Acute leukemia

Hematological malignancy in leukocyte cell lineage Leukemia Hematological malignancy in leukocyte cell lineage

Acute leukemia: outline Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis

Classification of leukemias Acute Chronic Myeloid origin Acute Myeloid Leukemia (AML) Chronic Myeloid Leukemia (CML) Lymphoid origin Acute Lymphoblastic Leukemia (ALL) Chronic Lymphocytic Leukemia (CLL)

ALL AML Hematopoietic stem cell Neutrophils Eosinophils Basophils Monocytes Platelets Red cells Myeloid progenitor Lymphoid B-lymphocytes T-lymphocytes Plasma cells germinal center naïve AML

Myeloid maturation MATURATION myeloblast promyelocyte myelocyte metamyelocyte band neutrophil MATURATION

accumulation of blasts in the marrow Acute Leukemia accumulation of blasts in the marrow

AML vs CML (dominant cells in the peripheral blood test) Myeloid cell CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q q

Adult acute leukemia Hematologic urgency Usually fatal within weeks-months without chemotherapy With treatment, high mortality due to disease or treatment-related complications (unlike childhood acute leukemia)

Classification of acute leukemias ALL mainly children Male > Female curable in 70% of children curable in minority of adults AML mainly adults Male > Female 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: infections, sepsis anemia: fatigue, pallor thrombocytopenia: bleeding

Infiltration of tissues or 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 Blast ≥ 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 examination determining type prognosis Acute leukemias: presence of > 20% blasts in bone marrow

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

FAB (1976) Classification for AML M0 -- Undifferentiated AML M1 -- AML without maturation M2 -- AML with maturation M3 -- Acute Promyelocytic Leukemia M4 -- Acute Meylomonocytic Leukemia M5 -- Acute Monocytic Leukemia M6 -- Erythroleukemia (DiGuglielmo’s) M7 -- Megakaryoblastic Leukemia

FAB classification for ALL Subtype Morphology Occurrence (%) L1 Small round blasts 75 clumped chromatin L2 Pleomorphic larger blasts 20 clefted nuclei, fine chromatin L3 Large blasts, nucleoli, 5 vacuolated cytoplasm

FAB Classification of ALL L1: mostly in children L2: mostly in adults L3: “Burkitt” large basophilic B-cell blasts with vacuoles

Treatment of acute leukemias Choice of Regimen is influenced by: type (AML vs ALL) age curative vs palliative intent

Principles of treatment combination chemotherapy first goal: complete remission further regimen 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 Phases of AML treatment consolidation (post-remission therapy) 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 Adult ALL similar to or worse than AML