Acute leukemia 2nd year students
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ACUTE LEUKEMIA
Justiniano Castro MD
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BLAST CELL: DEFINITON
Blast cells are immature cells found in the bone marrow. They are not fully developed, and therefore, do not carry out any normal function in the blood. More than 5% of these cells in the bone marrow is abnormal and need to be evaluated for the possibility of a malignant disorder of the hematopoietic system.
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LEUKEMIA: DEFINITION
Leukemia is a malignant clonal condition of the bone marrow and blood. It is characterized by the acumulation of blast cells in the marrow, usually more than 20%. These blast cells are frequently seen in the peripheral blood.
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LYMPHOID VS. MYELOID CELLS Immature lymphoid cells have minimal
differentiation Myeloid blast has some differentiation Cytoplasmic granules in myeloid cells
(auer rod) Cytochemical stains (mpo and pas) Immunological markers, Ig and TCR
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Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2004;2004:101101
Figure 1. Arrow marks an Auer rod in this myeloid blast
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Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2005;2005:101390
Figure 1. Blasts may appear "rounded" or "regular" with scant cytoplasm
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PATHOPHYSIOLOGY OF AL Leukemias typically fill up the marrow with abnormal
cells, displacing normal hematopoiesis. The marrow here is essentially 100% cellular, but composed almost exclusively of leukemic cells. Normal hematopoiesis is reduced via replacement (a "myelophthisic" process) or by suppressed stem cell division. Thus, leukemic patients are prone to anemia, thrombocytopenia, and granulocytopenia and all of the complications that ensue, particularly complications of bleeding and infection.
Bone marrow failure secondary to leukemic infiltration producing anemia, neutropenia and thrombocytopenia
Maturation arrest and lineage infidelity Chromosomal abnormalities involving oncogenes and
tumor suppressor genes
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TECHNIQUE FOR ACUTE LEUKEMIA DIAGNOSIS
Morphologic features Cytochemical stains Flow cytometry and markers Chromosomal analysis Fluorescence In Situ hybridization
(FISH) PCR (polymerase chain reaction)
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ACUTE LYMPHOBLASTIC LEUKEMIA This a clonal disorder of hematopietic
cells There is accumulation of immature cells
and tissue infiltration. Risk factors (chemicals, family history,
radiation and chemotherapy)
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Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2007;2007:6-00053
Figure 2. A high power view reveals coarse chromatin with an irregular nuclear contour
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Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2004;2004:101018
Figure 11. Blasts have scant cytoplasm
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ACUTE LYMPHOBLASTIC LEUKEMIA Accumulation of lymphoblast Most common in children and better
prognosis than adults (3-7years) Disease in children is different than
the adults Rise incidence after 40 years with a
very poor prognosis
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CLASSIFICATION: ALL B VS. T
• Precursor B cell lymphoblastic leukemia/lymphoma, also called precursor B cell acute lymphoblastic leukemia (precursor B cell ALL)
• Precursor T cell lymphoblastic leukemia/lymphoma (precursor T-LBL), also called precursor T cell acute lymphoblastic leukemia (precursor T cell ALL)
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CLASSIFICATION OF ALLFAB (L1, L2 and L3) Immunological (B vs. T lineage)B cell 80% of all ALL. Tcell 20% of
all ALL.B cell precursor ALL (80% ALL)
CD10,CD19,CD20 and CD22) markers Early pre-B, CD10 neg (infant). Usually
CD34+ Pre-B, CD10+ (common ALL) B-ALL (Burkitt’s type or L3, large vacuole
and surface immunoglobulin). Its now consider a lymphoma
T-cell ALL (TdT, CD3, CD5 and CD7)
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DIAGNOSIS OF ALL
Peripheral smear with blast cellsBone marrow with >20% of blasts Immunophenotype
B vs. T cell, markersHelp to differentiate from myeloid
Chromosomal analysis (Hyper vs.hypodiploidy, t(9;22) or Ph+, t(4;11), t(v;11q23),t(12;21) and t(1;19))
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SPECIAL TEST IN ALL Due to high incidence of CNS
involvement a lumbar puncture is usually required and intrathecal treatment
CT’s Scan for T cell and Burkitt Testicular us Tumor lysis syndrome
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CYTOGENETICS IN ALL Philadelphia Chromosome present in 30% of
adult ALL with a very poor prognosis. T(4;11) association with secondary leukemia T(v;11q23),t(12;21) and t(1;19) TEL and AML1 genes are present in 30% of
childhood ALL and is associated with a good proognosis.
Tyrosine Kinase inhibitors are included in treatment strategies
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TREATMENT OF ALLCytotoxic chemotherapy include
induction, consolidation, intensification and maintenance
Complete response after induction is 80%
Cure 35-40% in the adult population
T cell and L3 ALL require special consideration
Response and cure in children could be as high as 90%
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PROGNOSIS IN ALLCure rate of 75-90% in children’sCure rate in adults of 30% CD10 negative ALL has worse
prognosisA presentation with a WBC >
30,000/m3 is associated with a poor prognosis
CytogeneticsSlow response to induction is
considered a poor prognosis feature
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SUPPORTIVE CARE IN AL
Blood products Hydration and treatment with allopurinol
Prevention of N/VAggressive antibiotic cover
Central line catheters
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SALVAGE THERAPY IN ALBone marrow transplantCord Blood TransplantExperimental treatment
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ACUTE MYELOGENOUS LEUKEMIA
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CLINICAL OVERVIEW Acute myeloid leukemia (AML) is the most common acute
leukemia in the adult AML is cancer of the blood-forming tissue (bone marrow). Normal bone marrow produces red cells, white cells, and
platelets. AML causes bone marrow to produce too many immature
white blood cells (blast cells) . Suppresses normal blood cell production.
Anemia, leucopenia, thrombocytopenia
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RISK FACTORS
Age Older adults are more likely to develop AML
Smoking 20% of AML cases are linked to smoking Doubles the risk of disease in people > 60 y/o
Genetic disorders Down syndrome, Fanconi’s anemia
High doses of radiation Long-term survivors of atomic bombs
Previous chemotherapy treatment Breast cancer, ovarian cancer, lymphoma
Exposure to industrial chemicals Benzene long term exposure
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3-5 new cases expected per 100,000 population
8,900 estimated deaths/year M:54%, F:46%
STATISTICS
5-year survival rate in adults under 65 is 33%
5-year survival rate in adults over 65 is 4-5%
Incidence:
Mortality:
Prognosis:
Prognosis:
Prognosis:
Incidence:
Mortality:
Prognosis:
Prognosis:
Prognosis: 20-30% experience remission or are cured
Sources: American Cancer Society; The Leukemia & Lymphoma Society,
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CLINICAL FEATURES OF AML
Bone marrow failureCoagulopathy (DIC) specially in APL
Tumor infiltration of monocytic leukemia
Tumor lysis syndrome specially with the initial chemotherapy
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CLASSIFICATION BY FAB Mo
Undifferentiated(5%) M1 no
maturation(20%) M2 maturation(30%)
M3 Promyelocytic (7%)
M4 myelomonocytic
M5 monocytic
M6 Erythroleukemia (very rare)
M7 Megakarioblast (very rare)
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AML BLAST WITH AUER ROD
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THE WHO CLASSIFICATION
Reduce the percentage of blast to 20%
Emphasis in the Cytogenetic characteristics
Recognize therapy related leukemia's
Recognize AML from previous Myelodyplasia
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CYTOGENETIC IN AML
Good prognostic groupT(15;17)T(8;21)Inv (16)
(p13q22) with eosinophilia
Poor prognostic groupDeletion of chromosome 5/7t(11;q23)t(6;9)
+8Complex rearrangement
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CYTOCHEMICAL STUDIES AND MARKERS
MPO or Sudan blackNonspecific esterasePeriodic Acid Shift (PAS)Markers CD13, CD33 an CD15 are only helpful for diagnosis of AML
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AML – PEROXIDASE STAIN
Blast with + MPD
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Acute Myelogenous Leukemia M2
T(8;21) (q22;q22) RUNX1-RUNX1T1 (TEL and AML1 genes)
Constitute 7% of AMLAuer rods are easily identified and
cytoplasm is generally basophilicFavorable prognosis in adults but
not in children
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Myeloid maturational arrest is demonstrated in this image, AML M2
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ACUTE MYELOGENOUS LEUKEMIA M4Approximately 20% of AML but 5%
of them are AML M4 with eosinophilia and inv(16)
Mixture of blast with myeloid and monocytic features
Better prognosis with the inv(16) expression.
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The dysphasic eosinophil precursors , AML M4 inv(16) eos
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ACUTE PROMYELOCYTIC LEUKEMIA
DIC very frequent t(15;17) is present in almost every case RAR gene present in chromosome 17
juxtaposition with PML gene in chrom 15 producing a maturation arrest
All transretinoic acid (ATRA) induce maturation
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AML M3 FAGGOT
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Cells with multiple Auer rods (arrow) may be appreciated AML M3
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ACUTE PROMYELOCYTIC LEUKEMIA
Retinoid acid syndrome is associated with an increase in WBC counts with respiratory problems, fever and hypotension
Arsenic trioxide is active in this leukemia
Antracyclines are essential in the treatment
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Proliferation: FLT3, Normal Cytogenetics A receptor tyrosine
kinase expressed in 70 – 100% of AML cases.
Activating mutations in FLT3 are seen in ~30% of AML cases. Tandem duplication
of the juxtamembrane region.
Point mutation within the activation loop of the kinase domain.
Activation of FLT3 leads to deregulated proliferation of AML cells.
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MANAGEMENT OF AML Supportive treatment similar to all AL AML M3 need special attention to DIC Monocytic leukemia's can infiltrate CNS,
gingival and skin Induction chemotherapy produce 70%
CR Usually 3 consolidation treatments Cure between 35 to 40% of the patients MUGA scan is necessary as one of the
initial test for evaluation of cardiovascular function
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SALVAGE TREATMENT IN AML
Allogeneic BMT can cure high risk and relapse AML
Monoclonal antibodiesExperimental therapy
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MYELODYSPLASTIC SYNDROME
A heterogeneous group of hematopoietic disorders characterized by peripheral blood cytopenias and hypercellular marrow
Clonal malignant disorder of the hematopoietic cells
Transformation to AML is frequent
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FAB CLASSIFICATION IN MDS
Refractory anemia
RA with ring sideroblast
RA excess of blast
Chronic myelomonocytic leukemia
RA with excess of blast in transformation (RAEBT)
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MDS WITH DYSERYTHROPOIESIS
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Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.
Vardiman, J. W ASH Image Bank 2001;2001:100189
Figure 7. Refractory anemia with ringed sideroblasts (RARS)
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WHO CLASSIFICATION OF MDS
RA RARS Refractory anemia with multilineage
dysplasia (RCMD) RAEB 5q- syndrome Unclassifiable
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Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.
Vardiman, J. W ASH Image Bank 2001;2001:100188
Figure 9. Refractory cytopenia with multilineage dysplasia (RCMD)
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PROGNOSIS OF MDS
Presence of blast indicate poor prognosis Uniformly fatal disorder due to infection and
bleeding Chromosomal abnormalities are frequent
including partial loss of chromosome 5, 7 and trisomy 8
5q- syndrome usually involve band q13 to q33 with anemia but no thrombocytopenia
The International Prognostic Index ( % blasts cells, cytogenetic and number of cytopenias)
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PATHOGENESIS OF MDS
Toxic exposure and genetic predisposition Immune response Hypermethylation and angiogenesis RAS mutation as a late effect Transformation
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TREATMENT OF MDS BY RISK STRATIFICATION Cytogenetics Blast % No. cytopenias
Antiangiogenic Factor( Lenalidomide and thalidomide)
Hypomethylating agents Azacytidine and dezacitidine)
Bone Marrow Transplantation
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