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Slide 1 - Acute Leukemia David Lee, MD, FRCPC
Slide 2 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis
Slide 3 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL)
Slide 4 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL)
Slide 5 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) Myeloid maturation myeloblast promyelocyte myelocyte metamyelocyte band neutrophil MATURATION Adapted and modified from U Va website
Slide 6 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) Myeloid maturation myeloblast promyelocyte myelocyte metamyelocyte band neutrophil MATURATION Adapted and modified from U Va website Acute Leukemia accumulation of blasts in the marrow
Slide 7 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # q
Slide 8 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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
Slide 9 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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
Slide 10 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis
Slide 11 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis Causes of acute leukemias idiopathic (most) underlying hematologic disorders chemicals, drugs ionizing radiation viruses (HTLV I) hereditary/genetic conditions
Slide 12 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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
Slide 13 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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
Slide 14 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ
Slide 15 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy
Slide 16 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas NEJM 1998
Slide 17 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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
Slide 18 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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
Slide 19 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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
Slide 20 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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)
Slide 21 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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)
Slide 22 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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
Slide 23 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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
Slide 24 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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
Slide 25 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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
Slide 26 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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
Slide 27 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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
Slide 28 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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 Phases of AML treatment induction consolidation (post-remission therapy) post-remission therapy
Slide 29 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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 Phases of AML treatment induction 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
Slide 30 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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 Phases of AML treatment induction 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
Slide 31 - Acute Leukemia David Lee, MD, FRCPC Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis Classification of leukemias Acute Chronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 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 CML AML normal blasts q q promyelocytes q myelocytes q metamyelocytes q bands q neutrophils q # 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 differentiation block enhanced proliferation Acute Leukemia + Gain of function mutations of tyrosine kinases eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR Loss of function of transcription factors needed for differentiation eg. AML1-ETO CBFb-SMMHC PML-RARa Two-hit model of leukemogenesis 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/organs enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ Gum hypertrophy A B C Chloromas 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 Phases of AML treatment induction 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 Overview Concepts, biology Epidemiology Clinical and laboratory manifestations Diagnosis Management and prognosis