Block 18| Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis MODULE
Dr. MG. Alfeche
January 24, 2017
SUMMARY/OUTLINE
I. INTRODUCTION
II. CHRONIC MYELOPROLIFERATIVE
NEOPLASMS
A. Chronic Myelogenous Leukemia
B. Hypereosinophilic Syndrome
III. POLYCYTHEMIA VERA
IV. PRIMARY MYELOFIBROSIS
V. ESSENTIAL THROMBOCYTHEMIA
Book source
Audio notes
The Internet
Previous (upperclass) notes
INTRODUCTION
Concepts:
Neoplastic (clonal) disorders of
hematopoietic stem cells
Over-production of all cell lines, with
usually one line in particular
Fibrosis is a secondary event
Acute Myeloid Leukemia may occur
In short, any of the chronic
myeloproliferative neoplasm, not all,
but some can eventually lead to acute
myeloid leukemia
When we say myeloproliferative, there
is proliferation of young cells
particularly your myelocyte,
metamyelocyte, mature cells like your
neutrophils. There is basophilia but
only less than 5% of your myeloblasts
because if your myeloblasts is more
than 20%, that will already signify the
acute type of leukemia, whether
lymphocytic or myeloid in origin.
CML is one of the most common
leukemias that youll see in the clinics
In CML, you will see in your smear your
metamyelocyte or juvenile cells
This is how you do your bone marrow
aspiration. The patient lies sideways
and you get your specimen at the
posterior crest of the pelvic bone. Once
were in, when you hit the spongy
bone, you aspirate.
In biopsy, you will need a much longer
needle and then youll get a portion of
the bone and send it to the laboratory
for examination.
Myeloblasts
Team number | Members
Earliest precursors of
granulocytopoiesis that can be
identified by light microscopy
You will see these mononuclear cells
in leukemic patients. That is why we
always request for CBC in tertiary
hospitals.
It is needed, especially in
hematologic patients, because
some med techs cannot identify
these young precursor cells. If you
look at it, you will be confused if
youre looking at a monocyte or a
lymphocyte because its
mononuclear.
12 to 20 (other sources: 14 - 18) um in
diameter
Nucleus occupies most of the cell which
shows a very fine, dense chromatin
structure with as many as six nucleoli
Cytoplasmic rim is basophilic but may
show a range of hues from soft pale
blue or red.
Cytoplasm is agranular
Promyelocytes
Larger than myeloblasts
20-25 um in diameter
Largest cell of the granulocytpoietic
and erythropoietic lines
Chromatin pattern is coarser than that
of the myeloblasts, but nucleoli usually
are present
Small number of prominent, large red
granules are present
You can see in the cytoplasm some
broomstick like rod called Auer
Rods(azurophilic granules, can also be
seen in the myeloblasts)
Myelocyte
It is slightly smaller than promyelocyte
14 to 20 um in diameter
Most mature mitotic cell in the
myeloid lineage
Coarse promyelocytic granules become
more sparse, the typical fine
neutrophilic granularity becomes
predominant
Basophilic cytoplasm lightens from the
nucleus outward
Nucleoli are rarely visible
Page 1 of 22
 Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

Nucleus is much smaller Chronic Myelogenous Leukemia,

Metamyelocyte (Philadelphia chromosome t 9:22
About the same size as myelocyte q34;11 BCR/ABL positive)
Nucleus becomes indented or Chronic Neutrophilic Leukemia and
horseshoe-shaped the Hypereosinophilic Syndrome
Nuclear chromatin becomes even Polycythemia Vera
coarser and more dense Chronic Idiopathic Myelofibrosis
Cytoplasm and granules remain (with extramedullary
essentially the same hematopoiesis); Primary
CHRONIC MYELOPROLIFERATIVE Myelofibrosis
NEOPLASMS Essential Thrombocythemia/
Classic MPN: Thrombocytosis
1 BCRABL (+) Mastocytosis
a Chronic Myelogenous Chronic Myeloproliferative disease,
Leukemia unclassified
2 JAK2 V617F (+) Case Number 1
a Polycythemia Vera S.A. a 42 year old female housewife came in
b Essential Thrombocytosis for consult due to abdominal bloatedness. She
c Myelofibrosis noted progressive abdominal enlargement for
Non-classic MPN the past 6 months associated with weight loss
Chronic Myelomonocytic Leukemia and early satiety.
(CMML) (+) pallor (+) easy fatigability (+) drowsiness
(-) fever, gum bleeding, ecchymoses
Juvenile Myelomonocytic Leukemia Hb = 91 g/L
(JMML) Hct = 0.26 vol %
- PTP 11, NF1, RAS mutations WBC = 131.7 x 109/L
Chronic Neutrophilic Leukemia Platelets = 795 x 109/L
(CNL) Differential Count
- 20% JAK2 V617F (+) - Blasts = 8%
Chronic Eosinophilic Leukemia - Myelocyte = 11%
- Metamyelocyte = 16%
(CEL) - Neutrophils:
- PDGFRA/B mutation - Stabs = 11%
Chronic Basophilic Leukemia (CBL) - Segs = 43%
Hypereosinophilic Syndrome (HES) - Eosinophils = 3%; Basophils = 8%
Systemic Mastocytosis (SM) Ultrasound: (+) splenomegaly, (-)
hepatomegaly
- KIT mutation
Interpret the CBC, platelet count result.
Stem cell Leukemia Lymphoma What is your diagnosis?
(SCLL)
Know the normal values:
- FGFR1 mutation Hgb (female): 12-16 (or 120-160 g/L)
Unclassified MPD (UMPD) Hct: 33-40
- 20% JAK2 V617F (+) WBC: 4500-11,000 cells
Platelet: 150-400 x 109/L
WHO Classification of Chronic Interpretation:
Myeloproliferative Neoplasms WBC is elevated leukocytosis
Platelets elevated - thrombocytosis

Page 2 of 22
 Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis
Immature cells present
Basophilia (normally 0-1 only)
Diagnosis: Chronic Myelogenous
Leukemia
CHRONIC MYELOGENOUS LEUKEMIA
Result of an acquired genetic
abnormality that induces a
malignant transformation of a
single pluripotential
lymphohematopoietic cell
The Philadelphia (Ph) chromosome
is a reflection of the shortened
chromosome 22
Established by identifying a clonal
expansion of a hematopoietic stem
cell possessing a reciprocal
translocation between
chromosome 9 and 22 in more than
95% of patients.
Can also be negative for CML
chromosome but then will be
considered as unclassified
Translocation results in the head-to-
tail fusion of the breakpoint cluster
region (BCR) gene on chromosome
22q11 with ABL (Abelson murine
leukemia) gene located on
chromosome 9q34.
Undergo clonal evolution
Accelerated phase
Rapidly progressive phase resembling acute leukemia
(BLAST CRISIS)
Results from a somatic mutation in
a pluripotential
lymphohematopoietic cell
Characterized by anemia, extreme
blood granulocytosis and
granulocytic immaturity, basophilia,
often thrombocytosis, and
splenomegaly
Most of the cells are granulocytes
with blasts <5%, with basophilia,
often thrombocytosis with PE
usually splenomegaly
Incidence
1.5 per 100,000 people per year
Accounts for approx. 15% of all
cases of leukemia; 3% of childhood
leukemias
poorer prognosis for children
Age-adjusted incidence is higher in
men than in women (1.6:1)
Median age at diagnosis: 55-65
years old
Estimated 10-year survival rate:
85%due to advent of tyrosine
kinase inhibitors
Incidence increases slowly with age
until the middle forties, when it
starts to rise rapidly
Megakaryopoiesis is often
expanded
Erythropoiesis is usually deficient
Usually detected when patients
have routine CBC and PE exam
Etiology
No familial association
Not hereditary
Exposure to high-dose ionizing
radiation increases the incidence of
CML (atomic bomb survivors:
median time: 6.3 years)
o Peaks 5-10 years after
exposure & is dose-related
No association with benzene,
fertilizers, nor insecticides
No clear correlation with exposure
to cytotoxic drugs nor with viruses
just like in ALL
I also have a breast cancer patient
who developed CML. Nowadays,
double primary is very common,
Page 3 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

meaning two types of cancer can
occur simultaneously (eg CML and
breast Ca). I think its also due to
radiation exposure.
Atomic bomb survivors had an
increased incidence
Usually evolves into an accelerated
phase that often terminates in
acute leukemia
I had an OFW patient who was
asymptomatic. Labs showed
elevated WBC and she had
abdominal enlargement (abi
niya buy-on lang). There was no
fatigue nor easy bruisability but
there was weight loss which he
attributed to stress. There was
splenomegaly and
lymphadenopathy (kulani).

Signs and Symptoms

Fatigue
Malaise
Weight Loss
In requesting for FISH, you look at Early Satiety
how many fusions you get in the Left Upper Quadrant Pain
area and you get the percentage, Mass (Splenomegaly)
thats how you interpret results Also hepatomegaly in some
Pathophysiology cases
Chimeric gene is transcribed into a LEUKOSTATIC manifestations:
hybrid BCR/ABL mRNA in which o Vasoocclusive disease,
exon 1 of ABL is replaced by a CVAs, MIs, vascular
variable number of 5 BCR exons thrombosis, Priapism, visual
T(9;22) (q34;q11.2) present in more disturbances, pulmonary
than 90% insufficiency
Results from a balanced reciprocal Hematologic Findings:
translocation between the long o Elevated WBC with increases
arms of chromosome 9 and 22 in both mature and immature
Present in hematopoietic cells like granulocytes
myeloid, erythroid, megakaryocytes o <5% circulating blasts
and monocytes and <10% blasts and
Hybrid oncogene BCR-ABL1 promyelocytes are noted
oncoprotein with majority of them being
Translocation happens more at myelocytes,
the center (centromeric) metamyelocytes, and band
Has 3 phases: forms
o CHRONIC phase o Platelets are almost always
o ACCELERATED phase elevated
o BLAST CRISIS o Normochromic Normocytic
anemia
Clinical onset is generally
o Hypercellular marrow with
INSIDIOUS
increased myeloid to
Some patients are diagnosed while
erythroid ratio
still asymptomatic
Page 4 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

these myeloid cells are mostly Erythrocyte Anemia usually Anemia may be
composed of mature cells with s present present but
only <5% blasts variable NRBC not typical
anisocytosis,
pokilocytes,
NRBC present
LAP Score Low Increased

Chromosom Ph Normal
e chromosome
present
Phases: CML
1 Chronic phase
- Fatigue, abdominal pain
Tyrosine kinase inhibitor - Responds well to chemotherapy
(hematinin) will have a direct 2 Accelerated phase
effect on inhibition to avoid - Fever, fatigue, bone pain
formation of leukemic cells. - Abnormal white count cells
Differential Diagnosis - Spleen enlarged
Leukemoid 3 Blast crisis
Laboratory Reaction - Indistinguishable from acute
CML myeloblastic leukemia
Parameter Reactive
Leukocytosis - Number of blasts cell increases
Leukocytes Blasts and Blasts and promy in marrow and blood
promyelocytes in peripheral
in peripheral blood are rare
blood toxic granulation
changes are dohle bodies
usually absent + cytoplasmic
absolute vacuoles present
basophilia &/or no absolute
eosinophilia basophilia or
neutrophils eosinophilia
with single Usually due
lobed nuclei to infection;
and also usually
hypogranular no
forms may be splenomeg
present aly
Platelets Often Usually normal
increased with can be
abnormal elevated Chronic phase Accelerated phase
morphological but Blastic Crisis
forms present morphology
is normal Median duration Median duration
Median survival
Page 5 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis
3-5 years 6-9 months
3-6 months
CHRONIC PHASE
40% asymptomatic
Symptoms are vague, non-
specific, gradual in onset (weeks
to months)
Clinical features:
Fatigue, anorexia, weight loss,
excessive sweating
Signs and symptoms of
splenomegaly (abdominal
discomfort, early satiety)
Loss of sense of well-being
Uncommon presenting
symptoms: priapism
Priapism
- presence of a persistent, usually
painful, erection of the penis
unrelated to any sexual
stimulation or desire.
Sweet syndrome
- also called acute
neutrophilic dematosis
- perivascular infiltrate
neutrophils in the dermis
Patient will have rashes; look
like pustule
- Usually develops once in blast
crisis
Pulmonary insufficiency, loss of
coordination, confusion,
cerebrovascular accidents
Bleeding diasthesis: retinal
hemorrhages, GI bleeding
Splenomegaly
- most common physical finding
- 20-70%
Hepatomegaly 10-20%
Lymphadenopathy 5- 10%
Basophilia -> histamine
overproduction
Pruritus, diarrhea, flushing,
GI ulcers
Laboratory findings:
Peripheral blood smear
reflecting entire myeloid lineage
<10% blasts in peripheral smear
and bone marrow
t(9;22) translocation
BCR-ABL fusion gene
Hyperuricemia and
hyperuricosuria
- Frequent features of CML at
diagnostic or in relapse
Why does CML progress from chronic
phase?
CML precursor cells suffer
mutations in other genes that lead
to progression of CML
Somatic hypermutation of genes is
triggers by activation-induced
cytidine deaminase in myeloid
precursor cells
febrile
ACCELERATED PHASE
of Transition to accelerated phase
occurs approximately 30 to 40
months after the diagnosis
Occurs at any time after the initial
diagnosis and often precedes
blastic transformation
Heralded by an increase in
splenomegaly
Rising Leucocytosis refractive to
previous active chemotheraphy
Characterized by unexplained
fever, night sweats, weight loss,
malaise, arthralgias
Development of new
extramedullary sites of desease
containing blast cells first sign in
10% of patients
Blood changes include
hyposegmented neutrophils and
thrombocytopenia
Page 6 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

30% of patients in the accelerated - Abolishing symptoms

phase die before blastic crisis TREATMENT OPTIONS FOR CML
develops Rx Toxicity Response
Acute leukemia develops in most HU + Hematologic
patients in this phase IFN ++ CCR 10-30%
BMT +++ DFS >70%
About one-third of patients develop Imatinib + CCR ~70%
ALL HU- Hydroxyurea, IFN- Interferon
Laboratory findings:
BMT- Bone Marrow Transplant
Worsening of anemia
Development of thrombocytopenia HU and IFN are used before.
Prominent basophilia Nowadays, Imatinib is used as the
Increase in the number of first-line drug because of less toxicity
peripheral blood and bone marrow and complete cytogenetic response
blasts (CCR) >70%.
Increase in fibrosis of the marrow
BLASTIC CRISIS
Clinical features:
Unexplained fever, fatigue
Bone involvement: lead to severe
pain, tenderness, changes on x-ray
films
Isolated or diffuse
lymphadenopathy may occur
CNS involvement: usually
meningeal; preceded by headache,
vomiting, stupor, cranial nerve
palsies, and papilledema
Sometimes may also lead to bone
changes such as lytic lesions and
fractures
Laboratory finding: Nilotinib newer drug. Dosage used by
>30% blasts in peripheral blood Doc is 150 mg bid because most
and bone marrow Filipinos cannot tolerate the
Anemia may worsen with increasing recommended dose (300 mg).
anisopoikilocytosis Patients may have leukocytopenia
Thrombocytopenia less than 100 and thrombocytopenia.
000/ul A. Eastern Cooperative Oncology
Follows the course of acute leukemia. Group (ECOG), Zubrod
TREATMENT OF CML Performance Scale
Goals It is very important to know the
- Reducing the leukocyte mass performance status of the patient.
- Restoring bone marrow function Performance
Definition
- Reducing splenomegaly Status
0 Asymptomatic

Page 7 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

Symptomatic; fully
1
ambulatory
Symptomatic; in bed
2
<50 % of day
Symptomatic; in bed
3
>50 % of day
4 Bedridden

B. Karnofsky Performance Status

Scale
Value Level of Functional Capacity
100 Normal, no complaints, no
evidence of disease
90 Abe to carry in normal
activity, minor
signs or symptoms of disease
80 Normal Activity with effort,
same signs or symptoms of
disease

70 Cares for self, unable to carry

on normal activity or to do
active work

60 Requires occasional assistance

but is able to
care for most needs
50 Requires consider able PCR ideally every 3 months
assistance and frequent
medical care C. Sokal Score
40 Disabled requires special care - is a prognostic score done at
and assistance diagnosis to determine the patient as
30 Severely disabled, low-risk, intermediate-risk and
hospitalization is indicated
high-risk based on diagnosis markers
although death is not imminent
of the spleen size, platelet count,
20 Hospitalization is necessary,
age, blast count and cytogenetic
very sick, active supportive clonal evolution.
treatment necessary

10 Dead, fatal processes

progressing rapidly
Note the difference between ECOG
Performance Scale and
KarnofskyPerfomance Status Scale.
o ECOG: 0-asymptomatic; 4-
bedridden/dead
o Karnofsky: 100- asymptomatic;
10-dead
Page 8 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

o Transfusion treatment of severe

anemia
o Antibiotic for treatment of
infections
No treatment method has been
devised that will prevent eventual
blast transformation
Session lasts for 2 3 years
Treatment Goal:
Complete molecular remission and
cure
Complete molecular response
refers to BRCA ABL1 transcripts
(IS) <0.0032% found in the PCR
D. Hasford system results
Developed based on interferon a- Medications
treated patients Hydroxyurea
Identified % of circulating blasts, - Given for hyperleukocytosis
splenic size, platelet count, age, % - Inhibits ribonucleotide reductase
of eosinophils and basophils - Given orally at 1-6 grams per
day
- May sustain the chronic phase of
CML for a longer time
- Median survival: 5 years (2-3
years)

Sokal and Hansford are used to

compute for the risk of the patients
during emergency cases.
Treatment Methods of CML
Leukopheresis used to initially
reduce the leukocyte mass; like a ImatinibMesylate
dialysis, filters WBC
(Glivec/Gleevec)
Supportive measures - First line

Page 9 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

- Inhibits activity of mutant e of CCyR, kinase

(oncogenic) tyrosine kinase by domain mutation,
blocking ATP binding site insensitive to
- Shows specificity for Bcr-Abl, imatinib
receptor for platelet-derived CHR indicates complete hematologic response
growth factor, and Kit TK Four mechanisms of resistance to
- Induces apoptosis in cells Imatinib:
expressing Bcr-Abl - Gene amplification
- Starting dose in chronic phase: - Mutations at the kinase site
400mg/day (oral) - Enhanced expression of multidrug
- Usually takes 3 to 9 months to exporter proteins
achieve desired cytogenetic - Alternative signaling
response pathways functionality
- Side effects: vomiting, edema compensating for the
(fluid retention syndrome imatinib-sensitive
usually periorbital), muscle mechanisms
cramps, diarrhea, headache, o Options for CML patients who are not
abdominal pain doing well on Imatinib
- Event-free survival: 81% - 15-25% of CML patients on
- Overall survival rate: 85% Imatinib eventually require back
- Complete hematologic remission up therapeutic options
rate: 95% - Options now include:
- Complete cytogenetic remission: o Nilotinib 400mg bd (can cause
76% at 18 months severe anemia)
- Progression-free survival o Dasatinib 100mg/d
achieving complete cytogenetic o Bosutinib 500mg/d
remission but less pronounced o Clinical trials
molecular remission (5 yrs): o Stem cell transplants
98% o Common toxicities on 2nd gen TKIs
Blocks the binding of the - In separate Phase II trials in CML
substrate with the receptor, patients after failure:
blocking phosphorylation - Non-hematologic toxicities
Optimal Response (myalgia, nausea, rash and
2006 2009 headache) appeared to be more
3 No hematologic CHR and at least a
common in dasatinib than on
months response minor CyR
nilotinib therapy
(PH+<65%)
Response & survival on 2nd-line
6 Less than CHR At least a partial
nilotinib
months
No Cyr (Ph+ Cyr (Ph+<35%) After imatinib failure, 77% of
>95%) patients with chronic-phase
12 Less than partial CCyR (Ph+ >35%) CML respond to nilotinib
months Cyr 18 months later:
18 Less than CCyR MMR (3-log
months reduction in - 9/10 patients are alive
transcripts) - 2/3 are progression free
Anytim Loss of CHR, loss
Page 10 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

- ?/5 have a complete cytogenetic Autologous SCT

response Leukopheresis and Splenectomy
Phase II trial data:
Nilotinib or Dasatinib after Imatinib HYPEREOSINOPHILIC SYNDROME
in CML Defined as an eosinophilia of
greater than 1.5x106 cells/L for
more than 6 months with, at that
time, no other explanation and
evidence of organ damage
WHO takes the view that all
myeloproliferative variants of HES
are malignant conditions.
Prevalence:
1 in 50,000 person (rare)
Sporadic
No significant geographic or
environmental influences
Male> female
Pathogenesis:
the sporadic occurrence of striking
eosinophilia and cardiac and
neurologic injury as a consequence
Nilotinib (Tasigna)
of the noxious effects of the
- Tyrosine kinase inhibitor
eosinophil granule content:
- Contraindications: long QT
o Eosinophil granule contents
syndrome, hypokalemia,
- Major Basic Protein (MBP)
hypomagnesemia, pregnancy,
- EPO (eosinophilic
planned pregnancy, lactation
peroxidase)
- 150mg-200mg/tablet
- Eosinophilic-derived
- Adverse effects: headache,
neurotoxin
fatigue, nausea, vomiting,
- Eosinophilic cation
diarrhea, constipation, muscle
protein
and joint pain, rash, flu-like
o Strong agonist for platelet
symptoms
Used if resistant to Imatinib activation and production of
mast cells, basophils and
Dasatinib (Sprycel)
neutrophils
- Binds to the kinase domain
Major target organs for tissue
- 100mg/day
- Causes pleural effusion in 22% damage are the skin, heart, lungs,
of patients and nervous system
TREATMENT May be an inflammatory or a
Interferon before Imatinib, neoplastic process
treatment of choice Some cases are a polyclonal
Allogenic HSCT eosinophilia
Others monoclonal eosinophilia
Chemotherapy
(Chronic Eosinophilic Leukemia)
Page 11 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

HES appears to be a heterogeneous Nervous system dysfunction may

condition with some patients be profound including confusion,
having evidence of abnormal T-cell delirium, dementia, and coma
clones, some of which overproduce Has a heterogenous presentation.
IL-5, and some cases being because Can present with non-specific
of somatic mutations leading to symptoms such as general malaise,
constitutively active tyrosine weight loss, aches and pains, and
kinase. sweating attacks, or with one of the
organ-specific features.
It is a chronic disease that usually
presents in the 3rd or 4th decade but
can occur at any age, including
(rarely) in childhood.
Differential Diagnosis:
Allergic disease like allergy to
thermotolerant colonizing fungi
Two broad variants: myeloid and such as Aspergillus fumigatus and
lymphoid. Myeloid variant has Candida albicans.
features in common with Chronic infection with helminthic
myeloproliferative neoplasms, parasites
including raised serum vitamin B12 Severe asthma
and serum typtase, elevated
Chronic eosinophilic pneumonia
neutrophil alkaline phosphatase
Drug allergy
score, clonal chromosomal
abnormalities, anemia, and Malignancy
thrombocytopenia, splenomegaly, Eosinophilic gastroenteritis
and circulating blast cells. The (regarded as part of the HES
lymphoid variant of HES is spectrum)
presumed to be a result of the Laboratory features:
overproduction of eosinophil- Anemia occurs in most patients
related growth factors by aberrant Thrombocytopenia is seen
T cells. The eosinophils are normal occasionally
unlike the myeloid variant.
ALL patients have leukocytosis with
Clinical features:
a striking eosinophilia, usually
Onset with some or all of the ff: greater than 1500 eosinophils/ul
anorexia, wt loss, fatigue, nausea, Eosinophil count of 50,000/ul or
abdominal pain, diarrhea, cough, more are found in more than the
pruritic rash, fever, night sweats, patients
and venous thrombosis
The eosinophilia may be
Most patients have cardiac
progressive
involvement with congestive heart
The marrow shows only eosinophilia
failure, new murmurs, conduction
Therapy, Course, and Prognosis
defects and arrhythmias
Hepatosplenomegaly Sometimes indolent, but more often
progressive and fatal

Page 12 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

Organ damage is usually A slight overall male

progressive predominance has been observed
Cardiac failure may result from Etiology is unknown
endomyocardial fibrosis Familial incidence has been
CNS dysfunction: encephalopathy, occasionally reported.
polyneuropathy or stroke GENETIC MUTATION
Episodes of venous thrombosis may Mutation in JAK2 tyrosine kinase
complicate the course Cells become abnormally sensitive
The mainstays of treatment: to low levels of erythropoietin
Glucocorticoids and Neoplastic transformation of a
Hydroxyurea single normal hematopoietic
Glucocorticoid first line multipotential cell
Hydoryurea second line Erythropoietin Receptor
Other therapies: etoposide, Signaling. Binding of Epo to its
interferon-a, cladribine, and receptor (EpoR) results in receptor
leukopheresis homodimerization and
Stem cell transplant autophosphorylation of the
Newer therapies: anti-IL5 and receptor-associated Janus kinase 2
tyrosine kinase inhibitor (JAK2). Activated JAK2 in turn
imatinibmesylate mediates the phosphorylation of
Course and prognosis: 1973 report- key tyrosine residues on the distal
3 year survival of 12% with cardiac cytoplasmic region of EpoR, which
failure; latest report- 80% survival then serve as docking sites for
in 5 years.
downstream effectors, including
POLYCYTHEMIA signal transducer and activator of
Two major forms: transcription protein 5 (STAT5) and
1. Polycythemia Vera phosphatidylinositol 3 kinase (PI3
2. Secondary Polycythemia kinase). Activated STAT5
- in which only red cell production homodimerizes and translocates to
is increased in response to the nucleus to affect gene
appropriate or inappropriate transcription. In polycythemia
elevation in erythropoiesis vera, JAK-STAT is constitutively
POLYCYTHEMIA VERA
hyperactivated by gain-of-
Is a clonal disorder of a multipotent function JAK2 mutation.
hematopoietic progenitor cell that Other Abnormalities:
results in exaggerated proliferation
Decreased levels of the platelet
and accumulation of phenotypically
thrombopoietin receptor
normal RBCS, granulocytes and
platelets Deregulation of BCL-x, an inhibitor
of apoptosis
Accumulate in the absence of a
recognizable physiologic stimulus Increased expression of protein
tyrosine phosphatase activity by
Most common of the CMPN
red cell precursors
Occurs in 2 per 100,000 persons

Page 13 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

Increased mRNA levels of the Increased expression of the

Polycythemia rubra vera (PRV) 1 mRNA of PVR-1 (a
gene in granulocytes glycosylphosphatidylinositol
Acquired or heterozygosity of (GPI)-linked membrane
chromosome 9p as a result of protein)
uniparenteral disomy -> JAK2
V617F mutation located on
chromosome 9
This is a very important gene for
the development of both PV and
myelofibrosis
A. Somatic mutation, JAK2 V617F
Results in constitutive hyperactivity
of JAK2 stemming from the loss of
function of its negative regulatory
domain
B. Mutation in the Autoinhibitory,
pseudokinase domain of the tyrosine ALGORITHM FOR POLYCYTHEMIA
kinase JAK2 (which replaces valine with
phenylalanine [V617F] causes
constitutive activation of the kinase
central role in pathogenesis
C. Chromosomal abnormalities: 20q
and Trisomy 8 & 9
D. JAK2
member of the nonreceptor
tyrosine kinase family
Serves as the cognate tyrosine
kinase for the erythropoietin and
thrombopoietin receptors
The gene is located on the short
arm of chromosome 9
Also functions as an obligate
chaperone for the receptors in the
Golgi apparatus and is responsible Criteria for Diagnosis of
for their cell-surface expression Polycythemia Vera
E. JAK2 V617F (WHO, 2008)
basis for many of the phenotypic Major Criteria:
and biochemical characteristics of 1 Hgb > 18.5 g/dl (men), >16.5 g/dl
PV: (women), or,
Elevation of the leukocyte 2 Hgb or Hct > 99th percentile of
alkaline phosphatase (LAP) reference range for age, sex, and
score altitude of residence, or,

Page 14 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

3 Hgb > 17 g/dl (men), >15 g/dl - Sweating

(women) if associated with a
sustained increase of 2 g/dl from
baseline that cannot be attributed
to correction of iron deficiency, or,
4 Elevated red blood cell mass > 25%
above mean normal predicted
value, and,
5 Presence of JAK 2 V617F or similar
mutation
Minor criteria:
1 Bone marrow trilineage
myeloproliferation
2 Subnormal serum erythropoietin
level
3 Endogenous erythroid colony
formation
Diagnosis requires major criteria
plus one minor criterion or the first
major criterion plus two minor

Pruritus after bathing occurs in 40%

of patients; a specific complaint that
should suggest the diagnosis
Neurologic complaints:
- Vertigo
- Diplopia
- Scotomata
- Transient Ischemic Events
Associated disorders:
- Peptic ulcer disease
as a consequence of increased
criteria.
histamine levels
CLINICAL MANIFESTATIONS - Gout
Onset is insidious as a consequence of increased
Average age: 60 years old nucleic acid turnover and urate
Occurs rarely in children or young production
adults - Erythromelalgia
Symptoms occurring in at least syndrome of warmth of the
30% of patients: extremities, painful, reddened
- Headache digits, a burning sensation, and
- Weakness erythema of the fingers and
- Pruritus hands and feet, associated with
- Dizziness thrombocytosis

Page 15 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

A complication of the Basophilia (seen in all MPNs)

thrombocytosis of polycythemia Uric acid (can lead to gout)
vera Leukocyte alkaline phosphatase
Responds rapidly to low dose score
aspirin therapy Low EPO levels
Severe cases results in ischemic
Positive JAK2 V617F
necrosis of the digits
Elevated serum B12 level
amputation
- Thrombotic events Normal or near-normal arterial
occur in about one-third of oxygen saturation
patients prior to diagnosis
Occur in 40-60% during the first
10 years after the diagnosis
Include stroke, myocardial
infarction, deep venous
thrombosis, hepatic vein
thrombosis and pulmonary
embolism Risk of Polycythemia Vera
Bleeding and bruising occur in Low risk
1/4 of patients - no history of thrombosis
Patients with uncontrolled PV - age <60 years
undergoing surgery high risk of - no cardiovascular risk factors
bleeding and/or thrombosis High risk
Splenectomy early in the disease - history of thrombosis and
leads to uncontrolled, often age >60 years
fatal thrombosis \
Intermediate risk
LAB FINDINGS
- Neither low nor high risk but
Erythrocyte count, red cell mass is cardiovascular risk factors
usually elevated present.
Nucleated red cells are usually - Pegylated interferon is
NOT present in the blood early in effective for cytoreduction,
disease especially in pregnant
Reticulocyte percentage is usually women. Novel therapies for
slightly increased polycythemia vera are in
Absolute neutrophilia occurs in phase I/II trials.
2/3 of patients MANAGEMENT
Platelet count increased in over Therapy:
50% of patients Phlebotomy
- >1 million platelets in 10% - Best initial therapy for most
of cases patients
CBC - Average size: 450-500 ml about
- Hgb/Hct every 4 days
- WBC in 45% - Target hematocrit:
- Plts > 50% Less than 50% in men
Less than 45% in women
Page 16 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

- Includes iron deficiency 25% of patients are asymptomatic

Myelosuppressive agents: Symptoms:
- Should be considered in patients - Fatigue
with: - Weakness
Advanced age - Shortness of breath
Extreme thrombocytosis - Palpitations
Thrombotic or bleeding - Weight loss
complications - Night sweats
Severe systemic complaints - Bone pain
not responding to Nonrandom chromosome
phlebotomy, low-dose abnormalities:
aspirin - 9p, 20q-, 13q-, trisomy 8 and 9 or
The most important diagnostic partial trisomy 1q are common
features of - JAK2 V617 present in 50%
Polycythemia Vera are: PHYSICAL EXAM FINDINGS
Erythrocytosis (elevated Splenic enlargement and/or
hematocrit) infarction: left upper quadrant
Leukocytosis (especially fullness, pain or dragging
neutrophila) sensation, left shoulder pain, early
Thrombocytosis satiety
Hepatomegaly seen in 2/3 of
Splenomegaly
patients
PRIMARY MYELOFIBROSIS Splenomegaly is present in all
Agnogenic myeloid metaplasia or patients at the time of diagnosis;
myelofibrosis with myeloid massive in 1/3
metaplasia, or idiopathic DIAGNOSTIC ALGORITHM FOR SUSPECTED
myelofibrosis PMF
A clonal disorder of a multipotent
hematopoietic progenitor cell of
unknown etiology
Marrow fibrosis, extramedullary
hematopoiesis, and splenomegaly
Presence of immature granulocyte,
erythroid precursors and teardrop-
shaped red cells, varying degrees
of marrow fibrosis
Least common of the CMPN
Median age at diagnosis: 65 years
old
Sex incidence is equal in adults but
twice in female children
Etiology is unknown but Ph = Philadelphia; BM = bone marrow;
occasionally preceded by extended MDS = Myelodysplastic Syndrome;
exposure to benzene or very high- FISH = fluorescence in situ hybridization
ionizing radiation
Page 17 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

LABORATORY FINDINGS Megakaryocytes can be prominent

Normocytic, normochromic anemia even in hypocellular densely fibrotic
Aniso-poikilocytosis, tear-drop cells, specimens
nucleated RBCs Granulocytes may show hyper- or
Neutropenia occurs in 15% of hypolobulation, acquired Pelger-
patients Huet anomaly, nuclear blebs, and
Reticulocyte count is variable nuclear-cytoplasmic asynchrony
Hemolysis may be present and 50% express the JAK2 V617F
maybe autoimmune, with a (+) mutation
Coombs test 2008 WHO DIAGNOSTIC CRITERIA
Total WBC is usually <40,000/ul, FOR PMF
but may be as high as 100,000/ul All major criteria plus 2 minor criteria
with neutrophilic granulocytosis are required for diagnosis.
Myelocytes and metamyelocytes MAJOR MINOR
are present with 1-5% circulating 1. Megakaryocyte 1. Leukoerythroblastosis
blasts proliferation and (immature RBCs and
Pacytopenia occurs in 10% of atypia with either WBCs in the PB)
patients usually secondary to reticulin or collagen 2. Increased LDH
ineffective hematopoiesis fibrosis, or if no 3. Anemia
coupled with splenic fibrosis, 4. Splenomegaly
sequestration megakaryocytic
The presence of teardrop-shaped expansion must be
red cells, nucleated red cells, assoc. with
increased BM
myelocytes, and promyelocytes
cellularity
establishes the presence of
2. Not meeting WHO
extramedullary hematopoiesis,
criteria for CML, PV,
while the presence of leukocytosis,
MDS, or other
thrombocytosis with large and
myeloid disorders
bizarre platelets, and circulating
3. Demonstration of
myelocytes suggests the presence the JAK V617F
of an MPD as opposed to a mutation or other
secondary form of myelofibrosis. clonal marker or no
MARROW FINDINGS evidence of a
Marrow aspiration is usually reactive marrow
unsuccessful due to fibrosis (dry fibrosis
tap) TREATMENT
No specimen so proceed with Androgen therapy
reticulin/silver staining Glucocorticoids
Collagen fibrosis may be present
Hydroxyurea
and can be extreme
Interferon-alpha
Silver stain invariably shows
Allogenic BMT only curative
increased reticulin
method
Ruxolitinib (Jakavi)
- a JAK 1 and JAK 2 inhibitor
Page 18 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

- Treatment for PMF, post- Presently, the disorder is being

polycythemia vera MF or post- discovered in younger individuals
essenial thrombocytopenia MF and in asymptomatic individuals
- 5, 10, 15, 20 mg through routine CBC, platelet
counts
Rare familial cases have been
reported
Mild splenomegaly 40-50% of
patients
Patients may have ecchymoses and
bruising
DIAGNOSTIC ALGORITHM

DIAGNOSTIC CRITERIA
ESSENTIAL THROMBOCYTHEMIA
Persistent thrombocytosis more
A clonal disorder of multipotential
than 400,000/L in the absence of a
hematopoietic stem cells that is reactive cause
considered to be a chronic
Absence of iron deficiency (normal
myeloproliferative disorder related
serum ferritin for sex)
to PV, CML and myeloid metaplasia
with or without myelofibrosis JAK2 V617F assay (peripheral blood
Usually develops between ages 50 expression establishes the
presence of an MPD but not its
and 70 years old
type; absence does not exclude
Sex distribution is equal
MPD)
Megakaryopoiesis and platelet Hemoglobin <16g/dL in a man or
production depend on
<14g/dL in a woman (haematocrit
thrombopoietin and its receptor Mpl
47% in a man or 44% in a woman)
in the absence of splenomegaly;
Page 19 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

otherwise, red cell mass and Post-operative

plasma volume determinations are
mandatory if a JAK2 V617F assay is 2. Thrombotic complications
positive Thrombosis most common in
Negative Bcr-Abl FISH (peripheral cerebral, peripheral, and
blood) if a JAK2 V617F assay is coronary arteries; more often
negative arterial than venous
If there is anemia, macrocytosis or May present to the ER as
leukopenia, or evidence of stroke and lab exam would
extramedullary hematipoiesis (i.e. reveal elevated platelet
circulating nucleated erythrocytes, count, meaning the CVD was
immature myeloxytes or secondary to ET
splem=nomegaly), a bone 25% of all thrombotic events are
marrow examination (including lower-extremity deep venous
flow cytometry and cytogenetics) is thrombosis
mandatory regardless of JAK2 Use of aspirin occasionally
V617F exoression status lead to serious bleeding
MPD indicates myeloproliferative complications
disorder, and FISH, fluorescent in LABORATORY FINDINGS
situ hybridization. Platelet counts may range from only
Difficulty in diagnosis is how slightly above normal to several
to differentiate it from million platelets per microliter
reactive thrombocytosis Platelets may be large, pale blue-
THREE MAJOR PATHOPHYSIOLOGIC staining and hypogranular
CAUSES OF THROMBOCYTOSIS Nucleated megakaryocyte fragments
1. Clonal including essential having a lymphoblastoid appearance
(primary) thrombocytopenia and may be seen occasionally in the
other myeloproliferative disorder blood film
2. Familial including rare cases of Bleeding time is prolonged in less
nonclonal myeloproliferation than 20% of patients
resulting from thrombopoietin The diagnosis is made by
mutations
exclusion because there is no
3. Reactive in which
specific marker for the disease
thrombocytosis occurs secondary to
Leukocyte differential count is usually
a variety of acute and chronic
normal, without nucleated red cells
clinical conditions
Marrow shows increased cellularity
TWO MAJOR CAUSES OF MORBIDITY AND with megakaryocytic hyperplasia and
MORTALITY masses of platelet debris (platelet
1. Bleeding is common and is drifts)
characteristic of platelet disorder or Megakarocytes are frequently giant,
vascular disorder: with increased ploidy and occurs in
Mucosal clusters
Gastrointestinal Anemia is unusual
Cutaneous The following should be
Genitourinary demonstrated:
Page 20 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

- Platelet count is usually greater

than 600,000/ul (some patients Low Risk Intermediate High Risk
have platelet counts in the normal Risk
range or only slightly elevated) No history of Neither low nor History of
- Philadelphia chromosome is absent thrombosis high risk but thrombosis
- Patient is not iron deficient Age <60 cardiovascular Age >60 years
- No evidence for myelofibrosis years risk factors are
- No recognizable cause for Platelet present
secondary thrombocytosis count <1
2008 WHO DIAGNOSTIC CRITERIA FOR ET million
Diagnosis requires that all four A. The first line cytoreductive therapy of
criteria are met. choice is hydroxyurea for patients of
1. Platelet count >450 x 109L any age except women of childbearing
2. Bone marrow shows megakaryocytic age, for whom interferon alpha will be
proliferation with large and mature the treatment of choice.
morphology and little or no B. In patient with a platelet count of >1
granulocyte or erythroid proliferation million, acquired von Willebrand
3. Patient does not meet WHO criteria for syndrome must be ruled out before
CML, PV, PMF, MDS or other myeloid starting aspirin because it can cause
neoplasms severe bleeding. Anogrelide may also
4. Demonstration of JAK2 V617F mutation be used to lower the platelet count.
or other clonal markers and no 1. HYDROXYUREA
evidence of reactive thrombocytosis
Highly effective as initial
TREATMENT treatment
Asymptomatic Patients Nonspecific
- The need to treat is myelosuppressive drug,
controversial WBCs and Hb can be
Symptomatic Patients decreased as well
- Lowering the platelet count in Inhibits ribonucleotide
patients with active bleeding reductasse, which converts
and/or thrombosis is beneficial ribonucleotide diphosphates to
- Prompt reduction is especially deoxyribonucleotides
warranted in patients with 10-30 mg/kg/day orally
microvascular digital or Leukemogenic
cerebrovascular ischemia May cause reversible painful leg
- Urgent reduction can be ulcers
achieved by platelet pheresis Renal excretion is major source
rebound increase in platelet of elimination
count 2. ANAGRELIDE
Treatment Algorithm for Essential Thrombocytosis Inhibits marrow megakaryocyte
Risk Cytoreductio Aspirinb maturation
na More specific, inhibits
Low No Yes megakaryocytes alone
Intermediate No Yes
High Yes Yes
Page 21 of 22
Block 18 | Module 3 | Lesson 1
Chronic Myeloproliferative Diseases, Polycythemia Vera, Thrombocytosis

Effective alternative first-line Blasts = 21%

therapy Eosinophils = 11%
Starting dose 0.5mg 4x/day or 1mg Myelocyte = 33% Basophils
2x/ day = 8%
Weekly dose adjustments Metamyelocyte = 5%
Side effects: neurologic and Neutrophils: Stabs = 6%;
gastrointestinal symptoms, Segmenters = 16%
palpitations and fluid retention
3. RECOMBINANT INTERFERON- Ultrasound: (+) splenomegaly
(-) hepatomegaly
Suppresses the abnormal
megakaryocyte clone A. Interpret the CBC, platelet count
3 million units subcutaneously daily result.
Principal side effect: flu-like B. What is your clinical impression?
symptoms Chronic Myelogenous
4. ASPIRIN THERAPY Leukemia, Blast Crisis
Controversial C. What specific diagnostic test/s are
The major cause of morbidity and you going to request?
FISH, karyotyping
mortality are thrombosis and
D. It is the most common of the CMPN.
hemorrhage
Polycythemia Vera
POST TEST E. Described as a sporadic occurrence
1. R.B., a 24-year-old, male, unemployed, of striking eosinophilia and cardiac
came in for consult due to abdominal and neurologic injury due to the
bloatedness. He observed progressive noxious effects of eosinophil
enlargement of this abdomen for the granule content.
past 4 months associated with weight Hypereosinophilic Syndrome
loss and early satiety. F. The best initial therapy for most
Pertinent positives: pallor, easy patients with polycythemia vera?
fatigability, dizziness Phlebotomy
Pertinent negatives: fever, gum
bleeding, ecchymoses Reference:
Hb = 37 g/L
Hct = 0.11 L/L Williams Hematology Chap 62:
WBC = 131,7 x109/L Eosinophils and Related Disorders
Platelets = 195 x10/L
Differential count:

Page 22 of 22