloblast promyelocyte myelocyte metamyelocyte band neutrophil MATURATION Adapted and modified from U Va website Acute Leukemia • accumulation of blasts in the marrow How to distinguish AML vs CML from looking at peripheral blood Myeloid cell blasts promyelocytes myelocytes metamyelocytes bands neutrophils CML q q q q q q AML q normal # q Significance of adult acute leukemia • a hematologic urgency • usually fatal within weeks to months without chemotherapy • with treatment, high mortality due to disease or treatment-related complications (unlike childhood acute leukemia) • notify Hematologist promptly if acute leukemia is suspected Classification of acute leukemias ALL • mainly children • M>F • curable in 70% of children • curable in minority of adults AML • mainly adults • M>F • curable in minority of adults Two-hit model of leukemogenesis Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR differentiation block + enhanced proliferation Acute Leukemia Causes of acute leukemias • • • • • • idiopathic (most) underlying hematologic disorders chemicals, drugs ionizing radiation viruses (HTLV I) hereditary/genetic conditions Clincal manifestations • symptoms due to: – marrow failure – tissue infiltration – leukostasis – constitutional symptoms – other (DIC) • usually short duration of symptoms Marrow failure • neutropenia: • anemia: • thrombocytopenia: infections, sepsis fatigue, pallor bleeding Infiltration of tissues/organs • • • • enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy Chloromas A B C NEJM 1998 Leukostasis • accumulation of blasts in microcirculation with impaired perfusion • lungs: hypoxemia, pulmonary infiltrates • CNS: stroke • only seen with WBC >> 50 x 109/L Constitutional symptoms • fever and sweats common • weight loss less common Laboratory features • WBC usually elevated, but can be normal or low • blasts in peripheral blood • normocytic anemia • thrombocytopenia • neutropenia • DIC Bone marrow in acute leukemia • • • • necessary for diagnosis useful for determining type useful for prognosis Acute leukemias are defined by the presence of > 20% blasts in bone marrow (% of nucleated marrow cells) Distinguishing AML from ALL • light microscopy – AML: Auer rods, cytoplasmic granules – ALL: no Auer rods or granules. • flow cytometry • special stains (cytochemistry) AML AML Auer rods in AML ALL Treatment of acute leukemias Choice of Rx is influenced by: • type (AML vs ALL) • age • curative vs palliative intent Principles of treatment • combination chemotherapy – first goal is complete remission – further Rx to prevent relapse • supportive medical care – transfusions, antibiotics, nutrition • psychosocial support – patient and family Chemotherapy for acute leukemias • Phases of ALL treatment – induction – intensification – CNS prophylaxis – maintenance post-remission therapy • Phases of AML treatment – induction – consolidation (post-remission therapy) Hematopoietic stem cell transplantation • permits “rescue” from otherwise excessively toxic treatment • additional advantage of graft-vs-leukemia effect in allogeneic transplants • trade-off for allogeneic transplantation: greater anti-leukemic effect but more toxic Prognosis Adult AML Age < 60 > 60 CR 75% 50% DFS ~ 30% 5-15% Adult ALL similar to or worse than AML Overview • • • • • Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis