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Todays Quranic verse
And hold fast, all together, by the rope which God (stretches out
for you), and be not divided among yourselves; and rememberwith gratitude God's favour on you; for ye were enemies and He
joined your hearts in love, so that by His Grace, ye became
brethren; and ye were on the brink of the pit of Fire, and He
saved you from it. Thus doth God make His Signs clear to you:
That ye may be guided. [003:103]
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Never deprive anyone of hope; it could be theNever deprive anyone of hope; it could be the
only thing a person owns.only thing a person owns.
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DISORDERSOF WHITEBLOOD CELLS
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White blood cell types (WBC differential)
Neutrophils (103/L) 1.4-6.5 (50-65%)
Band neutrophils (103/L) (3-6%)
Lymphocytes (103/L) 1.2-3.4 (25-40%)
Monocytes (103/L) 0.1-0.6 (3-7%)
Eosinophils (103/L) 0-0.5 (0-3%)
Basophils (103/L) 0-0.2 (0-1%)
White blood cell (WBC) count
Normal Count : 4.8-10.8 (103/L)
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Name the different cells.
Neutrophil (Band Cell)
Platelet
Eosinophil
Monocyte
Lymphocyte
MatureNeutrophil
Basophil
Red Blood Cell
(Mature Erythrocyte)
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BENIGN DISORDERSOF LEUKOCYTES
Leukocytosis
Condition characterized by abnormally increased number of WBC.
It may be generalized or involve only individual granulocytes oragranulocytes.
Leukopenia:Condition characterized by abnormally reduced number of WBC. It
may be generalized or involve only neutrophils or lymphocytes
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Neutrophilic
leukocytosis
Acute bacterial infections, especially those caused by pyogenic organisms; sterile
inflammation caused by, for example, tissue necrosis (myocardial infarction, burns)
Eosinophilic
leukocytosis
Allergic disorders such as asthma, hay fever, allergic skin diseases (e.g., pemphigus,
dermatitis herpetiformis); parasitic infestations; drug reactions; certain malignancies (e.g.,
Hodgkin disease and some non-Hodgkin lymphomas); collagen vascular disorders and
some vasculitides; atheroembolic disease (transient)
Basophilic
leukocytosis
Rare, often indicative of a myeloproliferative disease (e.g., chronic myelogenous leukemia)
Monocytosis Chronic infections (e.g., tuberculosis), bacterial endocarditis, rickettsiosis and malaria;collagen vascular diseases (e.g., systemic lupus erythematosus) and inflammatory bowel
diseases (e.g., ulcerative colitis)
Lymphocytosis Accompanies monocytosis in many disorders associated with chronic immunologic stimulation(e.g., tuberculosis, brucellosis); viral infections (e.g., hepatitis A, cytomegalovirus, Epstein-
Barr virus); Bordetella pertussis infection
LEUKOCYTOSIS
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Reduced or ineffective productionof neutrophils
Accelerated removal of neutrophils
from the circulating blood
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Leukemoid reaction
Leukemoid reaction is defined as a reactive leukocytosis in excess of 50000/L. It is usually seen in response to infection, inflammation, ortherapeutic agents such as growth factors and is less commonly caused
by malignancy. Milder elevations in leukocyte count are common both incarcinoma and Hodgkin lymphoma.
Cells are more mature than myelocytes in peripheral smear
Leukocytic alkaline phosphatase activity is high
Neutrophils contain toxic granules (Dohle bodies)
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LEUKEMIAS
Neoplastic Proliferations of White Cells
Lymphoid neoplasms Myeloid neoplasms
Histiocytoses
LymphomaChloroma
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Leukemia
Malignancy of hematopoietic cells
Starts in bone marrow, can spread to blood, nodes
Myeloid or lymphoid Acute or chronic
Lymphoma
Malignancy of hematopoietic cells
Starts in lymph nodes, can spread to blood, marrow
Lymphoid only
Hodgkin or non-Hodgkin
Hematologic Malignancies
Multiple myeloma
Histiocytosis
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HEMOPOIESISMYELOID/ LYMPHOID
STEM CELLS(CD34)
LYMPHOID
STEM CELLS
MYELOID
STEM CELLS
LYMPHOCYTES OTHER BLOOD CELLS
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HEMOPOIESISMYELOID/ LYMPHOID
STEM CELLS(CD34)
LYMPHOID
STEM CELLS
MYELOID
STEM CELLS
LYMPHOCYTESRBC
OTHER
WBC
PLATELET
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HEMOPOIESIS
MYELOID/ LYMPHOID
STEM CELLS
(CD34)
MYELOID
STEM CELLSPRO-
NORMOBLAST
EARLY
NORMOBLAST
INTERMEDIATE
NORMOBLAST
LATE
NORMOBLAST
RETICULOCYTE
RBC
MONOBLAST
PROMONO
CYTE
MONOCYTE
MYELOBLAST
PRO-MYELOCYTE
MYELOCYTE
META-MYELOCYTE
BAND or STAB
GRANULOCYTES
MEGAKARYO
CYTE
MEGAKARYO
BLAS
T
PLATELET
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HEMOPOIESIS
MYELOID/ LYMPHOID
STEM CELLS
(CD34)LYMPHOID
STEM CELLS
Pre-T
Thymocyte
Peripheral T Cells
T-
Helper
T-
Supp.
Pro-B
Pre-B
B- Virgin
B- Mature
LPC
PLASMA
CELL
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Myeloid maturationmyeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATIONMATURATION
Adapted and modified from U Va website
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LEUKEMIAS
Leukemias are usually diseases of
unknown etiology
Abnormal Uncontrolled
WidespreadWidespread
Proliferation
of
WBC Clonal
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Leukemia
Etiology and Pathophysiology
Associated with the development of leukemia
Chemical agents
Chemotherapeutic agents Viruses
Radiation
Immunologic deficiencies
Underlying hematologic disorders
Hereditary/genetic conditions
Idiopathic
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LEUKAEMIAMYELOID/ LYMPHOID
STEM CELLS(CD34)
LYMPHOID
STEM CELLS
MYELOID
STEM CELLS
LYMPHOCYTESGRANULOCYTES
ACUTE
CHRONIC
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Lymphoblasts
Lymphocytes Granulocytes
Myeloblasts
ALL AML
CMLCLL
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HEMOPOIESIS
MYELOID/ LYMPHOID
STEM CELLS
(CD34)LYMPHOID
STEM CELLS
Pre-T
Thymocyte
Peripheral T Cells
T-
Helper
T-
Supp.
Pro-B
Pre-B
B- Virgin
B- Mature
LPC
PLASMA
CELL
ALL
CLL
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Acute Leukemiameans
Maturation Arrest
SustainedSELF-RENEWALAT THE EXPENSE OF
DIFFERENTIATION
Differentiation
(Maturation)
Self-renewal
Maturation Arrest
Sustained
self-renewal
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Learn how to say No courteoulsy & promptlyLearn how to say No courteoulsy & promptly.
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LEUKEMIAS
TYPES
INCIDENCE
AGE
PRESENTATION
BONE
MARROW
Anemia
Neutropenia
Thrombocytopenia
CNS
BONESKIN
LYMPHATICS
etc
OTHERS
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Acute Leukemias(AML/ALL)
Block in differentiationblasts with prolonged generation time
Accumulation of blasts
(Result from a clonal expansion & Failure of maturation)
Suppress normal hematopoiesis
( in normal RBCs, WBCs and Platelets)
Aim of TX is to reduce the leukemic clone to allow reconstitution
with the progeny of remaining normal stem cells
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Acute Leukemias (AML/ALL)
Clinical features
Abrupt onset
Symptoms related to BM depression Fatigue from anemia, fever from infection, bleeding from thrombocytopenia
Bone pain and tenderness BM expansion with subperiosteal infiltration
Generalized adenopathy, hepatosplenomegaly (ALL>AML)
CNS manifestations (ALL>AML) Headache, vomiting, nerve palsies
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Acute Leukemias (AML/ALL)
Laboratory
Leukocytosis (>100,000) with blasts in circulation & BM (count may be 60% of the patients achieve complete remission with chemotherapy, but only 15% to30% remain free from disease for 5 years
>90% of children with ALL achieve complete remission, and 2/3 can be cured
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Blasts
Features Myeloblasts Lymphoblasts
Cytoplasm Mod/abundant Scant/Mod
Cyt. Granules Common Uncommon
Nucleus (chromatin) fine Coarse
Nucleoli Prominent Variable
Auer rods Present Absent
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Acute leukemia: bone marrow biopsy
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Acute lymphoblastic leukemia Acute myeloid leukemia
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AML
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Acute Leukemia
For diagnosis: >20% blasts in the bone marrow
Further characterized byWright stain (H & E stain)
Cytochemical stains (myeloperoxidase, NSE, PAS)
Flow cytometry & immunohistochemistry
Cytogenetics
Using a combination of CDs specifically recognizing B-cell, T-cell, and
myeloid antigens, it is possible to distinguish
AML from ALL in 95% to 99% of cases
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AML
ACUTE LEUKEMIAS
FAB CLASSIFICATION
M0
M1
M2
M3M4
M5
M6
M7L1
L2
L3
ALL
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M0 - acute myeloblastic leukemia, minimally differentiated 2-3%
M1 - acute myeloblastic leukemia without maturation 20%
M2 - acute myeloblastic leukemia with maturation 30% good prog. t(8:21)
M3 - acute promyelocytic leukemia 5-10% DIC, t(15,17), Responds to ATRA
M4 - acute myelomonocytic leukemia 20-30% better prognosis inv16/del16q
M5 - acute monocytic leukemia 10%, pediatric age-young adults, 11q23
M6 - acute erythroblastic leukemia 5%, older adults
M7 - acute megakaryoblastic leukemia Myelofibrosis
Acute Myeloid Leukemia
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Auer rods in AML (M3)
Hypergranular promyelocytes, many auer rods5-10% DIC, t(15,17), Responds to ATRA
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CD M1/M2 M3 M4/M5 M6 M7
CD11b - + ++ - -
CD13 + + ++ + +
CD14 - - ++ - -
CD15 + + ++ - -
CD33 ++ + ++ + +
CD34 ++ + + + +
Immunophenotyping of AML
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L1
FAB CLASSIFICATIONACUTE LYMPHOBLASTIC LEUKEMIAS
Lymphoblasts: Small & Monomorphic
L2
Lymphoblasts: Large & Heterogeneous
L3
Burkitt ALL
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Precursor B- and T- Cell Lymphoblastic
Leukemia/Lymphoma
Aggressive tumors of children/young adults
Composed of immature lymphocytes (lymphoblasts)
Lymphoblastic tumors are indistinguishable morphologically with similarsymptomatology
Pre-B: present as leukemias with extensive BM involvement (CD19+ andCD10+)
Pre-T: mediastinal masses involving the thymus progress rapidly to a leukemicphase or involve BM (CD1+, CD2+, CD5+, and CD7+)
Both pre-B/T lymphoblastic tumors have the clinical appearance ofALL at sometime during their course
Hyperploidy (>50 chromosomes), polyploidy, and t(12;21), t(9;22) and t(4;11) >90% of children with ALL achieve complete remission, and 2/3 can be cured
ALLs comprise 80% of childhood leukemia (peaks at age 4) and areusually pre-B phenotype
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Immunophenotyping of ALL
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M1
M5
L2 LYMPHOBLAST
MYELOBLAST
MONOBLAST
SPECIAL STAIN
S
*S
udan Black*Myeloperoxidase
*Specific Esterase
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Shed hate and rancour, they hurtShed hate and rancour, they hurt youyou more than they do others.more than they do others.
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Beware of who has nothing to lose.Beware of who has nothing to lose.
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Pallor
Purpura
Infection
Mucosal Bleeding
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Oral CandidiasisPneumonia
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Extensive Bruising
Gum Hypertrophy
Lymphadenopathy
Lymphadenopathy Leukemic Infiltrate
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Leukemic Infiltrate
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Lytic Skull Lesions
Mediastinal Involvement
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Chloroma
2% of AML have discrete tumors
Chloroma (Myeloblastoma)
Granulocytic Sarcoma
In the Orbit, Para-nasal sinuses, Brain, Spinal cord, Bone, Breast
Skin & Subcutaneous tissues
Called chloromas because of greenish color from MPO
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TreatmentChemotherapy & Bone marrow transplant
Prognosis for AML
Dismal
Some chromosomal abnormalities confer different prognosis
Prognosis for ALL
Immunophenotype (T is bad)
Age (1-10 good)
WBC (
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The Future
Clinical trials
New drug treatments
Vaccines
Immunotherapy
Leukemia type-specific therapy
Gene therapy Block encoding instructions of an oncogene
Target the oncoprotein
Blood and marrow stem cell transplantation
Bone marrow transplantation provides long-term, disease-free survivalamong patients in remission
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Chronic Myeloproliferative
DisordersClonal stem cell disorders characterized by proliferation of one or more
of the myeloid lineages (granulocytic, erythroid, megakaryocytic) in
bone marrow.
Characterized by:Normal maturation,
Insidious onset
Progression to myelofibrosis/transformation
Includes:
Chronic myelogenous leukemia (CML)Polycythemia vera (PV)
Myeloid metaplasia with myelofibrosis (MMF)
Essential thrombocythemia (ET)
Features common to all 4
Occur only in adults
Long clinical course
o WBC with left shift
Hypercellular marrow
Splenomegaly
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Chronic Myeloid
Leukemia
The First Disease
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The First Disease
The 1st disease for which the term leukemia was used (Virchow 1845; White Blood)
The 1st malignancy ~ with a recurring chromosomal abnormality (Philadelphia Chromosome)
The first disease in which the associated chromosomal abnormality was found to result from
the translocation of genetic material from one chromosome to another to form fusion gene
(BCR/ABL)
The first disease in which the fusion gene was recognized as giving rise to an abnormal fusion
protein fundamental in the pathogenesis of the disease.
The first disorder in which a therapeutic agent Glivec has been designed to specifically target
the molecular defect
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CML
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Chronic Myeloid Leukemia (Peripheral smear)
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Chronic
Phase
Accelerated
Phase
CML
Blast
Crisis
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PHASES (STAGING) OF CML
Three main stages, determined by percentage of blast cells in the blood
- Chronic Phase- Patient usually diagnosed
- Fewer than 10% of cells in blood and bone marrow are blast
- Prognosis: (with imatinib) 5yr: 70%, 10yr: 30-40%
- Accelerated Phase- 10-19% of cells in blood or bone marrow are blast, Basophilia 20%
- Blastic Phase, aka blast crisis- Fulminant symptoms of disease, multiple organ involvement
- 20-30% or more blasts in bone marrow and blood
- Prognosis: UNPROMISING, 2 months, may extend survival with newerdrugs or chemotherapy
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BCR
+
ABLFUSION
Normal chromosomes Chromosomes in CML
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Ph chromosomePh chromosome
BCRBCR--ABLABL (activatedactivated
tyrosine kinase)tyrosine kinase)
BCRBCR ABLABL
CMLCML
The Philadelphia (Ph) Chromosome Leads to
CML
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bcr
abl
Fusion abl/bcr (9)
Fusion bcr/abl (22)
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Practical Guidelines to Diagnose and Monitor CML
Test Guidelines
Routinecytogenetic analysis
At diagnosis and every year
I-FISH Pretreatment to have baseline percent of Ph-positive cells,then every 2-3 mo until Ph
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Treatment
Chemotherapy:
Tyrosine kinase inhibitor:
Interferon-E.
Stem cell transplant.
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Own up to your mistakes.Own up to your mistakes.
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Imatinib (Gleevec)
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Normal Bcr-Abl Signaling
The kinase domainactivates a substrateprotein, eg, PI3 kinase, byphosphorylation
This activated substrateinitiates a signalingcascade culminating incell proliferation andsurvival PP P
ADP P
P
PP P
ATP
SIGNALING
Bcr-Abl
Substrate
Effector
ADP = adenosine diphosphate; ATP = adenosine triphosphate;
P = phosphate.
Savage and Antman. NEngl J Med. 2002;346:683
Scheijen and Griffin. Oncogene. 2002;21:3314.
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Imatinib MesylateMechanism of Action
Imatinib mesylate occupies
the ATP binding pocket of
the Abl kinase domain
This prevents substrate
phosphorylation and
signaling
A lack of signaling inhibitsproliferation and survival
P
PP P
ATP
SIGNALING
Imatinibmesylate
Bcr-Abl
Savage and Antman. NEngl J Med. 2002;346:683.
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Impressive Results in CML ...
0
10
20
30
40
5060
70
80
90
100
Late chronic phase Accelerated phase Blast crisis
Hematologic response Major cytogentic response (MCR)
(n=532) (n=235) (n=260)
89%
68%
55%
23%29%
15%
< 10% of patients on IFN have MCR1
1 Kantarjian, 1998
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Chronic myelofibrosis
Panmyelosis then marrow fibrosis
Extramedullary hematopoiesis
Teardrop red cells
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Dont hesitate to lose a battle if it helps you win the war
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Chronic LymphoidLeukemia
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Chronic Lymphocytic Leukemia
(CLL)
Most common form of leukemia in North America and Northern Europe Essentially identical to small lymphocytic lymphoma (SLL)
M > F (2 : 1) Elderly (>60)
Mostly asymptomatic Hepatosplenomegaly may be present (in later stages) Symmetrical lymphadenopathy
Peripheral lymphocytosis (>200,000) B cells but CD5+ Increased susceptibility to bacterial infection (most frequent cause of death) May associated with autoimmune hemolytic anemia (AIHA) & Thrombocytopenia
Indolent but considered incurable (50% 5 year survival)
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Indolent clinical course
Median survival : 4-6 yrs
Occasional transformation to large non-Hodgkins lymphoma(Richters syndrome) --- 3 to 5 %
Chronic Lymphocytic Leukemia
(CLL)
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CLL:
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Chronic Lymphoid Leukemia (Peripheral smear)
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Chronic Lymphoid Leukemia (Bone marrow)
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Investigation:
CBC:
WBC:o.
Diff:lymphocytosis ,theabsolute lymphocyte countis>5x109/l and may be upto 300x109/l or.
Blood film:
70-99% of white cells mature lymphocyte.
Smudge or smear cells also present.Immunophenotyping:
Shows that the lymphocyte are B cells
(CD19) expressing one form of light chain
(O or P only) cells are also CD5 & CD23+ve.
Bone marrow aspiration:
Lymphocytic replacement of normal marrow.
Immunoglobulinelectrophoresis:
qof Ig, more marker with advance disease.
Cytogenetic :
The 4 most common abnormalities are; deletion of13q14,trisomy 12, deletion of11q23 & structural abnormality of 17p involving the p53 gene.
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RaiStaging
CLL
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Normal
Marrow
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CLL
Marrow
>40%LC
LC
>
15,000/uL
No
Palpable
L.N.
No
Palpable
Disease
Normal
Hb
Normal
Platelets
SURVIVAL
150
months
Stage 0
CLL
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CLL
Marrow
>40%LC
LC
>
15,000/uL
Palpable
L.N.
No
Palpable
Disease
Normal
Hb
Normal
Platelets
SURVIVAL
101
months
Stage I
CLL
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CLL
Marrow
>40%LC
LC
>
15,000/uL
Palpable
L.N.
Hepato-
Spleno-
megaly
Normal
Hb
Normal
Platelets
SURVIVAL
71
months
Stage II
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CLL
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CLL
Marrow
>40%LC
LC
>
15,000/uL
Palpable
L.N.
Hepato-
Spleno-
megaly
Anemia Thrombo-
cytopenia
SURVIVAL
19
months
Stage IV
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BinetStaging
CLL
CLL
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CLLGroup A
No anemia or thrombocytopenia,< three of five lymph node areas
Group B
No anemia or thrombocytopenia,Three or more lymph node areas
Group C
Anemia (Hb
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Chronic myeloid leukemia Chronic lymphocytic leukemia
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Acute leukemia
Sudden onset
Can occur in either adults or children
Rapidly fatal without treatment
Composed of immature cells (blasts)
Chronic leukemia
Slow onset
Occurs only in adults
Longer course
Composed of mature cells
Acute vs. chronic leukemia
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Do onto others as you wish others did onto you.
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Hairy Cell Leukemia
Uncommon variant of peripheral B-cell neoplasm
Clinically Middle age to elderly (younger than CLL)
splenic red pulp involvement
Histologically Lymphocyte with finger-like projections Phenotypically TRAP (Tartrate Resistant Acid Phosphatase)
CD19, CD20
H i C ll L k i
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Hairy Cell Leukemiaclinical
M > F (3-5 : 1)
Splenic red pulp involvementp red pulp lake
Bone marrow & liver involvement Tends to follow an indolent course
Pancytopenia - most prominent feature
- Granulocytopeniap recurrent bacterial infection
- Anemia p fatigue - Thrombocytopeniap bleeding
Good response to some chemotherapy regimen
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Myelodysplastic Syndrome Group of Clonal stem cell disorders characterized by ineffective hematopoiesis,
hypercellular marrow with left-shift (increase of blasts, 5- 10%) may eventually transform into acutemyeloid leukemia or progress into marrow failure.
Types Primary or Idiopathic = > 50yrs, Gradual in onset, risk of AML
Rx ( RT orDrugs) related (t MDS) = after 2 -8 of RX, complication of Rx, Higher risk
of AML ( ) Pathogenesis
Unknown
FAB classification (based on % blasts and ringed sideroblasts)
1. Refractory anemia (RA)2. Refractory anemia with ringed sideroblasts (RARS)3. Refractory anemia with excess blasts (RAEB)4. Refractory anemia with excess blasts in transformation (RAEB-T)5. CMML (chronic myelomonocytic leukemia)
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Cytogenetic abnormalities Deletions (5q,7q,20q), Monosomy (5 & 7), Trisomy (8)
Morphology
Marrow = usually Hypercellular, Erythroid precursors - ring Sideroblasts, budding nucleated cells, Granulocytic Megaloblastoid, Pseudo Pelger Huet neutrophils( two
nuclear segments), Megakaryocytes- Pawn ball type( multinucleate)
Peripheral Blood = Cytopenias ( Pancytopenia)
Patients present with Refractory Anemias (not responding to hematenics even after6 months of Rx )
Myelodysplastic Syndrome
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Dont be afraid to say I dont know and Im sorryDont be afraid to say I dont know and Im sorry
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Normal neutrophil
(top left)
Neutrophil with
toxic granulation
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Dhle bodies
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Cytoplasmic vacuolization
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Left shift
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Leukoerythroblastotic reaction
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Mature neutrophilia
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Immature neutrophilia
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Mature lymphocytosis
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Reactive lymphocytosis
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Downey cells
IIIIII
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