Transcript Overview of hematologic malignancies
HEMATOLOGIC MALIGNANCIES
BIOLOGY
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Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic “stem cell”
FAILURE OF TERMINAL DIFFERENTIATION
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Result: accumulation of rapidly dividing immature cells
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Example: acute leukemias, aggressive lymphomas
FAILURE TO UNDERGO APOPTOSIS
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Result: accumulation of relatively well differentiated, slow-growing cells
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Example: chronic lymphocytic leukemia, indolent lymphomas
THE NEOPLASTIC STEM CELL
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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
Blood 2006;107:265
MYELOID NEOPLASIA
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Myeloproliferative disorders
Polycythemia vera
Essential thrombocytosis
Myelofibrosis/myeloid metaplasia
Chronic myelogenous leukemia
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Myelodysplasia Acute myelogenous leukemia
MYELOPROLIFERATIVE DISORDERS
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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
MYELOPROLIFERATIVE DISORDERS
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Polycythemia Vera Essential Thrombocythemia Myelofibrosis/Myeloid Metaplasia
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Chronic Myelogenous Leukemia
Polycythemia vera Essential thrombocythemia
Myeloid metaplasia CML
MARROW FIBROSIS H&E Reticulin stain
MYELOPROLIFERATIVE DISORDERS
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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
VASO-OCCUSION IN POLYCYTHEMIA VERA
NEJM 2004; 350:99
NEJM 2004; 350:99
Mayo Clin Proc 2004;79:503
SPLENOMEGALY IN MYELOFIBROSIS
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JAK2 MUTATION IN CHRONIC MYELOPROLIFERATIVE 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
Mayo Clin Proc 2005;80:947
Diagnostic algorithm for polycythemia vera
Mayo Clin Proc 2005;80:947
CHRONIC MYELOGENOUS LEUKEMIA
BIOLOGY
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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
NEJM 2003;349:1451
NEJM 2003;349:1451
CHRONIC MYELOGENOUS LEUKEMIA Blood smear Buffy coat Marrow biopsy
LEUKOSTASIS IN CML NEJM 2005;353:1044 WBC 300K
CHRONIC MYELOGENOUS LEUKEMIA
Natural history
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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
CHRONIC MYELOGENOUS LEUKEMIA
TREATMENT
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Gleevec (imatinib) – inhibits bcr-abl protein kinase Hydroxyurea Alfa interferon Early allogeneic BMT in eligible pts (vs Gleevec Rx?)
NEJM 2003;349:1399
MYELODYSPLASIA
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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%
MYELODYSPLASIA
WHO Classification
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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)
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Mixed myeloproliferative/myelodysplastic disorders Chronic myelomonocytic leukemia Atypical CML (bcr-abl negative)
SURVIVAL IN MYELODYSPLASIA
* Overall survival
J Clin Oncol 2005;23:7594
Leukemia-free survival * Mortality of low-risk (RA) patients >70 no different from general population
Myelodysplasia: blood smear
Myelodysplasia: blood smears with abnormal neutrophils
Myelodysplasia: marrows showing dyserythropoeisis and hypolobulated megakaryocyte
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
MDS: micromegakarycyte MDS: hypercellular marrow
MDS: ringed sideroblast CMML
RAEB – marrow blasts RAEB – circulating blast, agranular PMN
MYELODYSPLASTIC SYNDROME
Myeloblast (red arrow) and abnl RBC precursor (blue arrow)
ACUTE LEUKEMIA
Biology
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Leukemic clone: cells unable to terminally differentiate
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May be lymphoid or myeloid
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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
ACUTE LEUKEMIA
Pathophysiology
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Bone marrow failure
fatigue (anemia)
infection (neutropenia) bleeding (thrombocytopenia)
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Tissue infiltration
organomegaly
skin lesions organ dysfunction pain
ACUTE LEUKEMIA
Pathophysiology (cont)
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Leukostasis (WBC > 50-100K)
retinopathy
encephalopathy/CNS bleeding pneumonopathy
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Biochemical effects of leukemic cell products
hyperuricemia/tumor lysis syndrome
DIC renal tubular dysfunction (lysozymuria)
lactic acidosis hypercalcemia (rare) spurious hypoglycemia/hypoxemia/hyperkalemia
Hyperleukocytosis in AML NEJM 2003;349:767
Normal Patient (WBC 250K) 26 yo with fever, encephalopathy, retinopathy, dyspnea, lymphadenopathy
ACUTE LEUKEMIA
Information used in classification
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Clinical setting Morphology Histochemistry Surface markers Cytogenetics Molecular genetics
ACUTE LEUKEMIA
Adverse prognostic features
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Old age, poor performance status Therapy-induced Prior myelodysplastic/myeloproliferative disorder High tumor burden Cytogenetics: Ph 1 chromosome, deletion of 5 or 7, multiple cytogenetic abnormalities
ACUTE MYELOGENOUS LEUKEMIA
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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
ACUTE MYELOGENOUS LEUKEMIA
Epidemiology
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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
ACUTE MYELOGENOUS LEUKEMIAS
FAB (French-American-British) classification
• • • • • • • • • 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)
Newer classification schemes place more emphasis on cytogenetics and less on morphology
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WHO classification of AML
AML with recurrent cytogenetic abnormalities
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t(8;21)
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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
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Minimally differentiated
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Without maturation With maturation
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Acute myelomonocytic leukemia Acute monoblastic and monocytic leukemia Acute erythroid leukemia
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Acute megakaryblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma AML with ambiguous lineage
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Undifferentiated AML
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Bilineal AML
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Biphenotypic AML
ACUTE PROMYELOCYTIC LEUKEMIA
(APML; FAB M3)
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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
M0 M1
M2 M3
M4 M5
M6 M7
Auer rod in AML
ACUTE LYMPHOCYTIC LEUKEMIA
Classification
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Morphology (FAB)
L1 (uniform)
L2 (pleomorphic) L3 (Burkitt-type)
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Immunophenotypic
B-cell (Burkitt-type, 2-3% of cases)
Pre-B cell (80% ) T-lineage Mixed lineage (lymphoid-myeloid)
L1 ALL L2 ALL L3 ALL
ACUTE LYMPHOCYTIC LEUKEMIA
Epidemiology
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About 3000 cases/yr in US 2/3 of cases in children (most common
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childhood cancer) In adults, most cases in elderly
ACUTE LEUKEMIA
Treatment
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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
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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
SURVIVAL ACCORDING TO AGE IN PATIENTS WITH FAVORABLE CYTOGENETICS TREATED FOR AML (Excluding APML)
Blood 2006;107:3481
SURVIVAL ACCORDING TO AGE IN PATIENTS WITH INTERMEDIATE CYTOGENETICS TREATED FOR AML
Blood 2006;107:3481
SURVIVAL ACCORDING TO AGE IN PATIENTS WITH UNFAVORABLE CYTOGENETICS TREATED FOR AML
Blood 2006;107:3481
EFFECT OF AGE AND PERFORMANCE STATUS ON EARLY MORTALITY IN TREATED AML
Blood 2006;107:3481