2. The myeloproliferative diseases (MPDs) areThe myeloproliferative diseases (MPDs) are
clonal stem cell disorders characterised byclonal stem cell disorders characterised by
leukocytosis, thrombocytosis, erythrocytosis,leukocytosis, thrombocytosis, erythrocytosis,
splenomegaly, and bone marrowsplenomegaly, and bone marrow
hypercelularityhypercelularity
3. Myeloproliferative DisordersMyeloproliferative Disorders
(old classification)(old classification)
a group of disease characterized by overgrowth of one or morea group of disease characterized by overgrowth of one or more
hematologic cell lines in BMhematologic cell lines in BM
1. chronic myelogenous leukemia (CML)1. chronic myelogenous leukemia (CML)
2. polycythemia vera (PV)2. polycythemia vera (PV)
3. essential thrombocythemia3. essential thrombocythemia
4. agnogenic myeloid metaplasia/myelofibrosis4. agnogenic myeloid metaplasia/myelofibrosis
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7. CML results from a somatic mutation in aCML results from a somatic mutation in a
pluripotential hematopoietic cellpluripotential hematopoietic cell
CML is a MPD characterized by increasedCML is a MPD characterized by increased
granulocytic cell line, associatedgranulocytic cell line, associated often withoften with
platelet hyperplasiaplatelet hyperplasia
The disease usually envolves into anThe disease usually envolves into an
accelerated phase that often terminates inaccelerated phase that often terminates in
acute phaseacute phase
--chronic phasechronic phase 3-5 years3-5 years
--accelerated phaseaccelerated phase 6-9 months6-9 months
--blastic phaseblastic phase 3-6 months3-6 months
8. EtiologyEtiology
Exposure to high- dose ionizing radiationExposure to high- dose ionizing radiation
Chemical agents have not been established asChemical agents have not been established as
a ca caauseuse
9. EpidemiologyEpidemiology
CML accounts for approximately 15 percent ofCML accounts for approximately 15 percent of
all cases of leukemia and approximately 3all cases of leukemia and approximately 3
percent of childhood leukemiaspercent of childhood leukemias
The median age of onset is 53 yearsThe median age of onset is 53 years
10. PathogenesisPathogenesis
Hematopoietic abnormalityHematopoietic abnormality
Expansion of granulocytic progenitors and aExpansion of granulocytic progenitors and a
decreased sensitivity of the progenitors todecreased sensitivity of the progenitors to
regulation – increased white cell countregulation – increased white cell count
Megakaryocytopoiesis is often expandedMegakaryocytopoiesis is often expanded
Erythropoiesis is usually deficientErythropoiesis is usually deficient
Function of the neutrophils and platelets isFunction of the neutrophils and platelets is
nearly normalnearly normal
11. PathogenesisPathogenesis
Genetic abnormalityGenetic abnormality
CML is the result of an acquired geneticCML is the result of an acquired genetic
abnormalityabnormality
A translocation between chromosome 9 andA translocation between chromosome 9 and
2222 [t(9;22)] – the[t(9;22)] – the Philadelphia chromosomePhiladelphia chromosome
The oncogene BCThe oncogene BCRR-ABL encodes an-ABL encodes an
enzyme – tyrosine phosphokinase (usuallyenzyme – tyrosine phosphokinase (usually
p210)p210)
13. Philadelphia ChromosomePhiladelphia Chromosome
• More than 95% of patients with CML haMore than 95% of patients with CML haveve
Philadelphia (Ph) chromosomePhiladelphia (Ph) chromosome
A subset of patients with CML lack aA subset of patients with CML lack a
detectable Ph chromosome but have thedetectable Ph chromosome but have the
fusion product for the bcr/abl translocationfusion product for the bcr/abl translocation
detectable by reverse transcriptase-detectable by reverse transcriptase-
polymerase chain reaction (RT-PCR)polymerase chain reaction (RT-PCR)
14. The bcr/abl fusion proteinThe bcr/abl fusion protein
Uncontrolled kinase activityUncontrolled kinase activity
1.1. Deregulated cellular proliferationDeregulated cellular proliferation
2.2. Decreased adherence of leukemia cells toDecreased adherence of leukemia cells to
the bone marrow stromathe bone marrow stroma
3.3. Leukemic cells are protected from normalLeukemic cells are protected from normal
programmed cell death (apoptosis)programmed cell death (apoptosis)
15. Clinical featuresClinical features
30 -50% of patients are asymptomatic at the time of30 -50% of patients are asymptomatic at the time of
diagnosis (90% are diagnosed in chronic phase)diagnosis (90% are diagnosed in chronic phase)
Symptoms are gradual in onset:Symptoms are gradual in onset:
fatigue, malaise, anorexia, abdominal discomfort,fatigue, malaise, anorexia, abdominal discomfort,
weight loss, excessive sweatingweight loss, excessive sweating
●
Less frequent symptomsLess frequent symptoms::
Night sweats, heat intolerance- mimickingNight sweats, heat intolerance- mimicking
hyperthyroidism, symptoms of leukostasishyperthyroidism, symptoms of leukostasis
(tinnitus, stupor), splenic infarction (left upper-(tinnitus, stupor), splenic infarction (left upper-
quadrant and left shoulder pain), urticaria (resultquadrant and left shoulder pain), urticaria (result
of histamine release)of histamine release)
●
Physical signsPhysical signs::
Pallor, splenomegaly, sternal painPallor, splenomegaly, sternal pain
16. Laboratory featuresLaboratory features
The hemoglobin concentration is decreased or normalThe hemoglobin concentration is decreased or normal
Nucleated red cells in blood film can be seenNucleated red cells in blood film can be seen
The leukocyte count above 25000/The leukocyte count above 25000/μl (often aboveμl (often above
100000/μ100000/μll), granulocytes are at all stages of), granulocytes are at all stages of
developmentdevelopment
Hypersegmentated neutrophilsHypersegmentated neutrophils
The basophiles count is increasedThe basophiles count is increased
The platelet count is normal or increasedThe platelet count is normal or increased
Neutrophils alkaline phosphatase (GAF) activity is lowNeutrophils alkaline phosphatase (GAF) activity is low
or absent (90%)or absent (90%)
17.
18. Laboratory features (2)Laboratory features (2)
The marrow is hypercellular (granulocytic hyperplasia)-The marrow is hypercellular (granulocytic hyperplasia)-
proportion >10:1 (blasts <10% in chronic phase)proportion >10:1 (blasts <10% in chronic phase)
Reticulin fibrosisReticulin fibrosis
Hyperuricemia and hyperuricosuriaHyperuricemia and hyperuricosuria
Serum vitamin B12-binding proteine and serum vitaminSerum vitamin B12-binding proteine and serum vitamin
B12 levels are increasedB12 levels are increased
Pseudohyperkalemia, and spurious hypoxemia andPseudohyperkalemia, and spurious hypoxemia and
hypoglycemiahypoglycemia
Cytogenetic test-Cytogenetic test- presence of the Ph chromosomepresence of the Ph chromosome
Molecular testMolecular test – presence of the BCR-ABL fusion gene– presence of the BCR-ABL fusion gene
19. DiagnosisDiagnosis
Diagnosis is based on blood counts (leukocytosis andDiagnosis is based on blood counts (leukocytosis and
frequently also thrombocytosis) and differentialfrequently also thrombocytosis) and differential
(immature granulocytes, from the metamyelocyte to(immature granulocytes, from the metamyelocyte to
the myeloblast, and basophilia). Splenomegaly isthe myeloblast, and basophilia). Splenomegaly is
present in >50% of cases of CML in the initial chronicpresent in >50% of cases of CML in the initial chronic
phase, but 50% of patients are asymptomatic.₃phase, but 50% of patients are asymptomatic.₃
Proof of diagnosis is attained by demonstration of theProof of diagnosis is attained by demonstration of the
Philadelphia (Ph) chromosome (22q–) resulting fromPhiladelphia (Ph) chromosome (22q–) resulting from
the balanced translocation t(9; 22) (q34;q11), and/orthe balanced translocation t(9; 22) (q34;q11), and/or
the BCR–ABL rearrangement in peripheral blood orthe BCR–ABL rearrangement in peripheral blood or
bone marrow cells.bone marrow cells.
20. Accelerated phase of CMLAccelerated phase of CML
Most patients eventually became resistant to therapyMost patients eventually became resistant to therapy
and the disease enters a more agressive phaseand the disease enters a more agressive phase
Criteria of accelerated phaseCriteria of accelerated phase
1.1. Blasts in blood or bone marrow-10-Blasts in blood or bone marrow-10-229%9%
2.2. BasophiliaBasophilia ≥≥ 20%20%
3.3. Thrombocytopenia <100G/lThrombocytopenia <100G/l
4.4. Thrombocytaemia >1000G/lThrombocytaemia >1000G/l
5.5. Additional chromosomal aberrationsAdditional chromosomal aberrations
6.6. RRefractory splenomegalyefractory splenomegaly or refractory leucocytosisor refractory leucocytosis
21. BlastBlast phasephase (blast crisis)(blast crisis) of CMLof CML
• Criteria of blast phaseCriteria of blast phase
1.1. BlastsBlasts ≥≥330%0% in PB or BMin PB or BM
2.2. extramedullary tumorsextramedullary tumors
• Phenotype of blastsPhenotype of blasts
1.1. Mieloblasts - 50%Mieloblasts - 50%
2.2. Limphoblasts - 30%Limphoblasts - 30%
3.3. Megakarioblasts – 10%Megakarioblasts – 10%
4.4. Acute myelofibrosisAcute myelofibrosis
23. Differential diagnosisDifferential diagnosis
Polycythemia veraPolycythemia vera
MMyelofibrosisyelofibrosis
EssentialEssential thrombocytemiathrombocytemia
Chronic myelomonocytic leukemia (Mo>1000/µl)Chronic myelomonocytic leukemia (Mo>1000/µl)
Extreme reactive leukocytosis (GAF is increased)Extreme reactive leukocytosis (GAF is increased)
24. TreatmentTreatment
Algorithm for treating CMLAlgorithm for treating CML
DIAGNOSIS
Imatinib for all
Response to imatinib
‘Failed” response
to imatinib
Continue
Consider for other TKI
or SCT
25.
26.
27. Leukemoid
reaction
CML
WBC High High
Anemia (-) (+)
PBS Shift to the Left
Toxic granulation
Dohle bodies
Shift to the left (blast)
Eosinophilia,
basophilia
LAP score High Low
Philadelphia
chromosome
(-) (+)
28.
29. Polycythemia VeraPolycythemia Vera
(lots of red cells - for real)(lots of red cells - for real)
An uncommon disorder - distinguish fromAn uncommon disorder - distinguish from
other causes of erythrocytosisother causes of erythrocytosis
Diagnosis depends on knowledge ofDiagnosis depends on knowledge of
erythropoeisiserythropoeisis
Complications most commonly fromComplications most commonly from
thrombosis and vascular incidentsthrombosis and vascular incidents
Long natural history with treatmentLong natural history with treatment
30. Definition of ErythrocytosisDefinition of Erythrocytosis
Normal hematocrit :Normal hematocrit :
Male 47Male 47 ±± 5 percent5 percent
Female 42Female 42 ±± 5 percent5 percent
Normal hemoglobin :Normal hemoglobin :
Male 15Male 15 ±± 2 gm/dl2 gm/dl
Female 13.5Female 13.5 ±± 1.5 gm/dl1.5 gm/dl
35. Polycythemia VeraPolycythemia Vera
P. vera is a rare diseaseP. vera is a rare disease
Median age 60 - 65 yearsMedian age 60 - 65 years
Clinical featuresClinical features
Attributed to increased blood viscosity andAttributed to increased blood viscosity and
poor oxygen delivery to organs (brain)poor oxygen delivery to organs (brain)
Poor OPoor O22 delivery leads to ischemia anddelivery leads to ischemia and
thrombosisthrombosis
Expanded blood volume and viscosityExpanded blood volume and viscosity
leads to increased cardiac work loadleads to increased cardiac work load
37. P. Vera - DiagnosisP. Vera - Diagnosis
(PVSG criteria)(PVSG criteria)
CriteriaCriteria
RBC mass elevatedRBC mass elevated
SaOSaO22 > 92%> 92%
Splenomegaly (or)Splenomegaly (or)
thrombocytosisthrombocytosis
LeukocytosisLeukocytosis
high LAPhigh LAP
high Bhigh B1212
SignificanceSignificance
True vs. spuriousTrue vs. spurious
R/O most 2R/O most 2°° causescauses
Evidence for MPDEvidence for MPD
False Positive 0.5%False Positive 0.5%
smokers, drinkerssmokers, drinkers
38. P. vera - Bone Marrow BiopsyP. vera - Bone Marrow Biopsy
39. Treatment Options - SummaryTreatment Options - Summary
A g e > 7 0
H y d r o x y u r e a
3 2 P ?
A g e 5 0 - 7 0
H y d r o x y u r e a
P h le b o to m y
A g e < 5 0
P h le b o to m y
H y d r o x y u r e a
P . V e r a
P h le b o to m iz e to H C T < 4 5
40.
41.
42. Essential ThrombocythemiaEssential Thrombocythemia
Rare disorder (1.5 per 100,000)Rare disorder (1.5 per 100,000)
proliferation of megakaryocytes causing marked increase inproliferation of megakaryocytes causing marked increase in
circulating platelets (>1 million)circulating platelets (>1 million)
morphologically abnormal plateletsmorphologically abnormal platelets
splenomegaly, mucosal hemorrhage, thrombosessplenomegaly, mucosal hemorrhage, thromboses
arrow: macrothrombocyte
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43. Essential ThrombocythemiaEssential Thrombocythemia
Incidence:Incidence: 1.5 per 100,0001.5 per 100,000
Age at Dx:Age at Dx: 60 y/o60 y/o (~20% <40 y/o)(~20% <40 y/o)
F to M ratio:F to M ratio: 1.6 : 11.6 : 1
Social risk factor:Social risk factor: 1. long-term use of dark hair dyes1. long-term use of dark hair dyes
2. living in tuff house2. living in tuff house
3. electrician3. electrician
Clinical features:Clinical features: - near normal life expectancy- near normal life expectancy
- frequent vasomotor and thrombo-- frequent vasomotor and thrombo-
hemorrhagic episodeshemorrhagic episodes
Treatment:Treatment: low-dose acetylsalicylic acidlow-dose acetylsalicylic acid
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44.
45.
46. MyelofibrosisMyelofibrosis
bone marrow fibrosisbone marrow fibrosis
•
fibroblasts may be “innocent bystanders”fibroblasts may be “innocent bystanders”
•
fibrosis probably driven by neoplastic megakaryocytesfibrosis probably driven by neoplastic megakaryocytes
middle aged adults (50-60 y/o)middle aged adults (50-60 y/o)
extramedullary hematopoiesis (spleen, liver)extramedullary hematopoiesis (spleen, liver)
may occur as an extension of CML or PVmay occur as an extension of CML or PV
abnormal peripheral RBCs (“tear-drop” & nucleated RBCs)abnormal peripheral RBCs (“tear-drop” & nucleated RBCs)
immature WBC and abnormal plateletsimmature WBC and abnormal platelets
infection, thrombosis and hemorrhage as a major complicationinfection, thrombosis and hemorrhage as a major complication
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52. Produced in the bone marrowProduced in the bone marrow
Function to combat parasiticFunction to combat parasitic
infections, ectoparasites, certain viralinfections, ectoparasites, certain viral
infections, and amplify responses ofinfections, and amplify responses of
mast cells in atopymast cells in atopy
This is largely accomplished byThis is largely accomplished by
generating ribonucleases, oxidativegenerating ribonucleases, oxidative
species = apoptosis, and inducingspecies = apoptosis, and inducing
degranulation of basophils and mastdegranulation of basophils and mast
cellscells
Eosinophils are attracted to tissues byEosinophils are attracted to tissues by
certain chemokines (RANTES,certain chemokines (RANTES,
CCL11/24) and leukotrienesCCL11/24) and leukotrienes
They require IL-5 (Eosinophil growthThey require IL-5 (Eosinophil growth
factor, secreted by T-cells) forfactor, secreted by T-cells) for
proliferation and to prevent apoptosisproliferation and to prevent apoptosis
They are VERY sensitive to steroidsThey are VERY sensitive to steroids
Eosinophils – The BasicsEosinophils – The Basics
53. These granules are full of:These granules are full of:
Major Basic Protein = toxic toMajor Basic Protein = toxic to
helminths and epithelial cellshelminths and epithelial cells
Ribonuclease A (aka EosinophilRibonuclease A (aka Eosinophil
Cationic Protein)Cationic Protein)
Eosinophil Peroxidase =Eosinophil Peroxidase =
generation of hypobromite used togeneration of hypobromite used to
combat Helminths and TBcombat Helminths and TB
Proteases that are involved inProteases that are involved in
tissue remodelingtissue remodeling
Eosinophils – The BasicsEosinophils – The Basics
54. Represents a heterogenous group of uncommonRepresents a heterogenous group of uncommon
disorders marked by blood or tissue eosinophiliadisorders marked by blood or tissue eosinophilia
Known causes of secondary or reactive eosinophilia must beKnown causes of secondary or reactive eosinophilia must be
ruled outruled out
Range from benign idiopathic eosinophilia to eosinophilicRange from benign idiopathic eosinophilia to eosinophilic
leukemialeukemia
for secondary etiologies of hypereosinophiliafor secondary etiologies of hypereosinophilia
Hypereosinophilic SyndromesHypereosinophilic Syndromes
56. Morbidity and mortalityMorbidity and mortality
associated with theseassociated with these
syndromes = usuallysyndromes = usually
due to cardiac anddue to cardiac and
neuropathicneuropathic
complicationscomplications
These representThese represent
medical emergenciesmedical emergencies
that require emergentthat require emergent
treatment withtreatment with
corticosteroidscorticosteroids
Hypereosinophilic SyndromesHypereosinophilic Syndromes
Main DDx include:Main DDx include:
Systemic mastocytosisSystemic mastocytosis
Occult malignancy, solidOccult malignancy, solid
(adenocarcinoma) or liquid(adenocarcinoma) or liquid
(leukemia/lymphoma)(leukemia/lymphoma)
Churg StraussChurg Strauss
AtopyAtopy
Parasitic infectionsParasitic infections
Chronic TBChronic TB
Other granulomatousOther granulomatous
disease such as sarcoid anddisease such as sarcoid and
IBDIBD
Endocrine causes such asEndocrine causes such as
hypoadrenalismhypoadrenalism
57. Primary cardiac complications includePrimary cardiac complications include
cardiogenic shock or heart failure due tocardiogenic shock or heart failure due to
Loeffler’s endocarditis = a restrictive cardiomyopathyLoeffler’s endocarditis = a restrictive cardiomyopathy
from eosinophilic infiltration leading to fibroticfrom eosinophilic infiltration leading to fibrotic
thickeningthickening
Endomyocardial fibrosis (aka Davies Disease, seen inEndomyocardial fibrosis (aka Davies Disease, seen in
the tropics)the tropics)
Other clinical manifestations include:Other clinical manifestations include:
Skin and mucosal ulcerationsSkin and mucosal ulcerations
Thromboembolic diseaseThromboembolic disease
SplenomegalySplenomegaly
Pleural effusions and/or pulmonary fibrosisPleural effusions and/or pulmonary fibrosis
Hypereosinophilic SyndromesHypereosinophilic Syndromes
58. Clinical ApproachClinical Approach
CBC with diff, serumCBC with diff, serum
tryptase, strongyloidestryptase, strongyloides
antibody, peripheralantibody, peripheral
lymphocyte clonal studieslymphocyte clonal studies
Bone marrow biopsy withBone marrow biopsy with
FISH/Flow, ANA, SPEPFISH/Flow, ANA, SPEP
TTE, CT chest andTTE, CT chest and
abdomenabdomen
59. Chronic eosinophilic leukemia (CEL)Chronic eosinophilic leukemia (CEL)
Diagnostic criteria:Diagnostic criteria:
● ≥1.5 x 10● ≥1.5 x 1099
/L peripheral blood eosinophils (persistent)/L peripheral blood eosinophils (persistent)
● Either peripheral blood blasts > 2%, bone marrow blasts >● Either peripheral blood blasts > 2%, bone marrow blasts >
5% or abnormal cytogenetics; exclusion of secondary5% or abnormal cytogenetics; exclusion of secondary
eosinophiliaeosinophilia
● Exclusion of other acute or chronic myeloid neoplasms● Exclusion of other acute or chronic myeloid neoplasms
● No evidence of phenotypically abnormal or clonal T● No evidence of phenotypically abnormal or clonal T
lymphocyteslymphocytes
● No evidence of PDFGRA, PDGFRB or FGFR1● No evidence of PDFGRA, PDGFRB or FGFR1
rearrangementsrearrangements
60.
61.
62.
63. Mast cell diseaseMast cell disease
MastocytosisMastocytosis is a group of rare disordersis a group of rare disorders
of both children and adults caused by theof both children and adults caused by the
presence of too many mast cellspresence of too many mast cells
((mastocytesmastocytes) and CD34+ mast cell) and CD34+ mast cell
precursors in a person's bodyprecursors in a person's body
ClassificationClassification
Cutaneous urticaria pigmentosa ,Cutaneous urticaria pigmentosa ,
Telangiectasia macularis eruptiva perstansTelangiectasia macularis eruptiva perstans
(TMEP)(TMEP)
systemicsystemic
64. Mast cells are located in connective tissue,Mast cells are located in connective tissue,
including the skin, the linings of theincluding the skin, the linings of the
stomach and intestine, and other sites.stomach and intestine, and other sites.
They play an important role in helpingThey play an important role in helping
defend these tissues from disease.defend these tissues from disease.
By releasing chemical "alarms" such asBy releasing chemical "alarms" such as
histamine, mast cells attract other keyhistamine, mast cells attract other key
players of the immune defense system toplayers of the immune defense system to
areas of the body where they are needed.areas of the body where they are needed.
Erythromelalgia: This 77-year-old woman with longstanding polycythemia vera had a six-month history of increasingly prolonged bouts of redness, swelling, and burning pain in her extremities. The severity and sites of involvement varied with each episode. At presentation, she was unable to ambulate without assistance.
