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MIELOPROLIFERATIVE
DISORDERS
INSTITUTUL REGIONAL DE
ONCOLOGIE IASI
CLINICA HEMATOLOGIE
2012-2013
CHRONIC MYELOPROLIFERATIVE
DISORDERS (MPD)
MPD are clonal
diseases originating in
pluripotential haematopoietic stem cell.
The clonal expansion results in increased and
abnormal haematopoiesis and produces a
group of interrelated syndromes, classified
according to the predominant phenotypic
expression of the myeloproliferative clone.
CHRONIC MYELOPROLIFERATIVE
DISORDERS (MPD)
Neoplastic (clonal) disorders of hemopoietic
stem cells
Over-production of all cell lines, with usually
one line in particular
Fibrosis is a secondary event
Acute Myeloid Leukemia may occur
HAEMATOPOIESIS
HEMATOPOIETIC PROGENITORS
Genetic
Mutation
National Cancer Institute
GENERALITIES
Hemopoietic stem cell disorder
– Clonal
– Characterized by proliferation
– Granulocytic
– Erythroid
– Megakaryocytic
Interrelationship between
– Polycythaemia
– Essential thrombocythaemia
– myelofibrosis
GENERALITIES
Normal maturation (effective)
Increased number of
Red cells
Granulocytes
Platelets
(Note: myeloproliferation in myelodysplastic syndrome is ineffective)
Frequent overlap of the clinical, laboratory & morphologic
findings
Leucocytosis, thrombocytosis, increased megakaeryocytes,
fibrosis & organomegaly blurs the boundaries
Hepatosplenomegaly
Sequestration of excess blood
Extramedullary haematopoiesis
Leukaemic infiltration
Rationale for classification
Classification is based on the lineage of the
predominant proliferation
Level of marrow fibrosis
Clinical and laboratory data (FBP, BM,
cytogenetic & molecular genetic)
CHRONIC MYELOPROLIFERATIVE
DISORDERS
WHO Classification of CMPD
 Ch Myeloid leukemia
 Ch Neutrophillic leukemia
 Ch Eosinophillic leukemia / Hyper Eo Synd
 Polycythemia Vera
 Essential Thrombocythemia
 Myelofibrosis
 CMPD unclassifiable
MYELOPROLIFERATIVE
DISORDERS
MPD
•PRV
•ET
•MF
CML
CMML
MDS
•RA
•RARS
•RAEB I
•RAEB II
AML
CHRONIC MYELOPROLIFERATIVE
DISORDERS
Chronic Myeloid leukemia (BCR-ABL positive)
Polycythemia Vera
Essential Thrombocythemia
Myelofibrosis
– Specific clincopathologic criteria for diagnosis and
distinct diseases, have common features
– Increased number of one or more myeloid cells
– Hepatosplenomegaly
– Hypercatabolism
– Clonal marrow hyperplasia without dysplasia
– Predisposition to evolve
Bone marrow stem cell
Clonal abnormality
Granulocyte
precursors
Chronic myeloid
leukemia
Red cell
precursors
Polycythaemia
rubra vera
(PRV)
10%
70%
AML
Megakaryocytes
Reactive
fibrosis
Essential
thrombocytosis
(ET)
Myelofibrosis
10%
30%
CHRONIC
MYELOGENOUS
LEUKEMIA (CML)
CML - INTRODUCTION
Clonal malignant myeloproliferative disorder
characterized by increased proliferation of the
granulocytic cell line without the loss of their
capacity to differentiate
Results in increases in myeloid cells, erythroid cells
and platelets in peripheral blood and marked myeloid
hyperplasia in the bone marrow
Originate in a single abnormal haemopoietic stem cell
CML - BACKGROUND
CML was the first human malignancy to be
associated with a specific genetic lesion, the
Philadelphia chromosome, harboring the BCRABL oncogene. Since then, it has become a
paradigm for the discovery of molecular
mechanisms
and
targeted
therapeutic
approaches in the field of hematologic
neoplasias.
CML - EPIDEMIOLOGY
CML accounts for 20% of all leukemias affecting
adults.
Frequency - 10-15 new cases, each year, for one
million population.
In general, this disease occurs in the fourth and fifth
decades of life.
Younger patients aged 20-29 years may be affected
and may present with a more aggressive form, such as
in accelerated phase or blast crisis.
Sex ratio is 1,4-2,2 (m/f).
CML - ETIOLOGY
Etiology
– Not clear
– Little evidence of genetic factors linked to the
disease
– Increased incidence
Survivors of the atomic disasters at Nagasaki &
Hiroshima
Post radiation therapy
LEUKEMOGENESIS
Philadelphia chromosome is an
acquired cytogenetic anomaly
that is characterizes in all
leukaemic cells in CML
90-95% of CML pts have Ph
chromosome
Reciprocal translocation of
chromosome
22
and
chromosome 9
CML - Ph CHROMOSOME
LEUKEMOGENESIS
BCR (breakpoint cluster region) gene on
chromosome 22 fused to the ABL (Ableson
leukemia virus) gene on chromosome 9
Ph chromosome is found on myeloid,
monocytic, erythroid, megakaryocytic, B-cells
and sometimes T-cell proof that CML derived
from pluripotent stem cell
LMC - CROMOZOMUL Ph
Gena ABL – Crs 9
Ia
Ib
a2
a3
a11
3’
5’
Gena BCR – Crs 22
5’
e1
e1 ’
e2’
e6
b3
M-bcr
m-bcr
BC
R
b2
e19
3’
μ-bcr
ABL
P190
P210
P230
Consequences of p210BCR-ABL
Molecular consequence of the t(9;22) is the fusion
protein BCR–ABL, which has increased in tyrosine
kinase activity
BCR-ABL protein transform hematopoietic cells so that
their growth and survival become independent of
cytokines
It protects hematopoietic cells from programmed cell
death (apoptosis)
– deregulated cellular proliferation,
– decreased adherence of leukemia cells to the bone marrow stroma
– reduced apoptotic response to mutagenic stimuli
LMC - CROMOZOMUL Ph
CML – HISTORY (I)
Disease is biphasic, sometimes triphasic
The clinical manifestations of CML are insidious and
are often discovered incidentally
- 40%
asymptomatic
Chronic phase
Splenomegaly often massive
Symptoms related to hypermetabolism
–
–
–
–
Weight loss
Anorexia
Lassitude
Night sweats
CML – HISTORY (II)
Features of anaemia
– Pallor, dyspnoea, tachycardia
Abnormal platelet function
– Bruising, epistaxis, menorrhagia
Hyperleukocytosis
–
–
–
–
thrombosis
Increased purine breakdown : gout
Visual disturbances
Priapism
Some patients may present with complications –
spleen infarction, spleen fracture, peptic ulcer with
hemorrhagia.
CML – PHYSICAL (I)
Splenomegaly
(70–85%) - is the most
common physical finding in patients with
CML.
– The size of the spleen correlates with the
peripheral blood granulocyte counts
– A very large spleen is usually a harbinger of the
transformation into an acute blast crisis form of the
disease
Hepatomegaly also occurs, although less
commonly than splenomegaly , in 20–45%,
Lymphadehopaties - signifie the evolution to
the accelerated/blastic phase.
CML – PHYSICAL (II)
Fever, purpura.
Physical findings of leukostasis and
hyperviscosity can occur in some patients, with
extraordinary elevation of their WBC counts,
exceeding 300,000-600,000 cells/mmc :
–
–
–
–
–
–
–
headache,
dizziness,
vertigo,
tinnitus,
visual disturbances,
angina pectoris, or
intermittent claudications.
CML – PERIPHERAL BLOOD
Leucocytosis (a total WBC count of 20,000-over
100.000 cells/mL) with circulating immature cells
from the bone marrow, such as myeloblasts,
myelocytes, metamyelocytes, and nucleated red blood
cells, mimicking the findings in the bone marrow.
Basophilia - 2-4%, over 7% in 10 – 15 % patients
Eosinophilia
Mild-to-moderate anemia usually normochromic and
normocytic
Thrombocitosis - 500.000–600.000/mm3, to 1–2
million/mm3.
CML – PERIPHERAL BLOOD
CML – PERIPHERAL BLOOD
CML – BONE MARROW
Marrow aspirate - Bone marrow is
–
–
–
–
–
Hypercellular (reduced fat spaces)
Myeloid:erythroid ratio – 10:1 to 30:1 (N : 2:1)
Myelocyte predominant cell, blasts less 10%
Megakaryocytes increased & dysplastic
Increase reticulin fibrosis in 30-40%
BOM - confirms the hyperplasia of
hematopoietic tissue. Mild fibrosis is often
seen in the reticulin stain.
CML – BONE MARROW
CML – BONE MARROW
CML – BIOLOGY
the leukocyte alkaline phosphatase stains very
low to absent in most cells, resulting in a low
score .
markedly elevated serum vitamin B-12–binding
protein (TC-I);
hemostasis  thrombocytopathia with prolonged
bleeding
time
and
decreased
platelet
aggregability.
hyperuricemia and hyperuricuria, elevated LDH;
hyperhistaminemia;
CML - EVOLUTION
Chronic phase
Accelerated phase
Acute phase (blastic phase)
Complications
–
–
–
–
–
–
–
anemia, infections,
bleeding or thrombosis (priapism),
spleen infarction or fracture,
pulmonary (infarction, infections),
bone (pains, distruction, hypercalcemia),
neurologic (leucostasis, hemorragia, thrombosis),
metabolic (gout)
LMC – ACCELERATED PHASE
Median duration is 3.5 – 5 yrs before evolving to
more aggressive phases
May last for several months.
– Clinical features
Increasing splenomegaly refractory to chemo
Increasing chemotherapy requirement
– Lab features
Blasts>15% in blood
Blast & promyelocyte > 30% in blood
Basophil 20% in blood
Thrombocytopenia
Cytogenetic: clonal evolution
CML – BLASTIC PHASE
Criteria :
– Resembles acute leukaemia
– Diagnosis requires > 30% blast in marrow
– 2/3 transform to myeloid blastic phase and 1/3 to lymphoid
blastic phase
– Survival : 9 mos vs 3 mos (lym vs myeloid)
BCR-ABL – detection techniques
Conventional cytogenetic analysis
Fluorescece in situu hybridisation (FISH)
Polymerase chain reaction (PCR)
Reverse transcriptase – PCR (RT-PCR)
Real-time quantitative PCR (RQ-PCR) for BCRABL mRNA
Utility :
– Diagnosis positif and differential
– Monitorising drug therapy
– Assesment of minimal residual disease (MRD)
Diagnostic Considerations in
Chronic Myeloid Leukemia
Demonstrating the presence of the t(9;22) or its gene product is
absolutely essential in diagnosing a patient with CML
Karyotyping in CML
1)
Allows for the diagnosis of CML
2) Requires a bone marrow aspirate for optimal
metaphases
3) Allows for evaluation of clonal evolution as well as
additional chromosomal abnormalities in the nonPh+ clones
4) Occasional cryptic and complex karyotypes can
result in the missed identification of the t(9;22)
Source Undetermined
Diagnostic Considerations in
Chronic Myeloid Leukemia
Fluorescence in-situ hybridization
(FISH) in CML:
1) Allows for the diagnosis of CML
2) Does not require a bone marrow aspirate for
optimal results
3) Allows for the identification of potential
duplications of the Ph chromosome
4) Allows for the identification of the loss of the
der (9) chromsome
5) Allows for the identification of cryptic
translocations involving Bcr-Abl
Bcr- Ch 22
Abl – Ch 9
Bcr-Abl Fusion
Source Undetermined
LMC - FISH
Diagnostic Considerations in
Chronic Myeloid Leukemia
Bcr-Abl
cDNA
Quantitative RT-PCR
for Bcr-Abl in CML
Bcr
1)
Allows for the diagnosis of CML
Abl
2) Does not require a bone marrow aspirate for optimal
results
3) Can quantify the amount of disease
4) Allows for the identification of cryptic translocations
involving Bcr-Abl
5) Many primers sets only detect the p190 and/or the
p210 translocation and may miss the p230 or
alternative translocations
Source Undetermined
CML – PROGNOSTIC
Poor prognosis features in patients with CML
include :
–
–
–
–
–
–
–
–
older age
symptomatic presentation
poor performance status
Hepatomegaly, splenomegaly
negative Ph chromosome or bcr-abl
anemia
thrombocytopenia/thrombocytosis,
basophilia, or myelofibrosis (increased reticulin or
collagen)
– longer time to hematologic remission with
myelosuppression therapy
CML – PROGNOSTIC
Sokal Score
(+)/0(t) = Exp 0,0116 (Age - 43,4) +
0,0345 (spleen - 7,51)+ 0,188 (Pt/700)2 0,563 + 0,0887 (blasts - 2,10)
Score
– IS = < 0,8
– IS = 0,8 - 1,2
– IS = >1,2
Median survival
Survival at 48 months
60 months
44 months
32 months
62%
43%
33%
CML – GENERAL
MANAGEMENT
Discussion with family
– The disease & diagnosis
– Prognosis
– Choices of treatment
Cytotoxic drug vs bone marrow transplant
Side effect
CML – PRINCIPLES OF
TREATMENT
Relieve symptoms of hyperleukocytosis,
splenomegaly and thrombocytosis
– Hydration
– Chemotherapy (bulsuphan, Hydoxyurea)
Control and prolong chronic phase (non-curative)
– alpha interferon+chemotherapy
– imatinib mesylate
– chemotherapy (hydroxyurea)
CML – PRINCIPLES OF
TREATMENT
Treatment cont…
Eradicate malignant clone (curative)
– allogeneic transplantation
– alpha interferon ?
– imatinib mesylate/STI 571 ?(Thyrosine kinase
inhibitor)
LMC – MEDICAL CARE
Myelosupresive drugs
Interferon
Imatinib
Allogenic hematopoietic stem cell
transplantation
Autologous hematopoietic stem cell
transplantation
Experimental drugs
CHEMOTHERAPY
Busulphan
– Alkylating agent
– Preferred in older pts (not candidate for transplant)
– Side effect :
prolonged myelosuppression
Pulmonary fibrosis
Skin pigmentation
infertility
CHEMOTHERAPY
Hydoxyures
– Fewer side effect
– Acts by inhibiting the enzyme ribonucleotide reductase
Haematological remissions obtain in 80% for both
drugs
However disease progression not altered and
persistence of Ph chromosome containing clone
CHEMOTHERAPY
Recombinant human α- Interferon
–
–
–
–
Optimal dose : 3-5 MUI/m2/d
Prolong chronic phase and increase survival
Haematogical and cytogenetic remission
Side effect
Flu like symptoms
Fever and chills
Anorexia
Depression
CML – THERAPEUTICAL AIM
Therapeutic response
– Hematologic response
– Cytogenetic response
– Molecular response
Survival
– Overall survival (OS)
– Progression-free survival (PFS)
– Disease free survival (DFS)
– Time to progression (TTP)
HEMATOLOGIC RESPONSE
Complete hematologic response
WBC count normalised (under 10.000/mm3)
Disapearance of immature cells of peripheral blood
Platelets count normalised (under 350.000/mm3)
Disapearance of all signs and symptoms of disease
Spleen normalised
Partial hematologic response
Decreasing with at least 50% of leucocytosis (10.000
si 20.000/mm3 )
or complete hematologic response with persistent
splenomegaly
CYTOGENETIC RESPONSE
% cells Ph+ in bone marrow
Complete :
Partial :
Major :
Minor :
Minimal :
Eşec :
0
< 35
complet + parţial
35 - 95
> 95
100
MOLECULAR RESPONSE
Major molecular response (MajMR) = a
3 log reduction in BCR-ABL/BCR level
when
compared
to
the
median
pretreatment level.
Major molecular response(MajMR) =
BCR-ABL/BCR 0.045%
Complete molecular response(CMR) =
BCR-ABL unedetectable or reduction
BCR-ABL/BCR with > 4.5 log
Normal Bcr-Abl Signaling*
The kinase domain
activates a substrate
protein, eg, PI3 kinase,
by phosphorylation
This activated substrate
initiates a signaling
cascade culminating in
cell proliferation and
survival
Substrate
Effector
Bcr-Abl
ADP
P
PPP
ATP
PPP
ADP = adenosine diphosphate; ATP = adenosine triphosphate;
P = phosphate.
Savage and Antman. N Engl J Med. 2002;346:683
Scheijen and Griffin. Oncogene. 2002;21:3314.
SIGNALING
Imatinib Mesylate:
Mechanism of Action*
Imatinib mesylate
occupies the ATP
binding pocket of the
Abl kinase domain
This prevents
substrate
phosphorylation and
signaling
A lack of signaling
inhibits proliferation
and survival
Savage and Antman. N Engl J Med. 2002;346:683.
Bcr-Abl
P
ATP
PPP
Imatinib
mesylate
SIGNALING
Imatinib Mesylate in Chronic Phase
CML Following IFN- Failure: Overall
Survival*
1.0
Survival probability
0.9
0.8
0.7
0.6
0.5
0.4
Total
261
251
0.3
0.2
Dead
31
193
0.1
Imatinib mesylate
Others
(P<0.0001)
0
0
24
48
72
96
Months
Kantarjian et al. Blood. 2004;104;1979. Copyright American Society of Hematology, used with permission.
Imatinib - schema terapeutica
Recomendede dose :
– 400 mg/d for patients in chronic phase
– 600 – 800 mg/d for patients in accelerated
phase or in blastic phase.
The daily dose is administred in one dose,
with lunch, associated withat least 250 ml
water
Allogenic hematopoietic stem cell
transplantation (AHSCT)
“For the moment allogeneic bone marrow or
stem cell transplantation is the best and only
one treatment for cure of this disease. ”
But
The procedure is limited by the existance of a
potential donor and the high toxicity which limits
the age of the patients with potential indication
for transplantation.
Source of HSC
Source :
Bone marrow – bone marrow transplantation
Peripheral blood – peripheral blood HSC
transplantation
Peripheral blood source is preferred - because
Quicker engraftment
Less regimen related toxicity
Shorter post-therapeutic aplasia
Longer disease free – GvL effect is stronger
POLYCYTHEMIA VERA
POLYCYTHEMIA VERA (PV)
(Polycythaemia rubra vera)
Definition of polycythemia
Raised packed cell volume (PCV / HCT)
Male > 0.51 (50%)
Female > 0.48 (48%)
Classification
Absolute
Primary proliferative polycythaemia (polycythaemia vera)
Secondary polycythaemia
Idiopathic erythrocytosis
Apparent
Plasma volume or red cell mass changes
POLYCYTHEMIA
True / Absolute
– Primary Polycythemia
– Secondary Polycythemia
Epo dependent
– Hypoxia dependent
– Hypoxia independent
Epo independent
Apparent / Relative
– Reduction in plasma volume
ERYTHROCYTOSIS (Classification) (1)
I. Absolute erythrocytosis (Polycythemia):
A. Secondary erythrocytosis (abnormal increase of serum
erythropoietin level)
1. Erythrocytosis secondary to decreased tissue oxygenation:
a) chronic lung diseases
b) cyanotic congenital heart diseases
c) high-altitude erythrocytosis (Monge disease)
d) hypoventilation syndromes (Sleep apnoe)
e) hemoglobin-oxygen dissociation abnormalities
- hemoglobinopathies associated with high oxygen affinity
- carboxyhemoglobin in „smoker’s polycythemia”
67
ERYTHROCYTOSIS (Classification) (2)
I. Absolute erythrocytosis (Polycythemia):
A. Secondary erythrocytosis (abnormal increase of serum erythropoietin level)
2. Secondary to aberrant erythropoietin production or response:
a) Erythropoietin-producting tumors: hepatoma, uterine leiomyoma,
cerebellar hemangioblastoma, ovarian carcinoma, pheochromocytoma
b) Renal diseases: renal cell carcinoma, kidney cysts and
hydronephrosis, renal transplantation.
c) Androgen abuse: adrenal cortical hypersecretion, exogenous androgens
B. Primery erythrocytosis
1. Polycythemia vera
2. Familial erythrocytosis
II. Relative erythrocytosis (pseudopolycythemia):
1. Hemoconcentration
2. Spurious polycythemia (Gaisboek syndrome)
68
POLYCYTHEMIA VERA (PV)
Polycythaemia vera is a clonal stem cell disorder
characterised by increased red cell production
Abnormal clones behave autonomous
Same abnormal stem cell give rise to granulocytes and platelets
Disease phase
Proliferative phase
“Spent” post-polycythaemic phase
Rarely transformed into acute leukemia
Epidemiology
– 2-3 / 100000
– Median age at presentation: 55-60
– M/F: 0.8:1.2
POLYCYTHEMIA VERA (PV)
Clinical features
Age
– 55-60 years
– May occur in young adults and rare in childhood
Symptoms common to all erythrocytosis
– Headache, mental acuity, weakness
Symptoms more specific to P vera and myeloproliferative
diseases.
–
–
–
–
–
Pruritis after bathing
Erythromelalgia
Hypermetabolic symptoms
Thrombosis (arterial or venous)
Hemorrhage
POLYCYTHEMIA VERA
physical examination
1.
2.
3.
4.
Splenomegaly – is present in 75% of patients at the
time of diagnosis.
Hepatomegaly - is present in approximately 30% of
patients at the time of diagnosis.
Hypertension
On examination of the eye grounds, the vessels may be
engorged, tortuous, and irregular in diameter; the veins
may be dark purple.( fundus policythaemicus)
Facial plethora
POLYCYTHEMIA VERA
physical examination
Hepatosplenomegaly
Erythromelalgia
Erythromelalgia
– Increased skin temp
– Burning sensation
– Redness
Liver
40%
Spleen
70%
POLYCYTHEMIA VERA
Lab Findings
CBC
–
–
–
–
Hgb/Hct
WBC in 45%
Plts in 65%
Basophilia (seen in all MPDs)
 Uric acid (can lead to gout) and B12
 Leukocyte alkaline phosphatase score
Low epo levels
Positive JAK2 V617F
PV - typical blood count
WBC x 109/L
Hb g/L
HCt
MCV fl
Platelets x 109/L
18.0
200
0.62
75
850
[4-11]
[140-180]
[.42-.51]
[80-100]
[150-450]
Neuts x 109/L
Lymphs x 109/L
Monos x 109/L
Eos x 109/L
Basos x 109/L
14.6
2.0
0.8
0.1
0.5
[2-7.5]
[1.5-4]
[0.2-0.8]
[0-0.7]
[0-0.1]
Film: microcytosis: large and abnormal platelets present
PRV - DIAGNOSIS
exclude secondary polycythemia
look for features of primary polycythemia
measure erythropoietin
JAK-2 mutation analysis
SECONDARY POLYCYTHEMIA
Arterial blood gas
Hb electrophoresis
Oxygen dissociation curve
EPO level
Ultrasound abdomen
Chest X ray
Total red cell volume(51Cr)
Total plasma volume(125 I-albumin)
Diagnostic Criteria for Primary PV
Polycythemia Vera Study Group (PVSG) Criteria for PV
Minor Criteria
Major Criteria
▪ Elevated RBC mass
>36 cc/kg in men
>32 cc/kg in women
▪ Oxygen saturation >92%
▪ Splenomegaly
▪ Plt count > 400,000
▪ WBC > 12,000
▪ Elevated LAP score (>100)
▪ Serum vitamin B12 >900 pg/mL or serum
unbound B12 binding capacity >2,200 pg/mL
→ All 3 major criteria OR the first 2 major and any 2 minor criteria ←
2008 WHO Diagnostic Criteria for Primary Polycythemia Vera
Major Criteria
Minor Criteria
1) Hgb > 18.5g/dl (♂) or 16.5g/dl (♀)
or
Hgb or Hct > 99%
or
Hgb > 17g/dl (♂) or 15 g/dl (♀) and
a documented increase of 2 g/dl
or
RBC mass > 25% of mean normal
1) Bone marrow trilineage expansion
2) Subnormal EPO level
3) Endogenous erytyhroid colony growth
2) Presence of a JAK2 V617F or similar
mutation
→ two major or first major and two minor criteria ←
Tefferi et al. Leukemia (2008) 22, 14–22
PV - TREATMENT
Phlebotomy
Myelosuppressive agents
– Hydroxyurea
– Alkylating agents such as busulfan
– 32P
Interferon alpha
PV - PHLEBOTOMY
Generally, the best initial treatment for P vera
– No increase in progression to AML
– Rapid onset
– No BM suppression
Remove 500 cc blood 1-2x/wk to target Hct 45%,
then maintain
Downsides:
– Increased risk of thrombosis
– No effect on progression to spent phase
– May be insufficient to control disease
PV - MYELOSUPPRETION
Hydroxyurea
– can be used in conjunction with phlebotomy
– May increase the risk of leukemic transformation from 12% to 4-5%
32P
– increase the risk of leukemic transformation from 1-2% to
11%
– May be appropriate for pts intolerant of medications or for
elderly patients
– Single injection may control hemoglobin and platelet count
for a year or more.
PV – INTERFERON ALPHA
Benefits
–
–
–
–
No myelosuppression
No increase in progression to AML
No increase in thrombosis risk
OK in pregnancy
Drawbacks
– Must be given by injection
– Side effects may be intolerable in many pts,
include flu-like symptoms, fatigue, fever,
myalgias, malaise
POLYCYTHEMIA VERA
I. Patients under the age of 50 with no history of thrombosis and without
severe thrombocytosis (greater than 1000G/L)-phlebotomy alone
- initially 450-500 ml phlebotomy every every other day until the
hematocrit is less than 46%
- older patients or these with underlying cardiovascular disase should
undergo smaller phlebotomies 200-300mL twice weekly or
100-150mLevery day until Ht<46%
- subsequently, Ht should be mainted between 42-46%
- fluid replacement so that the patients remains isovolemic
II. Patients over the age of 70, or with history of thrombosis and with severe
thrombocytosis (greater than 1000G/L)-myelosuppresive agent
- Hydroxyurea 15-30mg/kg
III. Patients 50-70 years with no history of thrombosis and without severe
thrombocytosis (greater than 1000G/L) individualize therapy I or II
83
POLYCYTHEMIA VERA
IV. Antiplatelets agents
 Aspirin initially 150-300mg/d,
maintence therapy 75-100 mg
 Tiklid 2x1
 Dipyridamol
 Anagrelide 2-2,5 mg/d
V. Other modalities
1. Radioactive phosphorus (in older than 75 years)
2. Interferon alpha 3 million units 3 times weekly
VI. Special Topics
1. Pruritus:antihistaminic agent, cyproheptadine-4mg three times per day
2. Hyperuricemia-allopurinol 300mg/day
84
ESSENTIAL
THROMBOCYTHEMIA (ET)
THROMBOCYTOSIS
Definition: thrombocytosis is defined as a platelet count > 450,000 cells/μL
Etiology of Thrombocytosis
Primary - if the thrombocytosis is caused by a myeloproliferative neoplasm, the
platelets are frequently abnormal and the patient may be prone to both bleeding and
clotting events.
Secondary - if thrombocytosis is secondary to another disorder (reactive), even
patients with extremely high platelet counts (e.g., > 1,000,000 cells/μl) are usually
asymptomatic.
Differential Diagnosis of secondary thrombocytosis:
1. Malignancies
2. Infections and inflammatory disorders (e.g., Crohn’s disease)
3. Post surgical status
4. Connective tissue disorders
5. Iron deficiency anemia
6. Splenectomy
7. Recovery of the bone marrow from a stress (chemotherapy or alcohol)
8. Essential Thrombocythemia
ESSENTIAL THROMBOCYTHEMIA
(ET)
ET is a clonal myeloproliferative disorder
characterized by bone marrow hyperplasia
with
excessive
proliferation
of
megakaryocytes and sustained elevation of
the platelet count.
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ESSENTIAL
THROMBOCYTHEMIA (ET)
Neoplastic stem cell disorder causing
dysregulated production of large numbers of
abnormal platelets
Some cases non-clonal (esp young women)
Abnormal platelets aggregate in vivo,
causing thrombosis
Abnormal platelets also cause bleeding
ESSENTIAL THROMBOCYTHEMIA
clinical picture
1. Thrombotic complications (intermittent or permanent occlusion of small
blood vessels)
 transient cerebral and ocular ischemic episodes that may progress to
infarction
 peripheral arterial occlusive disease associated with „erythromelalgia”
(intermittent, painful errythema and cyanosis of the fingers and toes
2. Hemorrhagic complications - bleeding after surgery and spontaneus upper
gastrointestinal bleeding (the hemorrhagic tendency is worsened if
nonsteroidal anti-inflammatory agent are administered
3. Splenomegaly - 20-50% patients
4. Hepatomegaly - rarely
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ESSENTIAL THROMBOCYTHEMIA
laboratory findings
Thrombocytosis (in most patients patients>1000 G/l)
Numerous thrombocyte aggregates in peripheral blood
smear
Leukocytosis, usually less than 20G/l
Neutrophilia and a mild shift to the left(usually to
metamyelocyte)
Slight eosinophilia and basophilia
Marked hyperplasia of the megakaryocytes in the bone
marrow
90
ET-Typical Blood Count
WBC x 109/L
Hb g/L
MCV fl
Platelets x 109/L
10.0
156
85
1560
[4-11]
[140-180]
[80-100]
[150-450]
Neuts x 109/L
Lymphs x 109/L
Monos x 109/L
Eos x 109/L
Basos x 109/L
7.0
2.0
0.8
0.1
0.1
[2-7.5]
[1.5-4]
[0.2-0.8]
[0-0.7]
[0-0.1]
Film Comment: many large and abnormal platelets
present
ET – DIAGNOSTIC CRITERIA
2008 WHO Diagnostic Criteria for Essential
Thrombocytosis
1. Platelet count > 450,000
2. Megakaryocytic proliferation with large, mature morphology and
with little granulocytic or erythroid expansion
3. Not meeting WHO criteria for CML, PV, PMF, MDS or other
myeloid neoplasm
4. Demonstration of the JAK2V617F or other clonal marker or lack
of evidence of a secondary (reactive thrombocytosis)
→ Diagnosis of essential thrombocythemia requires meeting all four major criteria ←
Teferri et al. Leukemia (2008) 22, 14–22
ET - DIAGNOSIS
Criteria of exclusion
–
–
–
–
–
No evidence of Polycythaemia vera
No evidence of CML
No evidence of myelofibrosis (CIMF)
No evidence of myelodysplastic syndrome
No evidence of reactive thrombocytosis
Bleeding
Trauma
Post operation
Chronic iron def
Malignancy
Chronic infection
Connective tissue disorders
Post splenectomy
ET - OUTCOMES
Most patients with ET enjoy a normal life expectancy
Like PV, the major risks are secondary to thrombosis and disease
transformation:
▪ 15-year cumulative risks:
▪ thrombosis - 17% risk
▪ clonal evolution into either myelofibrosis (4%) or AML (2%)
High risk for thrombosis:
▪ age ≥ 60
▪ prior thrombosis
▪ long-term exposure to a plt count of > 1,000,000
ESSENTIAL THROMBOCYTHEMIA
-THERAPY
1. No treatment- asymptomatic( without thrombotic and bleeding
complications), young (< 60 r.ż.) patients with platelet count<1000G/L
2. Cytoreductive therapy – patients with platelet count>1000 G/L, especially
for these with previous thrombotic or bleeding problems
- hydroxyurea at doses 15-30mg/kg,, to maintein platelet count
between 400-600 G/l
3. Anti-aggregating therapy: Aspirin 75-150mg/d  dipyridamol for older
patients and/or with a cardiovascular risk
4. Anagrelide (Agrylin)- drug that produces selective platelet cytoreduction,
and it also inhibits platelet activation  doses from 0,5mg every 6 hours,
to max. 10 mg/d )
5. Interferon-: 3 million units/d s.c.
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ESSENTIAL THROMBOCYTHEMIA
-THERAPY
Low Risk:
▪ Age <60 years
▪ No previous history of thrombosis
▪ Platelet count <1 million/μl
→ aspirin (81 mg daily) if vasomotor Sx or other medical need for ASA
→ if otherwise low risk and plt >1.5 X 106, screen for an acquired von Willebrand
disease before instituting ASA
High Risk:
▪ Age ≥60 years
▪ A previous history of thrombosis
→ hydroxyurea + aspirin (81 mg daily)
→ if plt >1.5 X 106, screen for an acquired von Willebrand disease before
instituting ASA
→ anagrelide is an option, but when c/w hydroxyurea, it was assn with an
increased risk of arterial thrombosis, venous thrombosis, serious
hemorrhage, or death from vascular causes
MYELOFIBROSIS
MYELOFIBROSIS
AKA: agnogenic myeloid metaplasia with myelofibrosis
Clonal stem cell disorder affecting megakaryocytes
predominantly
All myeloproliferative disorders can result in a spent phase
which can be difficult to distinguish from primary MF
Myeloid metaplasia refers to earlier proliferative phase where
extramedullary hematopoiesis predominates.
MYELOFIBROSIS
Myelofibrosis is a chronic myeloproliferative disease with
clonal
hematopoesis
and
secondary(non-clonal)
hyperproliferation of fibroblasts (stimulated by PDGF, EGF,
TGF- released from myeloid cells, mainly from neoplastic
megakaryocytes) with increased collagen synthesis. It
produces bone marrow fibrosis and to extramedullary
hematopoesis in the spleen or in multiple organs
Other terms
–
–
–
–
–
agnogenic myeloid metaplasia
primary myelofibrosis,
osteomyelofibrosis,
idiopathic myelofibrosis,
myelofibrosis with myeloid metaplasia
MYELOFIBROSIS
Insidious onset in older people
– asymptomatic (15% - 30%)
– severe fatigue
Splenomegaly- massive
Hepatomegaly
Hypermetabolic symptoms
– Loss of weight, fever and night
sweats
Bleeding problems
Bone pain
Gout
Can transform to acute
leukaemia in 10-20% of cases
MYELOFIBROSIS
Anaemia
High WBC at presentation
Later leucopenia and
thrombocytopenia
Leucoerythroblastic blood film
Tear drops red cells
Bone marrow aspiration- Failed
due to fibrosis
Trephine biopsy- fibrotic
hypercellular marrow
Increase in NAP score
JAK2+ (V617F) in
approximately 50% of cases
Pathological Features of Peripheral Blood and Bone
Marrow in Patients with Myelofibrosis with Myeloid
Metaplasia
Tefferi A. N Engl J Med 2000;342:1255-1265
MF – DIAGNOSTIC CRITERIA
2008 WHO Diagnostic Criteria for Primary Myelofibrosis
Major:
1. Megakaryocytic proliferation and atypia with either reticulin or collagen fibrosis
or
If no fibrosis, mekakaryocytic expansion must be assn. w/increased BM
cellularity
2. Does not meet WHO criteria for CML, PV, MDS, or other myeloid neoplasm
3. Demonstration of the JAK2 V617F mutation or other clonal marker
or
no other evidence of a reactive marrow fibrosis
Minor:
1. Leukoerythroblastosis (immature RBCs and WBCs in the PB)
2. Increased LDH
3. Anemia
4. splenomegaly
→ Diagnosis of primary myelofibrosis (PMF) requires meeting all three major criteria and two minor criteria ←
Teferri et al. Leukemia (2008) 22, 14–22
MF - OUTCOME
 As fibrosis progresses, cytopenias worsen leading to a transfusion
dependency
▪ symptoms related to extrmedullary hematopoiesis increase (worsening
splenomegaly and ‘B’ symptoms) also are frequently identified
 Rarely do patients transform to Acute Leukemia (~ 4%)
▪ clonal evolution was common in these patients
▪ some evidence that in all MPNs, cases of JAK2 (-) Acute Leukemia arise
out of a JAK+ MPN, causing speculation that there are additional genetic
changes that either initiate and/or propagate these diseases
 Despite the lack of transformation to leukemia, three-year survival rate is
approximately 52%
MF – RISK ASSASSEMENT
Mayo Scoring System
(pts age < 60)
Score
Median Survival
0
173 mo
1
61 mo
≥2
26 mo
Transplant Scoring System
(pts age < 55)
Score
Median Survival
0 or 1
15 yrs
≥2
3 yrs
Risk Factors: Hemoglobin <10 g/dL
White blood cell count <4000/μl or >30,000/ μl
Absolute monocyte count >1000 μL
Platelet count <100,000/ μL
Risk factors: Hemoglobin <10 g/dL
‘B’ symptoms present (eg, fever, NS, weight loss)
Circulating blasts >1 percent
Elliott et al. Leuk Res. 2007;31(11):1503-9.
Dupriez et al. Blood 1996 Aug 1;88(3):1013-8.
MYELOFIBROSIS - TREATMENT
Androgens(oxymetholone 2-4mg/kg) in anemia from decreased red cell
production -overall response is about 40%
Cortykosteroids(prednisone 1mg/kg) in anemia with shortened red cell
life-span-response in 25-50% of patients
Hydroksyurea (15- 20mg/kg) for the control of leukocytosis,
thrombocytosis, or organomegaly
Allopurinol-to prevent hyperuricaemia
Vit. D3-analogues(1,25-dihydroxycholecalciferol-1ug/d (?)
Transfusions of packed red cells for anemia or platelets for
thrombocytopenia with bleeding
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MYELOFIBROSIS - TREATMENT
Splenectomy should be considered for: portal hypertension, painful
splenomegaly, refractory anemia and thrombocytopenia, or
exccessive transfusion requirement. However,the procedere is
hazardous (an operative mortality is up to 38%).
Splenic irradiation: when there is a contrindication to splenectomy
Allogeneic stem-cell transplantation: for young patients who have a
poor prognosis and have a suitable donor identified.
Experimental
therapies:
Interferon-,
antifibrotic
and
antiangiogenic drugs (anagrelide, suramin, pirfenidone,
thalidomide,)
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MF - TREATMENT
Risk stratification is critical in deciding on therapeutic options
(see previous scoring systems)
‘Low Risk’ without symptoms – expectant management
‘Low Risk’ with symptoms – hydroxyurea
androgenic and corticosteroids
splenectomy if adequate BM hematopoiesis
splenic irradiation
thalidomide or lenalidomide
‘High Risk’ and age < 55(?) – consider a reduced intensity allogeneic
BMT
MYELOFIBROSIS
- prognosis
- a median survival of 3,5 to 5,5 years
- the principal causes of death are infections,
thrombohemorrhagic events, heart failure, and
leukemic transformation
- leukemic transformation occurs in
approximately 20% of patients during first 10
years
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