hematologic malignancies failure of terminal differentiation failure of differentiated cells to...
TRANSCRIPT
![Page 1: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/1.jpg)
HEMATOLOGIC MALIGNANCIESHEMATOLOGIC MALIGNANCIES
• Failure of terminal differentiation• Failure of differentiated cells to undergo
apoptosis• Failure to control growth• Neoplastic “stem cell”
BIOLOGY
![Page 2: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/2.jpg)
FAILURE OF TERMINAL DIFFERENTIATIONFAILURE OF TERMINAL DIFFERENTIATION
• Result: accumulation of rapidly dividing immature cells
• Example: acute leukemias, aggressive lymphomas
![Page 3: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/3.jpg)
FAILURE TO UNDERGO APOPTOSISFAILURE TO UNDERGO APOPTOSIS
• Result: accumulation of relatively well-differentiated, slow-growing cells
• Example: chronic lymphocytic leukemia, indolent lymphomas
![Page 4: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/4.jpg)
THE NEOPLASTIC STEM CELLTHE NEOPLASTIC STEM CELL
• Propagation of malignant clone may depend on a subset of cells with stem cell-like properties
• Some neoplastic stem cells retain the ability to differentiate into more than one cell type (eg, myeloproliferative/myelodysplastic disorders)
• Eradication of neoplastic stem cell essential to cure disease?
• Neoplastic stem cells may be slow-growing and resistant to treatment
![Page 5: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/5.jpg)
Blood 2006;107:265
![Page 6: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/6.jpg)
MYELOID NEOPLASIA
• Myeloproliferative disorders Polycythemia vera Essential thrombocytosis Myelofibrosis/myeloid metaplasia Chronic myelogenous leukemia
• Myelodysplasia• Acute myelogenous leukemia
![Page 7: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/7.jpg)
MYELOPROLIFERATIVE DISORDERSMYELOPROLIFERATIVE DISORDERS
• Affected cell: myeloid stem cell All three cell lines affected; clonal hematopoiesis in
most cases• Differentiation: normal to mildly abnormal• Kinetics: effective hematopoiesis• Marrow: hypercellular, variably increased reticulin
fibrosis• Peripheral blood: increase in one or more cell lines in
most cases Exception: myelofibrosis
![Page 8: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/8.jpg)
MYELOPROLIFERATIVE DISORDERSMYELOPROLIFERATIVE DISORDERS
• Polycythemia Vera• Essential Thrombocythemia• Myelofibrosis/Myeloid Metaplasia
• Chronic Myelogenous Leukemia
![Page 9: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/9.jpg)
Polycythemia vera Essential thrombocythemia
![Page 10: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/10.jpg)
Myeloid metaplasia CML
![Page 11: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/11.jpg)
MARROW FIBROSIS
H&E Reticulin stain
![Page 12: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/12.jpg)
MYELOPROLIFERATIVE DISORDERSMYELOPROLIFERATIVE DISORDERS
• Diagnosis usually determined by peripheral blood counts
• High Hct or platelet count may cause vaso-occlusive symptoms
• Risk of portal vein thrombosis• Splenomegaly, constitutional symptoms
frequent• Phlebotomy to control high Hct, hydroxyurea or
other myelosuppressive Rx to control platelets, constitutional sx, etc
• Transition to myelofibrosis or acute leukemia possible
![Page 13: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/13.jpg)
VASO-OCCUSION IN POLYCYTHEMIA VERA
![Page 14: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/14.jpg)
NEJM 2004; 350:99
![Page 15: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/15.jpg)
NEJM 2004; 350:99
![Page 16: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/16.jpg)
SPLENOMEGALY IN MYELOFIBROSIS
Mayo Clin Proc 2004;79:503
![Page 17: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/17.jpg)
JAK2 MUTATION IN CHRONIC JAK2 MUTATION IN CHRONIC MYELOPROLIFERATIVE DISORDERSMYELOPROLIFERATIVE DISORDERS
• Activation of JAK2 tyrosine kinase by cytokines initiates an important signaling pathway in myeloid cells
• A single point mutation of JAK2 (Val617Phe) has been identified in a high proportion (65-95%) of patients with polycythemia vera, and also in a substantial proportion of cases of essential thrombocytosis and myelofibrosis
• This mutation markedly increases the sensitivity of the cells to the effects of erythropoietin and other cytokine growth factors
• Testing for this mutation represents an important diagnostic tool
• This finding may lead to development new targeted therapies for myeloproliferative disorders
![Page 18: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/18.jpg)
Mayo Clin Proc 2005;80:947
![Page 19: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/19.jpg)
Diagnostic algorithm for polycythemia vera
Mayo Clin Proc 2005;80:947
![Page 20: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/20.jpg)
CHRONIC MYELOGENOUS LEUKEMIACHRONIC MYELOGENOUS LEUKEMIA
• Virtually all cases have t(9;22) (Ph1 chromosome) or variant translocation involving same genes
• bcr gene on chromosome 22 fused with abl gene on 9
• Fusion gene encodes active tyrosine kinase• Clonal expansion of all myeloid cell lines
BIOLOGY
![Page 21: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/21.jpg)
NEJM 2003;349:1451
![Page 22: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/22.jpg)
NEJM 2003;349:1451
![Page 23: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/23.jpg)
CHRONIC MYELOGENOUS LEUKEMIACHRONIC MYELOGENOUS LEUKEMIA
Blood smear Marrow biopsyBuffy coat
![Page 24: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/24.jpg)
LEUKOSTASIS IN CMLLEUKOSTASIS IN CML
NEJM 2005;353:1044
WBC 300K
![Page 25: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/25.jpg)
CHRONIC MYELOGENOUS LEUKEMIACHRONIC MYELOGENOUS LEUKEMIA
• Incidence 1:100,000/yr• Peak incidence in 40s and 50s• Leukocytosis with mixture of mature and immature
forms• Thrombocytosis common• Splenomegaly, constitutional symptoms, eventual
leukostasis• Transition to acute leukemia (blast crisis) in 20%/yr
blasts may be myeloid or lymphoid essentially 100% mortality without BMT
Natural history
![Page 26: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/26.jpg)
CHRONIC MYELOGENOUS LEUKEMIACHRONIC MYELOGENOUS LEUKEMIA
• Gleevec (imatinib) – inhibits bcr-abl protein kinase• Hydroxyurea• Alfa interferon • Early allogeneic BMT in eligible pts (vs Gleevec Rx?)
TREATMENT
![Page 27: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/27.jpg)
NEJM 2003;349:1399
![Page 28: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/28.jpg)
MYELODYSPLASIAMYELODYSPLASIA
• Affected cell: myeloid stem cell All cell lines affected, clonal hematopoiesis
• Differentiation: mildly to severely abnormal Morphology and function may be affected
• Kinetics: Ineffective hematopoiesis (apoptosis of maturing cells in marrow)
• Marrow: variable cellularity• Peripheral blood: decrease in one or more cell lines (usually
anemia with or without other cytopenias) Platelets and WBC occasionally increased
• Cytogenetic abnormalities frequent• Risk of transition to acute leukemia high when marrow blast
count > 5%
![Page 29: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/29.jpg)
MYELODYSPLASIAMYELODYSPLASIA
Myelodysplastic disorders• Refractory anemia• Refractory anemia with ringed sideroblasts• Refractory cytopenia with multilineage dysplasia• Refractory anemia with excess blasts-1 (5-10% blasts)• RAEB-2 (10-20% blasts)
Mixed myeloproliferative/myelodysplastic disorders• Chronic myelomonocytic leukemia• Atypical CML (bcr-abl negative)
WHO Classification
![Page 30: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/30.jpg)
SURVIVAL IN MYELODYSPLASIASURVIVAL IN MYELODYSPLASIA
Overall survival Leukemia-free survival
J Clin Oncol 2005;23:7594
*Mortality of low-risk (RA) patients >70 no different from general population
*
![Page 31: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/31.jpg)
Myelodysplasia: blood smear
![Page 32: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/32.jpg)
Myelodysplasia: blood smears with abnormal neutrophils
![Page 33: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/33.jpg)
Myelodysplasia: marrows showing dyserythropoeisis
and hypolobulated megakaryocyte
![Page 34: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/34.jpg)
Myelodysplasia: acquired -thalassemia with Hgb H inclusions in RBC. This is caused by somatic mutations in the -globin gene or an
associated regulatory gene, limited to the neoplastic clone
Blood 2005;105:443
![Page 35: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/35.jpg)
MDS: micromegakarycyte MDS: hypercellular marrow
![Page 36: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/36.jpg)
MDS: ringed sideroblast CMML
![Page 37: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/37.jpg)
RAEB – marrow blasts RAEB – circulating blast,
agranular PMN
![Page 38: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/38.jpg)
MYELODYSPLASTIC SYNDROMEMYELODYSPLASTIC SYNDROME
Myeloblast (red arrow) and abnl RBC precursor (blue arrow)
![Page 39: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/39.jpg)
ACUTE LEUKEMIAACUTE LEUKEMIABiology
• Leukemic clone: cells unable to terminally differentiate– May be lymphoid or myeloid– AML: May arise from abnormal stem cell
(eg in MDS/MPD) or de novo• Accumulation of immature cells (blasts)• Marrow replaced by leukemic cells• Blasts accumulate in blood and other
organs
![Page 40: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/40.jpg)
ACUTE LEUKEMIAACUTE LEUKEMIA
• Bone marrow failure fatigue (anemia) infection (neutropenia) bleeding (thrombocytopenia)
• Tissue infiltration organomegaly skin lesions organ dysfunction pain
Pathophysiology
![Page 41: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/41.jpg)
ACUTE LEUKEMIAACUTE LEUKEMIA
• Leukostasis (WBC > 50-100K) retinopathy encephalopathy/CNS bleeding pneumonopathy
• Biochemical effects of leukemic cell products hyperuricemia/tumor lysis syndrome DIC renal tubular dysfunction (lysozymuria) lactic acidosis hypercalcemia (rare) spurious hypoglycemia/hypoxemia/hyperkalemia
Pathophysiology (cont)
![Page 42: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/42.jpg)
Hyperleukocytosis in AMLNEJM 2003;349:767
Normal Patient (WBC 250K)
26 yo with fever, encephalopathy, retinopathy, dyspnea, lymphadenopathy
![Page 43: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/43.jpg)
ACUTE LEUKEMIAACUTE LEUKEMIA
• Clinical setting• Morphology• Histochemistry• Surface markers• Cytogenetics• Molecular genetics
Information used in classification
![Page 44: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/44.jpg)
ACUTE LEUKEMIAACUTE LEUKEMIA
• Old age, poor performance status• Therapy-induced• Prior myelodysplastic/myeloproliferative disorder• High tumor burden• Cytogenetics: Ph1 chromosome, deletion of 5 or
7, multiple cytogenetic abnormalities
Adverse prognostic features
![Page 45: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/45.jpg)
ACUTE MYELOGENOUS LEUKEMIA
• Affected cell: myeloid stem cell or committed progenitor cell
• Differentiation: arrested at early stage, with absent or decreased maturation
• Kinetics: marrow replacement by immature cells, decreased normal hematopoiesis
• Marrow: usually markedly hyercellular with preponderance of blast forms Hypocellular variants known
• Peripheral blood: variable decrease in all cell lines with or without circulating immature cells
![Page 46: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/46.jpg)
ACUTE MYELOGENOUS LEUKEMIAACUTE MYELOGENOUS LEUKEMIA
• 90% of adult acute leukemia: 2.2 deaths/100,000/yr• Incidence rises with age• Risk factors: exposure to ionizing radiation, alkylating
agents and other mutagens (implicated in10-15% of all cases), certain organic solvents (benzene)
• Precursor diseases: myelodysplastic & myeloproliferative disorders, myeloma, aplastic anemia, Down syndrome, Klinefelter syndrome, Fanconi syndrome, Bloom syndrome
Epidemiology
![Page 47: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/47.jpg)
ACUTE MYELOGENOUS LEUKEMIASACUTE MYELOGENOUS LEUKEMIAS
• M0 (minimal differentiation)• M1 (myeloid blasts)• M2 (some differentiation)• M3 (promyelocytic)• M4 (myelomonocytic)• M5 (monocytic)• M6 (erythroleukemia)• M7 (megakaryoblastic leukemia)• Unclassifiable (evolved from MDS, other
secondary leukemias)
FAB (French-American-British) classification
Newer classification schemes place more emphasis Newer classification schemes place more emphasis on cytogenetics and less on morphologyon cytogenetics and less on morphology
![Page 48: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/48.jpg)
WHO classification of AML• AML with recurrent cytogenetic abnormalities
– t(8;21)– inv(16)– Acute promyelocytic leukemia – t(15;17) and variants– AML with 11q23 (MLL gene) abnormalities
• AML with multilineage dysplasia• AML/MDS, therapy-related• AML not otherwise categorized
– Minimally differentiated– Without maturation– With maturation– Acute myelomonocytic leukemia– Acute monoblastic and monocytic leukemia– Acute erythroid leukemia– Acute megakaryblastic leukemia– Acute basophilic leukemia– Acute panmyelosis with myelofibrosis– Myeloid sarcoma
• AML with ambiguous lineage– Undifferentiated AML– Bilineal AML– Biphenotypic AML
![Page 49: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/49.jpg)
ACUTE PROMYELOCYTIC LEUKEMIAACUTE PROMYELOCYTIC LEUKEMIA
• t (15;17)• Translocation involves retinoic acid
receptor gene• High incidence of DIC/fibrinolysis• All-trans retinoic acid induces remission
in high proportion of cases• Favorable prognosis
(APML; FAB M3)
![Page 50: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/50.jpg)
M1M0
![Page 51: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/51.jpg)
M2 M3
![Page 52: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/52.jpg)
M5M4
![Page 53: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/53.jpg)
M7M6
![Page 54: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/54.jpg)
Auer rod in AML
![Page 55: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/55.jpg)
ACUTE LYMPHOCYTIC LEUKEMIAACUTE LYMPHOCYTIC LEUKEMIA
• Morphology (FAB) L1 (uniform) L2 (pleomorphic) L3 (Burkitt-type)
• Immunophenotypic B-cell (Burkitt-type, 2-3% of cases) Pre-B cell (80% ) T-lineage Mixed lineage (lymphoid-myeloid)
Classification
![Page 56: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/56.jpg)
L1 ALL L2 ALL L3 ALL
![Page 57: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/57.jpg)
ACUTE LYMPHOCYTIC LEUKEMIAACUTE LYMPHOCYTIC LEUKEMIA
• About 3000 cases/yr in US• 2/3 of cases in children (most common
childhood cancer)• In adults, most cases in elderly
Epidemiology
![Page 58: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/58.jpg)
ACUTE LEUKEMIAACUTE LEUKEMIA
• Remission induction: aggressive combination chemotherapy
• Post-remission AML: consolidation (high-dose) or auto-BMT ALL: consolidation, then maintenance (lower dose)
• Allogeneic bone marrow transplant in selected patients
• Cure rates 75%+ in childhood ALL; as high as 50% in "good risk" adults, up to 60% in BMT recipients
• Overall cure rates still low in adults
Treatment
![Page 59: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/59.jpg)
SURVIVAL ACCORDING TO AGE IN PATIENTS WITH FAVORABLE CYTOGENETICS TREATED FOR AML
(Excluding APML)
Blood 2006;107:3481
![Page 60: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/60.jpg)
SURVIVAL ACCORDING TO AGE IN PATIENTS WITH INTERMEDIATE CYTOGENETICS TREATED FOR AML
Blood 2006;107:3481
![Page 61: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/61.jpg)
SURVIVAL ACCORDING TO AGE IN PATIENTS WITH UNFAVORABLE CYTOGENETICS TREATED FOR AML
Blood 2006;107:3481
![Page 62: HEMATOLOGIC MALIGNANCIES Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic](https://reader036.vdocuments.net/reader036/viewer/2022081504/56649dbb5503460f94aaca95/html5/thumbnails/62.jpg)
EFFECT OF AGE AND PERFORMANCE STATUS ON EARLY MORTALITY IN TREATED AML
Blood 2006;107:3481