Transcript Overview of hematologic malignancies

HEMATOLOGIC MALIGNANCIES
BIOLOGY
• Failure of terminal differentiation
• Failure of differentiated cells to undergo
apoptosis
• Failure to control growth
Neoplastic “stem cell”
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FAILURE OF TERMINAL DIFFERENTIATION
• Result:
accumulation of rapidly dividing
immature cells
• Example: acute leukemias, aggressive
lymphomas
FAILURE TO UNDERGO APOPTOSIS
• Result:
accumulation of relatively welldifferentiated, slow-growing cells
• Example:
chronic lymphocytic leukemia,
indolent lymphomas
THE 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
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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
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MYELOID NEOPLASIA
• Myeloproliferative disorders
Polycythemia vera
 Essential thrombocytosis
 Myelofibrosis/myeloid metaplasia
 Chronic myelogenous leukemia
• Myelodysplasia
• Acute myelogenous leukemia
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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
• Polycythemia Vera
• Essential Thrombocythemia
• Myelofibrosis/Myeloid Metaplasia
• Chronic Myelogenous Leukemia
Polycythemia vera
Essential thrombocythemia
Myeloid metaplasia
CML
MARROW FIBROSIS
H&E
Reticulin stain
MYELOPROLIFERATIVE DISORDERS
• Diagnosis usually determined by peripheral
blood counts
• High Hct or platelet count may cause vasoocclusive symptoms
• Risk of portal vein thrombosis
• Splenomegaly, constitutional symptoms
frequent
• Phlebotomy to control high Hct, hydroxyurea or
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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
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
• 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
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NEJM 2003;349:1451
NEJM 2003;349:1451
CHRONIC MYELOGENOUS LEUKEMIA
Blood smear
Buffy coat
Marrow biopsy
LEUKOSTASIS IN CML
WBC 300K
NEJM 2005;353:1044
CHRONIC MYELOGENOUS LEUKEMIA
Natural history
• Incidence 1:100,000/yr
• Peak incidence in 40s and 50s
• Leukocytosis with mixture of mature and immature
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forms
Thrombocytosis common
Splenomegaly, constitutional symptoms, eventual
leukostasis
Transition to acute leukemia (blast crisis) in 20%/yr
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blasts may be myeloid or lymphoid
essentially 100% mortality without BMT
CHRONIC MYELOGENOUS LEUKEMIA
TREATMENT
• 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
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)
SURVIVAL IN MYELODYSPLASIA
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Overall survival
Leukemia-free survival
*Mortality of low-risk (RA) patients >70 no different from general population
J Clin Oncol 2005;23:7594
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
• 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
ACUTE LEUKEMIA
Pathophysiology
• Bone marrow failure
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fatigue (anemia)
infection (neutropenia)
bleeding (thrombocytopenia)
• Tissue infiltration
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organomegaly
skin lesions
organ dysfunction
pain
ACUTE LEUKEMIA
Pathophysiology (cont)
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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
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
• Clinical setting
• Morphology
• Histochemistry
• Surface markers
• Cytogenetics
• Molecular genetics
ACUTE LEUKEMIA
Adverse prognostic features
• 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
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
WHO classification of AML
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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
ACUTE PROMYELOCYTIC LEUKEMIA
(APML; FAB M3)
• 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
• Morphology (FAB)
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L1 (uniform)
L2 (pleomorphic)
L3 (Burkitt-type)
• Immunophenotypic
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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
• About 3000 cases/yr in US
• 2/3 of cases in children (most common
childhood cancer)
• In adults, most cases in elderly
ACUTE LEUKEMIA
Treatment
• 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